Clinical trial NCT03987295
Conditions: Frontotemporal Dementia
Sponsor: Alector Inc.
Start date: 2019-09-27; Completion date: 2024-06-05
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 2 open label study evaluating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AL001 in participants with a Granulin mutation or C9orf72 mutation causative of frontotemporal dementia.

Detailed description:
This is a Phase 2, multicenter, open label study evaluating the safety, tolerability, PK and PD of AL001 administered intravenously in participants with a Granulin mutation or C9orf72 mutation causative of frontotemporal dementia.

Arms: arm 1: IV administration of AL001; 60 mg/kg, every 4 weeks \[q4w\]
Interventions: intervention 1: AL001
Intervention descriptions: intervention 1: 60 mg/kg of AL001 every 4 weeks

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of AL001 in Heterozygous 
Carriers of Granulin or C9orf72 Mutations Causative of Frontotemporal 
Dementia 
Investigational Product: 
AL001, human recombinant anti-human Sortilin IgG1 monoclonal 
antibody 
Indication: 
Frontotemporal Dementia (FTD) 
Study Phase: 
2 
IND Number: 
135892 
EudraCT Number: 
2019-000138-20 
ClinicalTrials.gov Identifier: 
NCT03987295 
Sponsor: 
Alector, Inc. 
131 Oyster Point Boulevard, Suite 600 
South San Francisco, CA 94080, US 
Telephone: +1 650-837-0384 
Sponsor Medical Monitor: 
Sam Jackson, MD 
Version of Protocol: 
Version 4.0 
Date of Protocol: 
04 Feb 2021 
Previous Versions: 
Version 3.2 United Kingdom (23 Nov 2020) 
Version 3.1 (13 Jul 2020)  
Version 3.0 (02 Jun 2020) 
Version 2.0 (26 Sep 2019) 
Version 1.4 (12 Sep 2019) 
Version 1.3 (02 Aug 2019) 
Version 1.2 (24 Jun 2019) 
Version 1.1 (22 Apr 2019) 
Version 1.0 (09 Apr 2019) Original Protocol 
CONFIDENTIAL 
This document contains confidential information. This document must not be disclosed to anyone other than the 
site study staff and members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. The information in this document cannot be used for any purpose other than 
the evaluation or conduct of the clinical investigation without the prior written consent of Alector, Inc.  


Clinical Study Protocol AL00 1-2, Version 4.0 
AL00l 
SPONSOR SIGNATURE PAGE 
Study Title: 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, 
Phannacokinetics, and Phannacodynamics of ALOO I in Heterozygous Carriers of 
Granulin or C9orj72 Mutations Causative ofFrontotemporal Dementia 
Version No. 
Version4.0 
Protocol Date: 
04 Feb 2021 
Protocol accepted and approved by: 
Alector Medical Lead 
Sam Jackson, MD 
Alector, Inc. 
131 Oyster Point Boulevard, Suite 600 
South San Francisco, CA 94080, US 
Confidential 
Date 
Page2 


Clinical Study Protocol ALOO 1-2, Version 4.0 
ALOOI 
PROTOCOL APPROVAL - LEAD STATISTICIAN 
Alector, Inc. 
Study Title: 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, 
Phannacokinetics, and Phannacodynamics of ALOO l in Heterozygous Carriers of 
Granu/in or C9orf72 Mutations Causative ofFrontotemporal Dementia 
Version No. 
Version4.0 
Protocol Date: 
o4 Feb 2021 
Protocol accepted and approved by: 
Lead Statistician 
YiJie, Liao PhD 
Alector, Inc. 
131 Oyster Point Boulevard, Suite 600 
South San Francisco, CA 94080, US 
Signa ure 
Confidential 
Date 
Page 3 


Clinical Study Protocol AL001-2, Version 4.0 
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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol entitled “A Phase 2, Multicenter, 
Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of AL001 in Heterozygous Carriers of Granulin or C9orf72 Mutations 
Causative of Frontotemporal Dementia” and the accompanying Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the protocol, Version 4.0, dated 04 Feb 2021, the International Council on 
Harmonisation Tripartite Guideline E6(R2): Good Clinical Practice and all applicable 
government regulations. I agree to administer study drug only to participants under my personal 
supervision or the supervision of a sub-investigator. 
I will not supply the study drug to any person not authorized to receive it. Confidentiality will be 
protected. Participant identity will not be disclosed to third parties or appear in any study reports 
or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without written authorization from Alector. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
Site Number 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
PROTOCOL APPROVAL – LEAD STATISTICIAN....................................................................3 
DECLARATION OF INVESTIGATOR .........................................................................................4 
PROTOCOL SYNOPSIS ..............................................................................................................12 
LIST OF ABBREVIATIONS ........................................................................................................20 
1.
INTRODUCTION ......................................................................................................24 
1.1. 
Background .................................................................................................................24 
1.1.1. 
Frontotemporal Dementia ...........................................................................................24 
1.1.2. 
Frontotemporal Lobar Degeneration, GRN, and C9orf72 ..........................................24 
1.1.3. 
Sortilin and AL001 .....................................................................................................25 
1.2. 
Findings from Nonclinical and Clinical Studies of AL001 ........................................25 
1.2.1. 
Nonclinical Studies .....................................................................................................25 
1.2.2. 
Clinical Studies ...........................................................................................................26 
1.2.2.1. 
Study AL001-1 (Completed) ......................................................................................26 
1.2.3. 
Study AL001-2 (Ongoing) ..........................................................................................27 
1.3. 
Risk/Benefit Assessment of AL001............................................................................28 
1.3.1. 
Known Risks of the Drug Class..................................................................................28 
1.3.2. 
Risks of AL001 ...........................................................................................................28 
1.3.3. 
Potential Benefits of AL001 .......................................................................................29 
1.3.4. 
Benefit Risk for AL001-2 Study Participants .............................................................30 
1.4. 
Rationale for the Study ...............................................................................................31 
1.4.1. 
Rationale for the Study Design ...................................................................................31 
1.4.2. 
Rationale for Dose Selection ......................................................................................31 
1.4.3. 
Rationale for Treatment Duration ...............................................................................31 
1.5. 
Study Population .........................................................................................................32 
2.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................33 
3.
INVESTIGATIONAL PLAN .....................................................................................37 
3.1. 
Study Design ...............................................................................................................37 
3.2. 
Study Duration ............................................................................................................40 
3.3. 
Description of Study Periods ......................................................................................41 


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3.3.1. 
Part 1 – Treatment Period ...........................................................................................41 
3.3.2. 
Part 2 – Optional OLE ................................................................................................41 
4. 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA .........................43 
4.1. 
Part 1 Study Population ..............................................................................................43 
4.1.1. 
Inclusion Criteria – Part 1 (Treatment Period) ...........................................................43 
4.1.2. 
Exclusion Criteria - Part 1 (Treatment Period) ...........................................................45 
4.2. 
Part 2 Study Population ..............................................................................................48 
4.2.1. 
Inclusion Criteria - Part 2 (Optional OLE) .................................................................49 
4.2.2. 
Exclusion Criteria - Part 2 (Optional OLE) ................................................................49 
4.3. 
Withdrawal of Participants from Study Drug and/or the Study .................................50 
4.3.1. 
Part 1 (Treatment Period) ...........................................................................................50 
4.3.1.1. 
Withdrawal from Study Drug (Part1) .........................................................................50 
4.3.2. 
Withdrawal From Study (Part 1) ................................................................................51 
4.4. 
Part 2 (Optional OLE) ................................................................................................51 
4.4.1. 
Criteria for Withdrawal of Participants in Part 2 ........................................................51 
4.5. 
Replacements (Part 1 Only) ........................................................................................52 
5. 
STUDY TREATMENTS............................................................................................54 
5.1. 
Treatments Administered ............................................................................................54 
5.1.1. 
Administration Instructions ........................................................................................54 
5.1.2. 
Infusion-Related and Injection-Related Reactions .....................................................54 
5.2. 
Identity of Investigational Product .............................................................................55 
5.2.1. 
Study Drug Formulation .............................................................................................55 
5.2.2. 
Study Drug Packaging and Labeling ..........................................................................55 
5.3. 
Management of Clinical Supplies ...............................................................................55 
5.3.1. 
Study Drug Supply .....................................................................................................55 
5.3.2. 
Study Drug Storage .....................................................................................................55 
5.3.3. 
Study Drug Accountability .........................................................................................56 
5.3.4. 
Study Drug Return or Disposal ...................................................................................56 
5.4. 
Misuse for Illegal Uses ...............................................................................................56 
5.5. 
Blinding ......................................................................................................................56 
5.6. 
Prior and Concomitant Therapy ..................................................................................56 


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6. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
6.1. 
Timing of Study Drug Administration .......................................................................58 
6.2. 
Rescreening Criteria ...................................................................................................59 
6.3. 
Sample Collections .....................................................................................................59 
6.4. 
Cerebrospinal Fluid Sampling ....................................................................................60 
6.5. 
Safety and Tolerability Assessments ..........................................................................60 
6.5.1. 
Adverse Events ...........................................................................................................60 
6.5.2. 
Concomitant Medications ...........................................................................................60 
6.5.3. 
Demographics .............................................................................................................60 
6.5.4. 
Medical History ..........................................................................................................61 
6.5.5. 
Physical Examinations ................................................................................................61 
6.5.6. 
Neurological Examinations ........................................................................................62 
6.5.7. 
Vital Signs and Weight ...............................................................................................62 
6.5.8. 
Electrocardiograms .....................................................................................................62 
6.5.9. 
Laboratory Assessments .............................................................................................62 
6.5.10. 
Sheehan Suicidality Tracking Scale ...........................................................................64 
6.5.11. 
Anti-Drug Antibodies .................................................................................................64 
6.6. 
Pharmacokinetic Assessments ....................................................................................64 
6.6.1. 
Serum Pharmacokinetic Samples ...............................................................................64 
6.6.2. 
Cerebrospinal Fluid Pharmacokinetic Samples ..........................................................64 
6.7. 
Pharmacodynamic Biomarker Assessments ...............................................................64 
6.7.1. 
Progranulin Plasma Samples ......................................................................................64 
6.7.2. 
Cerebrospinal Fluid Pharmacodynamic Samples .......................................................64 
6.7.3. 
Whole Blood Samples ................................................................................................64 
6.7.4. 
Exploratory Pharmacodynamic Biomarker Assessments ...........................................65 
6.7.4.1. 
Other Exploratory Pharmacodynamic Biomarker Samples ........................................65 
6.7.4.2. 
Magnetic Resonance Imaging .....................................................................................65 
6.8. 
Pharmacogenomic Assessments .................................................................................65 
6.9. 
Clinical Outcome Assessments – Neurocognitive and Functional Tests ...................65 
6.10. 
Unscheduled Visits .....................................................................................................66 
6.11. 
Part 1 End of Treatment Visit .....................................................................................66 


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6.12. 
End of Study Visit ......................................................................................................66 
6.12.1. 
Part 1 End of Study Visit ............................................................................................66 
6.12.2. 
Part 2 End of Study Visit ............................................................................................67 
6.13. 
Safety Follow-up Visit ................................................................................................67 
7. 
ADVERSE EVENTS..................................................................................................68 
7.1. 
Definitions of Adverse Events ....................................................................................68 
7.2. 
Serious Adverse Events ..............................................................................................69 
7.3. 
Eliciting and Documenting Adverse Events ...............................................................69 
7.4. 
Assessment of Causality .............................................................................................70 
7.5. 
Reporting Adverse Events ..........................................................................................70 
7.6. 
Reporting Serious Adverse Events .............................................................................71 
7.6.1. 
Protocol-Specific Disease Progression Adverse Event and Serious Adverse 
Event Reporting Requirements ...................................................................................71 
7.7. 
Assessment of Severity ...............................................................................................71 
7.8. 
Follow-up of Participants Reporting Adverse Events ................................................72 
7.9. 
Infusion Reactions ......................................................................................................73 
7.10. 
Anaphylaxis ................................................................................................................73 
7.11. 
Special Situations ........................................................................................................73 
7.12. 
Pregnancy ...................................................................................................................74 
8. 
STATISTICAL METHODS AND CONSIDERATIONS .........................................75 
8.1. 
Sample Size Estimations .............................................................................................75 
8.2. 
Analysis Populations ..................................................................................................75 
8.3. 
Description of Subgroups to be Analyzed ..................................................................76 
8.4. 
Statistical Analysis Methodology ...............................................................................76 
8.4.1. 
Study Population .........................................................................................................76 
8.4.1.1. 
Disposition of Participants ..........................................................................................77 
8.4.1.2. 
Protocol Deviations ....................................................................................................77 
8.4.2. 
Analysis of Primary Safety Endpoints ........................................................................77 
8.4.2.1. 
Demographic, Baseline, and Background Characteristics ..........................................77 
8.4.2.2. 
Prior and Concomitant Medications ...........................................................................77 
8.4.2.3. 
Study Drug Administration.........................................................................................77 


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8.4.2.4. 
Adverse Events ...........................................................................................................78 
8.4.2.5. 
Physical and Neurological Examinations ...................................................................78 
8.4.2.6. 
Vital Signs Analysis ...................................................................................................78 
8.4.2.7. 
Electrocardiogram Analysis........................................................................................78 
8.4.2.8. 
Clinical Laboratory Analysis ......................................................................................78 
8.4.2.9. 
Sheehan Suicidality Tracking Scale ...........................................................................78 
8.4.2.10. 
Immunogenicity Analysis ...........................................................................................79 
8.4.3. 
Analysis of Pharmacokinetic and Pharmacodynamic Biomarker Endpoints .............79 
8.4.3.1. 
Analysis of Secondary Pharmacokinetic Endpoints ...................................................79 
8.4.3.2. 
Analysis of Secondary and Exploratory Pharmacodynamic Endpoints .....................79 
8.4.3.3. 
Analyses of Exploratory Pharmacodynamic Biomarker Endpoints ...........................80 
8.4.4. 
Analyses of Exploratory Clinical Outcome Assessment Endpoints ...........................80 
8.4.5. 
Interim Analyses .........................................................................................................80 
9. 
DATA QUALITY ASSURANCE ..............................................................................81 
9.1. 
Data Management .......................................................................................................81 
10. 
ETHICS ......................................................................................................................83 
10.1. 
Independent Ethics Committee or Institutional Review Board ..................................83 
10.2. 
Ethical Conduct of the Study ......................................................................................83 
10.3. 
Participant Information and Consent ..........................................................................83 
11. 
INVESTIGATOR’S OBLIGATIONS ........................................................................85 
11.1. 
Confidentiality ............................................................................................................85 
11.2. 
Financial Disclosure and Obligations .........................................................................85 
11.3. 
Investigator Documentation ........................................................................................85 
11.4. 
Study Conduct ............................................................................................................86 
11.5. 
Adherence to Protocol ................................................................................................86 
11.6. 
Adverse Events and Study Report Requirements .......................................................86 
11.7. 
Investigator’s Final Report .........................................................................................86 
11.8. 
Records Retention .......................................................................................................86 
11.9. 
Publications .................................................................................................................87 
12. 
STUDY MANAGEMENT .........................................................................................88 
12.1. 
Independent Data Monitoring Committee (iDMC) ....................................................88 


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12.2. 
Monitoring of the Study..............................................................................................88 
12.3. 
Inspection of Records .................................................................................................88 
12.4. 
Management of Protocol Amendments and Deviations .............................................88 
12.4.1. 
Modification of the Protocol .......................................................................................88 
12.4.2. 
Protocol Deviations ....................................................................................................89 
12.5. 
Study Termination ......................................................................................................89 
12.6. 
Final Report ................................................................................................................89 
13. 
REFERENCE LIST ....................................................................................................90 
14. 
APPENDICES ............................................................................................................93 
APPENDIX 1. SCHEDULES OF ASSESSMENTS ..................................................................94 
APPENDIX 2. CLINICAL OUTCOME ASSESSMENTS – NEUROCOGNITIVE 
AND FUNCTIONAL TESTS ..................................................................................111 
APPENDIX 3. ADAPTATION OF TRIAL PROTOCOL DURING COVID-19 
PANDEMIC .............................................................................................................114 


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LIST OF TABLES 
Table 1: 
Part 1 (Treatment Period): Study Objectives and Endpoints ......................................33 
Table 2: 
Part 2 (Optional Open-Label Extension (OLE)): Objectives and Endpoints .............35 
Table 3: 
Laboratory Assessments .............................................................................................63 
Table 4: 
Schedule of Assessments for Part 1, Treatment Period (Through Week 53) .............94 
Table 5: 
Schedule of Assessments for Part 1, Treatment Period (Through Week 97) .............98 
Table 6: 
Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic 
Biomarker Sample and Imaging Assessments – Part 1, Treatment Period ..............101 
Table 7: 
Schedule of Assessments for Part 2 (Optional OLE) (Through Week 161) .............103 
Table 8: 
Schedule of Assessments for Part 2 (Optional OLE) (Through Week 197) .............106 
Table 9: 
Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic 
Biomarker Sample and Imaging Assessments – Part 2 (Optional OLE) ..................109 
 
LIST OF FIGURES 
Figure 1: 
Overview of Study Schema ........................................................................................39 
 


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PROTOCOL SYNOPSIS 
Protocol Number: 
AL001-2 
Title: 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of AL001 in Heterozygous Carriers of 
Granulin or C9orf72 Mutations Causative of Frontotemporal Dementia 
Sponsor: 
Alector, Inc. 
131 Oyster Point Boulevard, Suite 600 
South San Francisco, CA 94080, US 
Study Phase: 
Phase 2 
Investigational Sites: 
Approximately 13 investigational sites in North America and Europe 
Indication: 
Frontotemporal dementia (FTD) 
Study Design: 
The study has two parts: A phase 2 open-label treatment period (Part 1), followed by 
an open-label extension (OLE) period (Part 2). 
Part 1 is a 96-week evaluation of the safety, tolerability, pharmacokinetic (PK), 
pharmacodynamic (PD), and clinical effect of AL001 administered intravenously 
(60 mg/kg, every 4 weeks [q4w]), for a total of 25 doses (96-week dosing period), in 
asymptomatic and symptomatic carriers of loss-of-function GRN mutations causative 
of FTD, and in symptomatic carriers of C9orf72 hexanucleotide repeat expansion 
mutations causative of FTD. 
Part 2 is an optional OLE for eligible participants who have completed the 96-week 
Part 1 treatment period. The OLE period will evaluate the long-term safety and 
tolerability of AL001 administered at the same dose and regimen as Part 1 (60 mg/kg, 
q4w), for up to a total of 25 doses (96-week optional OLE period). 
Part 1 (Treatment Period): 
In Part 1 of the study, two cohorts will be enrolled: a GRN Cohort and a C9orf72 
Cohort. Both cohorts will enroll symptomatic participants with FTD; in addition, 
asymptomatic participants may enroll into the GRN Cohort, but only if they 
participated in the Phase 1 AL001-1 study. Both asymptomatic and symptomatic 
carriers of a GRN mutation who participated in Study AL001-1 may enroll into the 
GRN Cohort if they completed dosing, the required follow-up portion of Study 
AL001-1, did not experience AEs that would indicate that continued dosing with 
AL001 would be unsafe, and meet the inclusion/exclusion criteria of Part 1 of Study 
AL001-2. In addition, new participants who are symptomatic carriers of a GRN 
mutation will also be enrolled into the GRN Cohort. 
Symptomatic FTD participants may enroll in Part 1 of the study if they have either 1 
or more of the 6 behavioral/cognitive symptoms required for a diagnosis of possible 
behavioral variant FTD (bv FTD) (Rascovsky 2011), or a diagnosis of primary 
progressive aphasia (PPA) (Gorno-Tempini 2011). New symptomatic participants 
must also have a Clinical Dementia Rating (CDR®) plus NACC frontotemporal lobar 
degeneration (FTLD) global score of 0.5, 1, or 2. 
In Part 1, all participants will be administered open-label, IV AL001 at the 
investigational site (60 mg/kg, q4w) for 25 doses over a 96-week dosing period. 
An independent Data Monitoring Committee (iDMC) will review safety data during 
the course of Part 1 of the study to provide recommendations to Alector on study 
conduct. The iDMC will be comprised of two physicians (including one with disease 


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area expertise) and a statistician, each of whom are independent from Alector. Data 
reviews will be conducted after the first 6 participants complete approximately 
12 weeks of study drug, and then every 6 months thereafter until the last participant 
completes Part 1 of the study. The details of the iDMC are provided in a separate 
charter. 
The primary objective of Part 1 of the study is to assess safety and tolerability of 
96-week q4w dosing of IV AL001. Secondary and exploratory objectives of Part 1 
include evaluating the PK and the preliminary effect of AL001 on PD biomarkers and 
COAs in asymptomatic and symptomatic participants. For PD biomarkers evaluation, 
the aims are to evaluate increases in PGRN levels after repeated IV dosing of AL001 
in the blood plasma and CSF of asymptomatic and symptomatic participants, to 
evaluate changes in PD fluid biomarkers of neurodegeneration, lysosomal function, 
and glial activity, and to evaluate changes in imaging PD measures. 
Part 2 (Optional Open-Label Extension): 
Part 2 of the study is an optional 96-week, OLE period to assess the long-term safety 
and tolerability of AL001 in participants who have completed 96 weeks of treatment 
on Part 1 of the study. Continuation in the OLE is optional for Part 1 participants. A 
Part 1 participant may be excluded from continuing in the Part 2 OLE if, in the 
opinion of the investigator, continued treatment with AL001 at the conclusion of Part 
1 is not beneficial or safe for the participant. 
Continued study treatment in the optional OLE will be IV AL001 60 mg/kg, q4w (i.e., 
same dose and treatment regimen as in Part 1). An individual participant may 
continue to receive AL001 in the OLE portion of the study for up to 25 doses over a 
96-week dosing period, or until AL001 is commercially available in the country 
where the participant is being treated, whichever is earlier. In the event that an 
individual's participation in the OLE will extend beyond 96 weeks because AL001 is 
not commercially available in their country, they may be eligible to continue to 
receive AL001 under another Alector protocol or program. 
Participants will be discontinued from the OLE in the event of long-term placement in 
a skilled nursing facility; a CDR® plus NACC FTLD global score >2; if, in the 
opinion of the investigator and Alector, they are unable to follow protocol procedures; 
or, if they develop intercurrent illness that would confound the interpretation of safety 
and/or efficacy data. 
Objectives, Part 1 
(Treatment Period): 
Primary Objective – Part 1 (Treatment Period) 
The primary objective of the treatment period of the study is to evaluate the safety and 
tolerability of intravenous (IV) administration of AL001 over 96 weeks in 
asymptomatic and symptomatic carriers of a granulin (GRN) mutation causative of 
frontotemporal dementia (FTD) and in symptomatic carriers of a C9orf72 mutation 
causative of FTD. 
Secondary Objectives– Part 1 (Treatment Period) 
The secondary objectives of the treatment period of the study are to evaluate the 
effect of IV administration of AL001 over 96 weeks in asymptomatic and 
symptomatic carriers of a GRN mutation causative of FTD and in symptomatic 
carriers of a C9orf72 mutation causative of FTD on the following: 
• 
Pharmacokinetics (PK) 
• 
Longitudinal plasma and cerebrospinal fluid (CSF) progranulin (PGRN) 
concentration levels 


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• 
Longitudinal levels of Sortilin in white blood cells (WBCs) 
Exploratory Objectives – Part 1 (Treatment Period) 
The exploratory objectives of the treatment period of the study are to assess the effect 
of IV administration of AL001 over 96 weeks in asymptomatic and symptomatic 
carriers of a GRN mutation causative of FTD and in symptomatic carriers of a 
C9orf72 mutation causative of FTD on the following: 
• 
Longitudinal blood, plasma, and CSF concentration levels of exploratory 
pharmacodynamic (PD) biomarkers of neurodegeneration, lysosomal function, 
and glial activity 
• 
Magnetic resonance imaging (MRI) measures to evaluate changes in the brain 
• 
Correlations among exploratory fluid PD biomarkers, imaging PD measures, 
and clinical outcome assessments (COAs) 
• 
Clinical progression as measured by COAs 
Objectives, Part 2 
(Optional Open-Label 
Extension): 
Primary Objective – Part 2 (Optional OLE) 
The primary objective of the OLE period of the study is to assess the long-term safety 
and tolerability of IV administration of AL001 in participants who have completed 96 
weeks of treatment on Part 1 of the study. 
Exploratory Objectives – Part 2 (Optional OLE) 
COAs, correlative assessments (e.g., biomarker) and other efficacy assessments 
conducted during the OLE are considered exploratory.  
The exploratory objectives of the OLE period of the study are to assess the long-term 
effect of IV administration of AL001 in participants who have completed 96 weeks of 
treatment on Part 1 of the study on the following: 
• 
Pharmacokinetics (PK) 
• 
Longitudinal plasma progranulin (PGRN) concentration levels 
• 
Longitudinal blood and plasma levels of exploratory pharmacodynamic (PD) 
biomarkers of neurodegeneration, lysosomal function, and glial activity 
• 
Magnetic resonance imaging (MRI) measures to evaluate changes in the 
brain 
• 
Correlations among exploratory fluid PD biomarkers, imaging PD measures, 
and clinical outcome assessments (COAs) 
• 
Clinical progression as measured by COAs 
Number of Participants 
Planned: 
Part 1 (Treatment Period) 
Approximately 40 male or female participants 18 to 85 years of age will be enrolled at 
approximately 13 investigational sites in North America and Europe. 
Two cohorts will be enrolled: 
• 
GRN mutation Cohort (up to 20 asymptomatic and symptomatic participants), 
including: 
o 
All asymptomatic and symptomatic participants in Study AL001-1 may 
be enrolled 
o 
New symptomatic GRN mutation carriers may be enrolled 


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• 
C9orf72 mutation Cohort (up to 20 new symptomatic participants) 
Part 2 (Optional OLE) 
Participants who complete Part 1 may be eligible for continued treatment with 
AL001. 
Study Population: 
Part 1 (Treatment Period) 
Prospective participant meets all of the following criteria specific to their applicable 
participant category:  
Participant Category 1: GRN Mutation Carriers, Symptomatic, from Study AL001-1 
• 
Completed Study AL001-1 through the Day 57 visit and did not experience 
adverse events (AEs) that the investigator deems would prevent safe 
participation in Study AL001-2. 
o 
All previous participants in the AL001-1 study must be rescreened and meet 
all inclusion/exclusion criteria applicable to this study. 
• 
Meets 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis 
of possible behavioral variant frontotemporal dementia (bv FTD; Rascovsky 
2011) or has a diagnosis of primary progressive aphasia (PPA; Gorno-Tempini 
2011). 
Participant Category 2: GRN Mutation Carriers, Asymptomatic, from AL001-1 
• 
Prospective participant completed Study AL001-1 through the Day 43 visit and 
did not experience AEs that the investigator deems would prevent safe 
participation in Study AL001-2. 
o 
All previous participants in the AL001-1 study must be rescreened and meet 
all inclusion/exclusion criteria applicable to this study. If a participant 
becomes symptomatic during or after Study AL001-1, they will be screened 
under Category 3 (symptomatic). 
Participant Category 3: GRN Mutation Carriers, Symptomatic, New 
• Is a carrier of a loss-of-function GRN mutation causative of FTD and knows his or 
her mutation status. 
• Has a Clinical Dementia Rating Dementia Staging Instrument PLUS National 
Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration 
Behavior and Language Domains (CDR® plus NACC FTLD) global score of 0.5, 
1, or 2; and 1 or more of the 6 behavioral/cognitive symptoms required for a 
diagnosis of possible Behavioral variant frontotemporal dementia (bvFTD) 
(Rascovsky 2011), or a diagnosis of PPA (Gorno-Tempini 2011). 
Participant Category 4: C9orf72 Mutation Carriers, Symptomatic, New 
• 
Is a carrier of a hexanucleotide repeat expansion C9orf72 mutation causative of 
FTD and knows their mutation status 
• Has a CDR® plus NACC FTLD global score of 0.5, 1, or 2; and 1 or more of the 6 
behavioral/cognitive symptoms required for a diagnosis of possible bv FTD 
(Rascovsky 2011), or a diagnosis of PPA (Gorno-Tempini 2011). 
Part 2 (Optional OLE) 


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Participants who complete the 96-week Part 1 treatment period are eligible for 
continued treatment with AL001 in Part 2, provided they are able to give informed 
consent to continue treatment with AL001, are able to comply with the OLE study 
requirements, and have a study partner who can continue to assist with assessments 
throughout the OLE evaluation period. Part 1 participants who have been admitted to 
a nursing home/assisted living facility, or who have CDR® plus NACC FTLD global 
score >2, are not eligible for participation in the Part 2 OLE. 
 
Study Schema, Part 1 (Treatment Period) and Part 2 (Optional OLE) 
 
 
r 
'-
I , 
'-
" 
r 
'I 
GRN Mutation Carriers Cohort N=20 
C9orf72 Mutation Carriers Coho11 N=20 
Asymptomatic carriers from AL00l-1 
New symptomatic caITiers 
Symptomatic caITiers from AL00l-1 
ew symptomatic caITiers 
,) 
'-
_J 
+ 
+ 
Pa11 1: Screening 
I 
(Within 6 weeks prior to Day 1) 
• 
" 
Part 1: Baseline & 96-Week Open-Label Treatment 
25 doses of60 mg/kg IV AL00 l , q4w 
. COAs at baseline and every 12 weeks after Day 1 
. Blood samples collection at Baseline and throughout the study 
. CSF samples at Baseline and throughout the study 
. Brain MRI at Baseline and eve1y 24 weeks after Day 1 
/ 
' 
Participants who complete 96-week 
Part 1 treatment period and do not 
continue to Pa11 2 (Optional OLE): 
Pa111 : EOS Visit (at the scheduled 
Week 97 timepoin t) 
Safety Follow-up 
(10-week follow-up period after last dose) 
Perfonn final safety assessments 
Participants who complete 96-week Part 1 
treatment period and continue to Part 2 
(Optional OLE): 
Continuation from Week 97 to Week 101 
visit 
'---------------
• 
Pat1 2: 96-Week Optional OLE 
25 doses of 60 mg/kg IV AL00 I, q4w 
COAs every 24 weeks 
Blood sample collection eve1y 12 weeks 
Brain MRI eve1y 48 weeks 
Part 2: EOS Visit (at the scheduled Week 
197 timepoint) 
Safety Follow-up 
(10-week follow-up period after last dose) 
Perfo1m final safety assessments 


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Study Procedures: 
Part 1 (Treatment Period) 
Participants in Part 1 may be consented and screened up to 6 weeks prior to Day 1 to 
determine eligibility. All enrolled participants will undergo baseline evaluation with 
MRI, biofluid sampling for PD biomarker measurements, lumbar puncture for CSF 
collection, safety assessments, and several COAs. 
The Part 1 treatment period will be a total of 96 weeks. Study treatment (AL001 
60 mg/kg) will be administered IV q4w for a total of 25 doses. Clinical outcome 
assessments, including those performed by the participant and their study partner, will 
be conducted every 12 weeks. Imaging will be performed every 24 weeks. Lumbar 
puncture for CSF collection will be performed every 24 weeks. 
Every effort will be made to follow all enrolled participants for the full 96-week 
treatment period, irrespective of whether they discontinue study treatment. All 
participants will be followed for safety at 10 weeks after the last dose of AL001. 
Upon completion of the 96-week treatment period, participants who are eligible and 
provide consent will continue in Part 2 (Optional OLE) of the study. Participants who 
do not continue in Part 2 (Optional OLE) will return to the investigational site 
10 weeks after their last dose of AL001 for final safety assessments. 
Part 2 (Optional OLE) 
Upon completion of the 96-week treatment period in Part 1, participants who are 
eligible for continued treatment in Part 2 (OLE) will receive their next regularly 
scheduled dose of AL001 according to the OLE administration schedule (continuation 
from Week 97 to Week 101). 
The Part 2 OLE period will be up to 96 weeks. Study treatment (AL001 60 mg/kg) 
will be administered IV q4w for a total of up to 25 doses. Blood sampling for safety 
will be performed approximately every 12 weeks. Clinical outcome assessments, 
including those performed by the participant and their study partner, will be 
conducted approximately every 24 weeks. Imaging will be performed approximately 
every 48 weeks. 
Participants who discontinue study treatment early (e.g., due to participant decision, 
withdrawal criteria, AL001 commercial availability in the country where the 
participant in being treated) will be followed for safety at 10 weeks after the last dose 
of AL001. 
Safety and Tolerability 
Assessments: 
Key safety and tolerability assessments include monitoring AEs; physical 
examinations; neurological examinations; vital signs and weight; electrocardiograms; 
clinical laboratory analyses in blood and urine; and anti-drug antibodies throughout 
the study. 
Pharmacokinetic 
Assessments: 
Serum and CSF samples will be collected to measure AL001 concentrations in Part 1. 
Serum samples will be collected to measure AL001 concentrations in the optional 
Part 2. 
Pharmacodynamic 
Assessments: 
Key PD assessments in Part 1 will include levels of PGRN in plasma and CSF, and 
Sortilin in WBCs. Key PD assessments in Part 2 will include levels of PGRN in 
plasma. 
Clinical Outcome 
Assessments: 
Clinical outcome assessments include the following: 
• 
Clinical Dementia Rating Dementia Staging Instrument PLUS National 
Alzheimer’s Disease Coordinating Center Frontotemporal Lobar 
Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) 


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• 
Frontotemporal Dementia Rating Scale (FRS) 
• 
Clinical Global Impression of Improvement (CGI-I) 
• 
Clinical Global Impression of Severity (CGI-S) 
• 
Color Trails Test (CTT) Part 2 
• 
Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS) 
• 
Winterlight Labs Speech Assessments (for US, UK, and Canadian 
participants who agree to participate in these optional assessments only) 
Study Drug, Dosage, 
and Route of 
Administration: 
All participants will receive AL001 (60 mg/kg) q4w intravenously (IV) over 
approximately 60 minutes. 
Sample Size  
Part 1 (Treatment Period) 
The Part 1 sample size of 40 participants was chosen based on feasibility; however, 
the probability of detecting at least 1 clinically significant associated finding will be 
explored. When the probability of a clinically significant associated finding for a 
single participant is 0.1%, 1%, 5%, and 10%, then with a sample size of 
40 participants, the probability of detecting at least 1 clinically significant associated 
finding across all participants is 3.9%, 33.1%, 87.1% and 98.5% respectively. 
Part 2 (Optional OLE) 
It is estimated that up to approximately 40 participants from Part 1 of the study will 
be eligible to enroll in the optional Part 2 OLE portion of the study. 
Statistical Methods: 
Part 1 (Treatment Period) 
For Part 1, the statistical analysis will be performed using Statistical Analysis System 
(SAS) software Version 9.4 or later (SAS Institute Inc., Cary, North Carolina, USA). 
The statistical methods for this study will be described in a detailed Statistical 
Analysis Plan (SAP), which will be finalized before locking of the database. Changes 
from analyses planned in this protocol will be documented in the SAP. Any 
deviations from the planned analysis as described in the SAP will be justified and 
recorded in the final clinical study report. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of participants, 
mean, standard deviation, median, minimum, maximum, and 95% confidence interval 
[CI] where applicable). All summaries will be presented by combined participant 
status and dementia type at baseline (aFTD-GRN, FTD-GRN [bvFTD and PPA], 
FTD-C9orf72 [bvFTD and PPA], and All Patients). 
Data collected for participants who failed screening and were not enrolled will not be 
presented in any summaries or data listings. All other data will be listed in data 
listings. 
Baseline will be defined as the last non-missing assessment, including repeated and 
unscheduled measurements, prior to the start of first study drug administration. 
All CIs will be 2-sided and performed using a 5% significance level except for PK 
parameters for which 90% CI and geometric mean will be used. As the objectives of 
Part 1 of the study are exploratory in nature no adjustments for multiplicity will be 
made. 
No formal significance testing will be performed. 


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Part 2 (Optional OLE) 
For Part 2, no formal statistical testing will be performed. Descriptive statistics will be 
presented. The purpose of the OLE is to collect long-term safety and tolerability data 
from participants who have completed 96 weeks of treatment with AL001 under Part 
1 of the study. As the objectives of the OLE are exploratory in nature no adjustments 
for multiplicity will be made. 
Duration of 
Participation: 
Part 1 (Treatment Period) 
• 
A screening period (within 6 weeks prior to Day 1) 
• 
A treatment period (96 weeks, Day 1 through Week 97) 
• 
Participants who discontinue study drug prior to completing the 96-week 
Part 1 treatment period should be encouraged to complete all remaining 
scheduled assessment visits through Part 1 (including COAs, MRI, and CSF 
evaluations). 
o 
A Part 1 End of Treatment (EOT) visit will be completed by 
participants who discontinue study drug but remain in the study and 
continue to perform assessments. Part 1 EOT assessments should be 
completed as soon as possible after the decision is made. A Safety 
Follow-Up visit will be performed 10 weeks after their last study 
drug administration. The Safety Follow-up visit may be substituted 
by a scheduled visit if it occurs within the same window. 
o 
A Part 1 End of Study (EOS) visit will be completed by participants 
who discontinue study drug and all assessments. Part 1 EOS 
assessments should be completed as soon as possible after the 
decision is made. A Safety Follow-Up visit will be performed 10 
weeks after their last study drug administration. 
• 
At Week 97, participants who complete the Part 1 96-week treatment period 
will have the option to continue to receive AL001 in Part 2 (OLE) of the 
study. 
o 
Participants who do not continue in Part 2 will complete a Part 1 
EOS visit at the scheduled Week 97 timepoint. A Safety Follow-up 
visit will be performed 10-weeks after their last study drug 
administration. 
o 
Participants who continue in Part 2 will complete the Week 97 visit 
and continue to Part 2 (Week 101). 
Part 2 (Optional OLE) 
• 
OLE eligibility confirmation (prior to Week 101 study drug administration). 
• 
A treatment period (96 weeks, Day 101 through Week 197), or until AL001 
is commercially available in the country where the participant is being 
treated, whichever is earlier. 
• 
Participants who discontinue study drug and/or all assessments prior to 
completing the 96-week Part 2 treatment period will complete a Part 2 EOS 
visit as soon as possible after the decision is made. A Safety Follow-Up visit 
will be performed 10 weeks after their last study drug administration. 
• 
At Week 197, participants who complete the Part 2 96-week OLE period will 
complete a Part 2 EOS visit at the scheduled Week 197 timepoint. A Safety 
Follow-up visit will be performed 10-weeks after their last study drug 
administration. 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
ADRs 
Adverse drug reactions 
AE 
Adverse event 
aFTD-GRN 
asymptomatic frontotemporal dementia with heterozygous progranulin gene mutations 
AllFTD 
ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUCss 
Area under the concentration-time curve at steady state 
BP 
Blood pressure 
bvFTD 
Behavioral variant frontotemporal dementia 
CDR® 
Clinical Dementia Rating Scale 
CDR-GS 
Clinical Dementia Rating global score 
CDR-SB 
Clinical Dementia Rating sum of boxes 
CDR® plus 
NACC FTLD 
Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease 
Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains 
CDR® plus 
NACC FTLD-
SB 
Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease 
Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains 
Sum of Boxes 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
COA 
Clinical outcome assessment 
CRA 
Clinical research associate 
CRFs 
Case report forms 
CRO 
Clinical research organization 
CSF 
Cerebrospinal fluid 
CSR 
Clinical study report 
Ctrough 
Trough concentration 
CTT 
Color Trails Test 


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Abbreviation 
Definition 
CV 
Coefficient of variation 
DLAE 
Dose-limiting adverse event 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FPI 
Frontotemporal Dementia Prevention Initiative 
FRS 
Frontotemporal Dementia Rating Scale 
aFTD 
Asymptomatic frontotemporal dementia 
FTD 
Frontotemporal dementia 
FTD-C9orf72 
frontotemporal dementia with C9orf72 hexanucleotide repeat expansion mutations 
FTD-MND 
Frontotemporal dementia with motor neuron disease 
FTD-GRN 
frontotemporal dementia with heterozygous progranulin gene mutations 
FTLD 
Frontotemporal lobar degeneration 
FTLD-FUS 
Frontotemporal lobar degeneration – immunoreactive to the fused in sarcoma protein 
FTLD-TDP 
Frontotemporal lobar degeneration – transactive response DNA-binding protein 43 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GRN 
Progranulin gene 
GUID 
Global Unique Identifier 
HV  
Healthy Volunteer 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
iDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G  


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Abbreviation 
Definition 
IL-6 
Interleukin 6 
IP 
Investigational product 
IRB 
Institutional review board 
IRT 
Interactive Response Technology 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effect model of repeated measures 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
NfL 
Neurofilament-light chain 
NIA 
National Institute on Aging 
OLE 
Open-label extension 
PD 
Pharmacodynamic(s) 
PE 
Physical examination 
PGRN 
Progranulin protein 
PK 
Pharmacokinetic(s) 
PPA 
Primary progressive aphasia 
q4w 
Every 4 weeks 
QTcF 
QT interval corrected using Fridericia formula 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
SAE 
Serious adverse event 
SD 
Standard deviation 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SDV 
source data verification 
Sheehan-STS 
Sheehan Suicidality Tracking Scale 
SUSARS 
Suspected Unexpected Serious Adverse Reaction 
TDP-43 
Transactive response DNA-binding protein of 43 kD 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WGS 
Whole genome sequencing 


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Abbreviation 
Definition 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
WLA 
Winterlight Labs Speech Assessment 
WOCBP 
Woman of childbearing potential 
 


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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
Frontotemporal Dementia 
Frontotemporal dementia (FTD) is a rare, early-onset form of dementia afflicting approximately 
60,000 Americans (Tatton 2014) and 113,000 people in the European Union, Norway, Iceland, 
and Liechtenstein combined (EMA 2016). Frontotemporal dementia is typified by prominent 
executive dysfunction, behavioral and personality changes, and language deficits (Boxer 2013a; 
Boxer 2013b). It presents as 3 distinct clinical phenotypes (behavioral variant FTD [bvFTD], and 
2 variants of primary progressive aphasia [PPA]: semantic variant and non-fluent variant).  
The clinical FTD phenotypes include prominent social dysfunction and disinhibition, as well as 
language difficulties. Given the marked behavioral and personality changes of FTD and early 
onset of the disease, FTD patient care represents a significant burden for caregivers, families, 
and society (Galvin 2017). Symptoms in FTD are sometimes managed with off-label 
pharmacological treatment, including selective serotonin reuptake inhibitors, antipsychotics, or 
antiepileptics (Tsai 2014). However, no disease-modifying therapies have been approved for the 
treatment of FTD (Boxer 2013a; Boxer 2013b). 
1.1.2. 
Frontotemporal Lobar Degeneration, GRN, and C9orf72 
Frontotemporal lobar degeneration (FTLD) can be broadly split into 3 principal pathology 
categories based on manifest nuclear and cytoplasmic inclusions: (1) FTLD-TDP, with neuronal 
and glial inclusions immunoreactive for transactive response, transactive response DNA-binding 
protein of 43 kD (TDP-43); (2) FTLD-tau, with tau-positive inclusions containing fibrillar, 
hyper-phosphorylated tau; and (3) a small number of tau-negative, TDP-43-negative cases which 
are immunoreactive to the fused in sarcoma protein (FTLD-FUS) (Perry 2017; Mann 2017). 
TDP-43 pathology is seen in most FTD cases caused by a genetic mutation and is identified in up 
to 50% of FTD patients overall (Ng 2015). 
A family history is present in approximately 40% of FTD cases, with about 10% showing an 
autosomal dominant pattern of inheritance (Deleon 2018), indicating a strong genetic 
component. Granulin (GRN) mutations account for up to 20% of all heritable FTD cases, and 
5 to 10% of all cases of FTD are caused by a loss-of-function mutation in 1 allele of GRN 
(Gass 2006; Rademakers 2012; Rohlfing 2017; Cruts 2012). Heterozygous GRN deficiency 
almost invariably leads to development of FTD, making GRN a causal gene for the disease 
(Boxer 2013a; Boxer 2013b). 
GRN mutations include 77 different mutations in more than 240 unrelated families, which 
accounts for 16% of families worldwide carrying a neurodegenerative disease-causing mutation 
(Ghidoni 2012) that encodes for the secreted glyocoprotein progranulin (PGRN) (Rademakers 
2012). Frontotemporal dementia patients carrying this mutation have a >50% reduction in 
plasma and cerebrospinal fluid (CSF) levels of this secreted protein (Meeter 2016). Progranulin 
is associated with many cellular processes that include, but are not limited to, embryogenesis, 
inflammation, wound repair, neurodegeneration, and lysosome function (Chitramuthu 2017). In 


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the brain, PGRN promotes neurite outgrowth (Gass 2012) and enhances the survival of motor 
and cortical neurons (De Muynck 2013). The predominant clinical presentation of GRN mutation 
patients is bvFTD or PPA.  
C9orf72 hexanucleotide repeat expansions are also a significant contributor to FTD pathology. 
Expansion of a non-coding hexanucleotide repeat in C9orf72 is the most common single cause of 
FTD, representing approximately 25% of familial cases and 6% of sporadic FTD cases 
(Ng 2015). Currently, the pathophysiology of frontotemporal dementia in carriers of C9orf72 
hexanucleotide repeat expansion mutations causative of FTD is unclear but may involve 
haploinsufficiency of the C9orf72 protein or abnormal dipeptide repeat proteins (data on file). 
The predominant clinical presentation (>80%) of C9orf72 repeat carriers is bvFTD, with motor 
neuron disease (FTD-MND) or without motor neuron disease (Ng 2015). 
FTD patients with GRN and C9orf72 mutations exhibit a common pathology in frontotemporal 
degeneration associated with TDP-43 protein-related accumulation. Overlapping functional 
associations between GRN and C9orf72 proteins include processing of TDP-43, and abnormal 
glial activation in patients with FTD (Ayala 2008; Zhang 2009; Mann 2017; Valdez 2017; 
Busch 2016; Zhang 2007; Tanaka 2013; O’Rourke 2016). Moreover, studies have suggested that 
TMEM106b may be a genetic modifier of both C9orf72 and GRN (Gallagher 2014; 
van Blitterswijk 2014; Pottier 2018), suggesting that these genes may share a common pathway. 
Therapeutics targeted at reducing TDP-43 pathology and restoring lysosomal function may thus 
also slow FTD disease progression in patients with either GRN or C9orf72 mutations. 
1.1.3. 
Sortilin and AL001 
Human and mouse genetic studies identified the transmembrane receptor Sortilin, encoded by the 
Sortilin 1 gene, as the major negative regulator of PGRN levels in plasma and the brain 
(Hu 2010; Carrasquillo 2010). Sortilin binds PGRN and targets it for lysosomal degradation 
resulting in a reduction of extracellular PGRN. Blocking Sortilin/PGRN interactions, therefore, 
provides a therapeutic strategy for sustaining PGRN levels in the central nervous system (CNS) 
and minimizing progression of FTD-associated dementias. 
AL001 is a recombinant humanized monoclonal antibody that binds specifically to Sortilin and is 
being studied for the treatment of carriers of GRN mutations causative of FTD and carriers of 
C9orf72 hexanucleotide repeat expansion mutation causative of FTD. 
1.2. 
Findings from Nonclinical and Clinical Studies of AL001 
1.2.1. 
Nonclinical Studies 
To support clinical studies, the toxicology and pharmacokinetics (PK) of AL001 were evaluated 
in single- and repeat-dose PK studies and Good Laboratory Practices (GLP) repeat-dose (4-week 
and 26-week) intravenous (IV) toxicology studies in cynomolgus monkeys. Overall, for the dose 
levels assessed, there were no significant toxicology findings in the nonclinical studies. 
Refer to the AL001 Investigator’s Brochure (IB) for additional details regarding nonclinical 
pharmacology, PK, and toxicology data. 


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1.2.2. 
Clinical Studies 
1.2.2.1. 
Study AL001-1 (Completed) 
Study AL001-1 was a first-in-human (FIH) Phase 1 study that assessed the safety, tolerability, 
PK, and PD of AL001 in healthy volunteers (HV) and carriers of GRN mutations causative of 
FTD. The study was conducted in two parts. 
Part 1, Healthy Volunteers 
The first part of this study evaluated the effect of single doses of AL001 ranging from 2 mg/kg to 
60 mg/kg in HV to identify the safest maximum dose and explore pharmacokinetics (PK) and 
pharmacodynamics (PD) in plasma and cerebrospinal fluid (CSF). A total of 50 HV were 
enrolled: 42 participants in 5 randomized single-ascending-dose cohorts (Cohorts 1 through 5) 
with increasing dose levels of AL001 (or placebo) ranging from 2 mg/kg to 60 mg/kg via IV 
administration, plus 8 participants in the single-dose 60 mg/kg expansion cohort (Cohort 6).  
Plasma PGRN Concentrations: Administration of AL001 to HV at single doses of 2 mg/kg, 
6 mg/kg, 15 mg/kg, 30 mg/kg, and 60 mg/kg caused dose-dependent peripheral increases in 
plasma PGRN levels; the elevations of PGRN levels were sustained for a longer duration at the 
highest dose levels. Maximum concentrations of PGRN were measured 5 to 12 days after the 
infusion. At the 30 mg/kg dose, plasma PGRN concentrations remained elevated at more than 
twice the baseline level, from 2 days after dosing to 29 days after dosing. At the 60 mg/kg dose, 
plasma PGRN concentrations remained elevated at more than twice the baseline level, from 
2 days after dosing to more than 29 days after dosing. The maximum percent increase in percent 
change from baseline was statistically significant compared to pooled placebo for each of the HV 
dose cohorts, and ranged from 2.29 (2 mg/kg) to 3.14-fold (60 mg/kg) over baseline. CSF 
samples were collected from HV in the 15 mg/kg, 30 mg/kg, and 60 mg/kg dose cohorts before 
dosing and approximately 30 hours (Day 2) and 12 days (Day 13) after the infusion. 
CSF PGRN Concentrations: A statistically significant increase in CSF PGRN levels (compared 
to baseline) was seen at both post-dose time points for each of these 3 cohorts (Day 2 and 
Day 13). The maximum increase in CSF PGRN was observed 12 days after dosing: 1.57 times 
for 15 mg/kg, 1.84 times for 30 mg/kg, and 2.11 times for 60 mg/kg compared to baseline. No 
statistically different changes in CSF PGRN levels have been observed in subjects that received 
placebo. In the 60 mg/kg expansion cohort, 24 days after dosing, the PGRN level was increased 
1.83-fold over baseline and 42 days after dosing the PGRN level was increased 1.23-fold over 
baseline. Coefficients of variation were in the range of 20% to 40% for the 30 mg/kg and 
60 mg/kg cohorts over the cited sampling period. 
Safety: AL001 was generally safe and well tolerated through the highest dose assessed 
(60 mg/kg), without dose-limiting toxicities or apparent trends in adverse events (AEs). 
Part 2, Patients with Asymptomatic FTD-GRN or Symptomatic FTD-GRN 
The second part of the study was conducted in two cohorts: the first cohort assessed safety, PK, 
and PD after a single-dose of AL001 in asymptomatic carriers of a loss-of-function GRN 
mutation causative of FTD (asymptomatic FTD-GRN); while the second cohort assessed safety, 


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PK, and PD after repetitive dosing in symptomatic FTD carriers of a loss-of-function GRN 
mutation (symptomatic FTD-GRN). A total of 6 asymptomatic FTD-GRN participants and 
8 symptomatic FTD-GRN participants were enrolled and completed dosing in the second portion 
of the study. Asymptomatic FTD-GRN participants were administered a single IV dose of AL001 
at 60 mg/kg and symptomatic FTD-GRN participants were administered 3 doses of IV AL001 
30 mg/kg, q2w. 
Plasma PGRN Concentrations: Consistent with the literature (Meeter 2016), both the 
asymptomatic FTD-GRN cohort (N = 5  who received 60 mg/kg) and the symptomatic FTD-
GRN cohort (N = 8) had substantially lower baseline plasma PGRN concentrations than HV 
cohorts (1 asymptomatic participant was incorrectly dosed and is not included in the summary 
pharmacodynamic analyses). Mean baseline plasma PGRN concentration for the asymptomatic 
FTD-GRN cohort was 32.6 ng/mL (standard deviation [SD] of 13.6); for the symptomatic 
FTD-GRN cohort, mean baseline plasma PGRN concentration was 31.7 ng/mL (SD of 12.7). 
Treatment of the asymptomatic FTD-GRN cohort with a SD of 60 mg/kg AL001 resulted in an 
increase of plasma PGRN to approximately the baseline level of HV for 24 days (median 
concentrations of 118 to 124 ng/mL at Day 6 through Day 30 of the study). Treatment of the 
symptomatic FTD-GRN cohort with 3 doses of 30 mg/kg AL001 over a 4-week period resulted 
in an increase of plasma PGRN to at least 80% of the baseline level of HV for approximately 
49 days, beginning 7 days after the first dose (median concentrations of 93.7 to 97.6 ng/mL at 
Day 8 through Day 57 of the study). 
CSF PGRN Concentrations: Parallel to the results observed for plasma concentrations of PGRN, 
both the asymptomatic FTD-GRN cohort (N = 5 who received 60 mg/kg) and the symptomatic 
FTD-GRN cohort (N = 8) had substantially lower baseline PGRN concentrations in CSF than 
HV cohorts (mean of 1.67 ng/mL for the asymptomatic FTD-GRN cohort, 1.82 ng/mL for the 
symptomatic FTD-GRN cohort; approximately 55 to 58% of the HV mean of 3.1 ng/mL). 
Treatment of the asymptomatic FTD-GRN cohort with a single-dose of 60 mg/kg AL001 resulted 
in an increase of PGRN in CSF to 3.76 ng/mL, approximately 1.2 times the baseline level of HV, 
assessed 12 days after dosing. Treatment of the symptomatic FTD-GRN cohort with 3 doses of 
30 mg/kg AL001 over a 4-week period resulted in an increase of PGRN in CSF to 3.76 ng/mL, 
approximately 1.2 times the baseline level of HV, assessed 28 days after the third dose of 
30 mg/kg AL001 (57 days after the initial dose). 
Safety: There were no deaths, no AL001-related serious adverse events (SAE)s, and no 
dose-limiting AEs. AEs have been predominantly mild to moderate in severity.  
1.2.3. 
Study AL001-2 (Ongoing) 
The current Phase 2 study, AL001-2, will evaluate the long-term safety profile of AL001 in 
heterozygous carriers of GRN or C9orf72 mutations causative of FTD. The study will be 
conducted in two parts. During Part 1 (Treatment Period), participants will receive open-label 
treatment with 60 mg/kg IV AL001, administered every 4 weeks (q4w) for 96 weeks. Part 2 is an 
optional open-label extension (OLE) to assess long-term (up to 96 weeks extended treatment 
period) safety and tolerability in participants who complete the Part 1 96-week treatment period. 
Enrollment in this Phase 2 study was initiated in the third quarter of 2019. The first participant 


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was dosed on 27 September 2019. Target enrollment of 40 subjects is planned; up to 20 subjects 
with GRN mutations including participants from Study AL001-1 and up to 20 patients with 
C9orf72 mutations. See Section 1.4.3 for a discussion of the rationale for the dosing period. 
1.3. 
Risk/Benefit Assessment of AL001 
Refer to the IB for detailed information on safety profile of AL001. 
1.3.1. 
Known Risks of the Drug Class 
Immune Response: Monoclonal antibodies like AL001 may be associated with a potential 
immune response, such as hypersensitivity or hypersensitivity-like reactions, including severe 
anaphylactic reactions. 
1.3.2. 
Risks of AL001 
Risks Associated with AL001 Study Procedures and Assessments: The study procedures and 
assessments to be performed are not considered to be of great burden to patients and are not 
associated with high risk. 
Important Identified Risks: There are no important identified risks for AL001. 
Serious Adverse Drug Reactions: No serious adverse drug reactions (ADRs) have been 
identified in Study AL001-1 or Study AL001-2 and there are no expected serious ADRs for 
AL001. 
Immunogenicity: Subjects treated with AL001 have developed anti-drug antibodies (ADAs). The 
preliminary assessment of ADAs has not identified any associations between incident ADAs 
with PK, PD, or clinical safety in participants receiving single-dose AL001 or three doses of 
AL001 administered q2w. Based on the current information from studies with AL001, the impact 
of immunogenicity on AL001 exposure, PD effects, and clinical safety do not appear 
consequential with short duration of exposure. However, the impact of ADAs continues to be 
assessed in ongoing AL001 clinical studies with longer-term exposure. An ADA assay for 
neutralizing antibodies to AL001 is under development. See the IB for more information on 
immunogenicity. 
Adverse Events: AL001 has been generally safe and well-tolerated. There have been no deaths, 
no AL001-related SAEs, and no adverse events (AEs) leading to study discontinuation in the 
clinical trials of AL001 to date. AEs have been predominately mild to moderate in severity. 
Refer to the IB for a detailed summary of AEs. 
Summary of Adverse Events – Study AL001-1 (completed): There were no deaths and no 
dose-limiting adverse events (DLAEs). There was no higher incidence of treatment emergent 
adverse events (TEAEs) with AL001 treatment than with placebo, and the incidence of 
TEAEs was similar across all AL001 dosing regimens and between the HV and FTD-GRN 
cohorts. There were no dose-related trends in TEAEs. The most frequent TEAEs were 
post-lumbar puncture syndrome (i.e., headache after lumbar puncture), headache, puncture 
site pain, anemia, lipase increased, myalgia, vomiting, and upper respiratory tract infection. 


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There were 2 potentially life-threatening SAEs reported as unrelated to study drug in the HV 
cohorts: one event of rhabdomyolysis occurring in the pooled placebo cohort (attributed to 
 in a participant occurring 8 weeks after receiving placebo), and one event 
of rhabdomyolysis occurring in the SD 60 mg/kg AL001 HV cohort (attributed to 
 
n in a participant occurring 8 weeks after receiving AL001). All other 
TEAEs were mild or moderate in severity and generally resolved. 
Interim Safety Results – Study AL001-2 (ongoing): As of 18 December 2020, a total of 
26 participants had been exposed to AL001 on Study AL001-2, 24 of whom were receiving 
study treatment. As of the data cut off, 2 participants discontinued the study (1 participant 
withdrew consent, and 1 participant was discontinued at the investigator's discretion).  The mean 
age of participants as of the data cutoff was 59.6 years (range 32-78 years). 
AL001 has been generally safe and well-tolerated in this study. As of the data cutoff, there were 
44 TEAEs in 18 participants (5 participants in asymptomatic FTD-GRN, 6 participants in 
symptomatic FTD-GRN, and 7 participants in symptomatic FTD-C9orf72 cohorts). There have 
been no deaths. 
The most frequently reported TEAEs across the total safety population were fall (3 participants), 
rash (3 participants). All other TEAEs were reported by 2 or fewer participants. 
There was 1 severe SAE (venous thrombosis) that occurred in a 
-year-old 
 participant 
from the symptomatic FTD-GRN cohort who was previously enrolled in the Phase 1 study 
(Study AL001-1). This SAE led to treatment discontinuation but was considered by the 
investigator to be not related to study drug. 
All other TEAEs have been mild or moderate in severity. One TEAE of moderate severity, 
cellulitis (facial rash), which occurred in one participant in the FTD-C9orf72 cohort, led to 
treatment interruption, and was considered not related to study drug. One participant had study 
treatment interrupted due to elevated lipase. 
1.3.3. 
Potential Benefits of AL001 
AL001 is being evaluated as a potential disease-modifying treatment of adults at risk for or with 
FTD due to a mutation in GRN that leads to lower levels of PGRN. AL001 is a novel 
recombinant human monoclonal IgG1 antibody that blocks Sortilin, decreasing the rate of PGRN 
clearance, and raising the concentration of PGRN. AL001 may therefore decrease the rate of 
neurodegeneration and clinical decline associated with FTD among patients who carry GRN 
mutations. Treatment with AL001 represents a promising therapeutic strategy, not only for FTD 
patients, but also for individuals who are at risk for developing FTD and while the efficacy of 
treatment with AL001 is still under investigation, patients with or at risk for FTD may benefit 
from participating in clinical trials of AL001, which are designed to evaluate a potential 
treatment for a disease for which there is currently no treatment or cure. All participants will 
receive and potentially benefit from close medical monitoring and care from qualified 
professionals throughout their participation in the study. 


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1.3.4. 
Benefit Risk for AL001-2 Study Participants 
Frontotemporal dementia is a rare, early-onset form of dementia. Frontotemporal dementia 
progresses rapidly with survival after symptom onset of 3 to 14 years (Onyike and Diehl-Schmid 
2013). There are currently no approved treatments for FTD (Boxer 2013a, Boxer 2013b). 
Participation in Study AL001-2 offers the possibility of receiving AL001, a novel recombinant 
human monoclonal IgG1 antibody that blocks Sortilin, for the treatment of adults at risk for or 
with frontotemporal dementia due to a mutation in the GRN that leads to lower levels of PGRN. 
By blocking Sortilin, decreasing the rate of PGRN clearance and therefore raising the 
concentration of PGRN, AL001 may decrease the rate of neurodegeneration and clinical decline 
associated with FTD among patients who carry GRN mutations. Study participants will be 
randomly assigned to either AL001 or placebo. 
More detailed information about the known and expected benefits and risks of AL001 may be 
found in the current version of the AL001 IB. 
The potential benefit of AL001 to participants is described in Section 1.3.3 of the protocol, and 
based on completed Phase 1 study, AL001-1, which demonstrated that AL001 is associated with 
significant and dose dependent increases in plasma and CSF PGRN in both healthy volunteers, 
asymptomatic and symptomatic carriers of GRN mutations causative of FTD. Of note, 
administration of AL001 to subjects with GRN mutations restored CSF and plasma PGRN levels 
to normal. In addition, by blocking Sortilin, decreasing the rate of PGRN clearance and therefore 
raising the concentration of extracellular, AL001 may reduce TDP-43-associated pathology and 
decrease the rate of neurodegeneration and clinical decline associated with FTD among patients 
who carry C9Orf72 mutations. 
The safety profile of AL001 for participants in this study is described in Section 1.3.2, with 
further guidance for investigators provided in the IB. Any risks to participants in AL001-2 will 
be minimized through a combination of screening for appropriate eligibility criteria (see 
Section 4), and rigorous safety monitoring to mitigate risks and careful toxicity management (see 
Section 6.5, Section 7, and IB). Adverse event and/or severe adverse event collection will occur 
up to 8 weeks after last dose of study treatment. Frequent safety monitoring will ensure that 
updated safety information is available in a timely manner and that any future changes to the 
benefit-risk profile of AL001 are appropriately reported and managed. An independent Data 
Monitoring Committee (iDMC) with the capability of reviewing unblinded data will provide 
additional oversight of the study supplementing the Sponsor’s careful screening, diligent 
monitoring and management of patient safety. 
Taking the available data on the investigational therapy together with the study design and 
conduct, AL001 is anticipated to be generally safe, well tolerated and provide pharmacological 
effect at the dose of 60 mg/kg being administered. Subjects, regardless of the treatment group to 
which they are randomly assigned, will receive close medical monitoring and care from qualified 
professionals throughout their participation in the study. The assessment procedures included in 
the clinical studies are not considered to be of great burden to patients and are not associated 
with high risk. Informed consent processes are intended to both (1) describe these potential 
benefits and potential risks from participating in the study and (2) ensure, in accordance with 


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local regulation, that a legally authorized representative is identified for participants who may 
not have legal capacity to provide consent as described in Section 10.3 of the protocol. 
Therefore, it is plausible to conclude that the anticipated benefits of participating in this study 
outweigh the potential risks or inconveniences. 
1.4. 
Rationale for the Study 
1.4.1. 
Rationale for the Study Design 
Based upon the preliminary findings of dosing-associated increases in plasma and CSF PGRN 
levels seen in the Phase 1 study (AL001-1), the current Phase 2 study (AL001-2) will evaluate 
the long-term safety profile of AL001 in aFTD-GRN participants, in FTD-GRN participants, and 
in symptomatic carriers of C9orf72 hexanucleotide repeat expansion mutations causative of FTD 
(FTD-C9orf72). The study will be conducted in two parts. During Part 1 (Treatment Period), 
participants will receive open-label treatment with 60 mg/kg IV AL001, administered every 
4 weeks (q4w) for 96 weeks. PK, PD biomarkers, and clinical outcome assessments (COAs; 
Section 6.9) will be evaluated as secondary and exploratory objectives. Part 2 is an optional 
open-label extension (OLE) to assess long-term (up to 96 weeks extended treatment period) 
safety and tolerability in participants who complete the Part 1 96-week treatment period. The 
safety, PK, PD biomarker assessments and clinical outcome measures performed in this study are 
appropriate for this patient population and are commonly used in clinical studies in 
neurodegenerative diseases to assess treatment effect. 
1.4.2. 
Rationale for Dose Selection 
A suitable dose for individuals who are carriers of GRN and C9orf72 mutations causative of FTD 
is one which is deemed to be safe and well tolerated and which is anticipated to be associated 
with a PD effect that is sustained in the CNS compartment. Taking into account the available 
nonclinical and clinical pharmacological and PD data, dose regimens were selected with the goal 
of restoring and sustaining CSF PGRN concentration levels in GRN mutation carriers to normal 
levels. 
A dose regimen of 60 mg/kg q4w IV is used in the current study (Study AL001-2) and in the 
Phase 3 study (AL001-3). This dose regimen reflects the findings from the cumulative data from 
the Phase 1 study and the PK and PD modelling of both clinical and nonclinical data, which 
together indicated that an increase in CNS PGRN is more sustained at higher doses. 
Please see the AL001 IB for a discussion of the safety margins for multiple doses of 60 mg/kg 
administered q4w. 
1.4.3. 
Rationale for Treatment Duration 
Based on the interim safety and tolerability data review by the independent Data Monitoring 
committee (iDMC) for this study, and based on the observed treatment effects of AL001 on 
biomarkers and clinical assessments in subjects treated to date, the protocol was amended to add 


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an optional 96-week, open-label extension period to assess the long-term safety and tolerability 
of AL001 in participants who have completed 96 weeks of treatment on Part 1 of the study. 
The proposed mechanism of AL001 is to restore progranulin levels back to normal, thus 
counteracting the pathological consequences of progranulin deficiency in patients of FTD with 
heterozygous progranulin gene mutations (FTD-GRN) that cause the disease. The treatment goal 
of this potentially disease-modifying drug is to stop or slow down FTD progression, as measured 
by clinical outcome measures, and fluid and imaging biomarkers; the potential effects of AL001 
on these biomarkers and outcome measures can only be fully evaluated after long-term dosing. 
Therefore, the current protocol has been amended to offer the option for participants to extend 
the AL001 treatment period from 96 weeks to 192 weeks, with the total number of doses 
increased from 25 doses to 50 doses. Continuation in the OLE is optional. Extending the duration 
of the treatment period with AL001, the first molecule shown to elevate blood and CSF 
progranulin levels, provides the opportunity to follow subjects longitudinally for long-term 
safety, tolerability, and efficacy. Extension of the AL001 treatment duration is supported by the 
favorable safety profile of AL001 seen to date in both clinical and nonclinical studies; treatment 
duration of up to 1 year is supported based on preliminary safety data from the chronic 26-week 
repeat-dose study in cynomolgus monkeys, where no AL001-related findings have been 
observed, and based on the safety data from the FIH study (Study AL001-1). See the AL001 IB 
for additional information on clinical and nonclinical studies. 
1.5. 
Study Population 
The study population includes patients with aFTD-GRN, patients with FTD-GRN, and 
symptomatic carriers of C9orf72 hexanucleotide repeat expansion mutations causative of FTD 
(FTD-C9orf72). 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives and endpoints of this study are provided in Table 1 and Table 2. 
Table 1: 
Part 1 (Treatment Period): Study Objectives and Endpoints 
 
Objective(s) 
Endpoint(s) 
Primary 
The primary objective of the treatment period 
of the study is to evaluate the safety and 
tolerability of IV administration of AL001 over 
96 weeks in asymptomatic and symptomatic 
carriers of a GRN mutation causative of FTD 
and in symptomatic carriers of a C9orf72 
mutation causative of FTD. 
Primary Safety Endpoints: 
To assess the potential effect of cumulative exposure 
on the safety profile of AL001, the following will be 
evaluated by dose, such as by using tertiles of the 
actual dose (normalized to weight) received: 
• 
Incidence, nature, and severity of AEs and SAEs 
• 
Incidence of treatment discontinuations and 
study discontinuations due to AEs 
• 
Physical examination abnormalities 
• 
Neurological examination abnormalities 
• 
Changes in vital signs from baseline over time 
• 
Changes in ECGs from baseline over time 
• 
MRI abnormalities after dosing relative to 
baseline 
• 
Changes in clinical laboratory tests from 
baseline over time 
• 
Sheehan Suicidality Tracking Scale 
(Sheehan-STS) 
• 
Incidence of ADAs to AL001 
Secondary 
The secondary objectives of the treatment 
period of the study are to evaluate the effect of 
IV administration of AL001 over 96 weeks in 
asymptomatic and symptomatic carriers of a 
GRN mutation causative of FTD and in 
symptomatic carriers of a C9orf72 mutation 
causative of FTD on the following: 
 
Secondary PK Objective: 
• 
PK 
Secondary PK Endpoints: 
• 
Serum concentration of AL001 at specified time 
points 
• 
AL001 PK parameters (if data permit) 
o 
Cmax 
o 
Ctrough 
o 
AUCss 
Secondary PD Biomarker Objectives: 
• 
Longitudinal plasma and CSF PGRN 
concentration levels 
• 
Longitudinal levels of Sortilin in WBCs 
Secondary PD Biomarker Endpoints:  
• 
The overall change from baseline in PGRN in 
CSF 
• 
The overall change from baseline in PGRN in 
plasma 
• 
The overall change from baseline in Sortilin in 
WBCs plasma 


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Table 1: 
Part 1 (Treatment Period): Study Objectives and Endpoints (Continued) 
 
Objective(s) 
Endpoint(s) 
Exploratory 
The exploratory objectives of the treatment 
period of the study are to assess the effect of IV 
administration of AL001 over 96 weeks in 
asymptomatic and symptomatic carriers of a 
GRN mutation causative of FTD and in 
symptomatic carriers of a C9orf72 mutation 
causative of FTD on the following: 
 
 
Exploratory PD Biomarker Objectives: 
• 
Longitudinal blood, plasma, and CSF 
concentration levels of exploratory 
biomarkers of neurodegeneration, 
lysosomal function, and glial activity 
Exploratory PD Biomarker Endpoints: 
• 
The overall change from baseline in exploratory 
biomarkers of neurodegeneration, lysosomal 
function, and glial activity in blood, plasma, and 
CSF 
 
• 
MRI measures to evaluate changes in the 
brain 
• 
Global and regional brain MRI atrophy measures 
 
• 
Correlations among exploratory fluid PD 
biomarkers, imaging PD measures, and 
COAs 
• 
Correlations among exploratory fluid biomarkers, 
imaging measures, and COAs 
 
Exploratory Clinical Objectives: 
• 
Clinical progression as measured by COAs 
Exploratory Clinical Endpoints: 
The overall change from baseline on the scores of the 
instruments in the COAs  
• 
Clinical Dementia Rating Dementia Staging 
Instrument PLUS National Alzheimer’s Disease 
Coordinating Center Frontotemporal Lobar 
Degeneration Behavior and Language Domains 
(Clinical Dementia Rating (CDR®) plus NACC 
FTLD) 
• 
Frontotemporal Dementia Rating Scale (FRS) 
• 
Clinical Global Impression of Improvement 
(CGI-I) 
• 
Clinical Global Impression of Severity (CGI-S) 
• 
Color Trails Test (CTT) Part 2 
• 
Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS) 
• 
Winterlight Labs Speech Assessments (WLA; for 
participants who agree to participate in these 
optional assessments only) 
Abbreviations: ADA, anti-drug antibody; AE, adverse event; AUCss, area under the concentration-time curve at 
steady state; CDR® plus NACC FTLD, Clinical Dementia Rating Dementia Staging Instrument PLUS National 
Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains; 
CGI-I, Clinical Global Impression of Improvement; CGI-S, Clinical Global Impression of Severity; Cmax, maximum 
observed concentration; COA, clinical outcome assessment; CSF, cerebrospinal fluid; Ctrough, trough concentration; 
CTT, Color Trails Test; ECG, electrocardiogram; FRS, Frontotemporal Dementia Rating Scale; FTD, 
frontotemporal dementia; FTLD, frontotemporal lobar degeneration; GRN, granulin; IV, intravenous; MRI, 
magnetic resonance imaging; PD, pharmacodynamic; PGRN, progranulin; PK, pharmacokinetic; RBANS, 
Repeatable Battery for the Assessment of Neuropsychological Status; SAE, serious adverse event; WBC, white 
blood cell. 


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Table 2: 
Part 2 (Optional Open-Label Extension (OLE)): Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
The primary objective of the OLE 
period of the study is to assess the long-
term safety and tolerability of AL001 in 
participants who have completed 96 
weeks of treatment on Part 1 of the 
study. 
• 
Incidence, nature, and severity of AEs and SAEs 
• 
Incidence of treatment discontinuations and study 
discontinuations due to AEs 
• 
Physical examination abnormalities 
• 
Neurological examination abnormalities 
• 
Changes in vital signs from baseline over time 
• 
Changes in ECGs from baseline over time 
• 
MRI abnormalities after dosing relative to baseline 
• 
Changes in clinical laboratory tests from baseline 
over time 
• 
Sheehan-STS 
• 
Incidence of ADAs to AL001 
Exploratory 
COAs, correlative assessments (e.g., 
biomarker) and other efficacy 
assessments conducted during the OLE 
are considered exploratory. 
The exploratory objectives of the OLE 
period of the study are to assess the 
long-term effect of AL001 in 
participants who have completed 96 
weeks of treatment on Part 1 of the 
study on the following: 
 
 
• PK 
• 
Serum concentration of AL001 at specified time 
points  
• 
AL001 PK parameters (if data permit) 
o 
Cmax 
o 
Ctrough 
o 
AUCss 
 
• 
Longitudinal plasma and CSF 
PGRN concentration levels 
• 
Longitudinal blood, plasma, and 
CSF concentration levels of 
exploratory biomarkers of 
neurodegeneration, lysosomal 
function, and glial activity 
• 
The overall change from baseline in PGRN in 
plasma 
• 
The overall change from baseline in exploratory 
biomarkers of neurodegeneration, lysosomal 
function, and glial activity in blood, plasma, and 
CSF 
 
• 
Magnetic resonance imaging 
(MRI) measures to evaluate 
changes in the brain 
• 
Global and regional brain MRI atrophy measures 


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Table 2: 
Part 2 (Optional Open-Label Extension (OLE)): Objectives and Endpoints 
(Continued) 
 
Objectives 
Endpoints 
Exploratory 
(Cont.) 
• Correlations among exploratory 
fluid PD biomarkers, imaging PD 
measures, and clinical outcome 
assessments (COAs) 
• 
Correlations among exploratory fluid biomarkers, 
imaging measures, and COAs 
 
• Clinical progression as measured 
by COAs 
The overall change from baseline on the scores of the 
instruments in the COAs 
• 
 CDR® plus NACC FTLD 
• 
FRS 
• 
CGI-I 
• 
CGI-S 
• 
CTT Part 2 
• 
RBANS 
• 
Winterlight Labs Speech Assessments (for 
participants who agree to participate in these 
optional assessments only) 
Abbreviations: ADA, anti-drug antibody; AE, adverse event; AUCss, area under the concentration-time curve at 
steady state; Clinical Dementia Rating (CDR®) plus NACC FTLD, Clinical Dementia Rating Dementia Staging 
Instrument PLUS National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior 
and Language Domains; CGI-I, Clinical Global Impression of Improvement; CGI-S, Clinical Global Impression of 
Severity; Cmax, maximum observed concentration; COA, clinical outcome assessment; CSF, cerebrospinal fluid; 
Ctrough, trough concentration; CTT, Color Trails Test; ECG, electrocardiogram; FRS, Frontotemporal Dementia 
Rating Scale; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; GRN, granulin; IV, 
intravenous; MRI, magnetic resonance imaging; PD, pharmacodynamic; PGRN, progranulin; PK, pharmacokinetic; 
RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; SAE, serious adverse event. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This is a Phase 2, multicenter, open-label study evaluating the safety, tolerability, PK, PD, and 
effect on COAs of AL001 administered intravenously (60 mg/kg, q4w) in asymptomatic and 
symptomatic carriers of loss-of-function GRN mutations causative of FTD and in symptomatic 
carriers of C9orf72 hexanucleotide repeat expansion mutations causative of FTD. The study has 
two parts: A phase 2 open-label treatment period (Part 1), followed by an optional open-label 
extension (OLE) period (Part 2). 
Part 1 is a 96-week evaluation of the safety, tolerability, PK, PD, and clinical effect of AL001 
administered intravenously (60 mg/kg, every 4 weeks [q4w]), for a total of 25 doses (96-week 
dosing period), in asymptomatic and symptomatic carriers of loss-of-function GRN mutations 
causative of FTD, and in symptomatic carriers of C9orf72 hexanucleotide repeat expansion 
mutations causative of FTD. 
Part 2 is an optional OLE for eligible participants who have completed the 96-week Part 1 
treatment period. The OLE period will evaluate the long-term safety and tolerability of AL001 
administered at the same dose and regimen as Part 1 (60 mg/kg, q4w), for up to a total of 
25 doses (96-week optional OLE period). 
Part 1 (Treatment Period): 
Two cohorts will be enrolled in Part 1: a GRN Cohort and a C9orf72 Cohort. Both cohorts will 
enroll symptomatic participants with FTD; in addition, asymptomatic participants may enroll 
into the GRN Cohort, but only if they participated in the Phase 1 AL001-1 study (described in 
Section 1.2.2). Both asymptomatic and symptomatic carriers of a GRN mutation who 
participated in Study AL001-1 may enroll into the GRN Cohort if they completed dosing, the 
required follow-up portion of Study AL001-1 (further details are provided in Section 4.1.1), did 
not experience AEs that would indicate that continued dosing with AL001 would be unsafe, and 
meet the inclusion/exclusion criteria of Part 1of Study AL001-2. In addition, new participants 
who are symptomatic carriers of a GRN mutation will be enrolled into the GRN Cohort. In total, 
up to 20 participants will be enrolled into the GRN Cohort (asymptomatic and symptomatic 
participants). Up to 20 new symptomatic carriers of a C9orf72 hexanucleotide repeat expansion 
mutation will be enrolled into the C9orf72 Cohort. An overview of the study schema is presented 
in Figure 1. 
Symptomatic FTD participants may enroll in Part 1 of the study if they have either 1 or more of the 
6 behavioral/cognitive symptoms required for a diagnosis of possible bv FTD (Rascovsky 2011), 
or a diagnosis of PPA (Gorno-Tempini 2011). New symptomatic participants must also have a 
Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease 
Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains 
(Clinical Dementia Rating (CDR®) plus NACC FTLD) global score of 0.5, 1, or 2. 
Participants may be consented and screened up to 6 weeks prior to Day 1 to determine eligibility. 
All enrolled participants will undergo baseline evaluation with MRI, biofluid sampling for PD 


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biomarker measurement, lumbar puncture for CSF collection, safety assessments, and several 
COAs (Table 4). In Part 1, all participants will be administered open-label, IV AL001 at the 
investigational site (60 mg/kg, q4w) for 25 doses (over a 96-week dosing period). 
Evaluation of MRI, biofluid sampling for PK and PD biomarker measurements, lumbar puncture 
for CSF collection, and several COAs will occur during the treatment period (the full Schedules 
of Assessments is provided in Table 4 and Table 5).  
An independent Data Monitoring Committee (iDMC) will review safety data during the course 
of Part 1 of the study to provide recommendations to Alector on study conduct. The details of the 
iDMC are provided in Section 12.1. 
The primary objective of Part 1 of the study is to assess safety and tolerability of 96-week 
60 mg/kg q4w dosing of IV AL001. Secondary and exploratory objectives of Part 1 include 
evaluating the PK and the preliminary effect of AL001 on imaging and fluid PD biomarkers and 
COAs in asymptomatic and symptomatic participants. For PD biomarker evaluation, the aims are 
to evaluate increases in PGRN levels after repeated IV dosing of AL001 in the blood plasma and 
CSF of asymptomatic and symptomatic participants; to evaluate changes in PD biomarkers of 
neurodegeneration, lysosomal function, and glial activity; and to evaluate changes in imaging PD 
measures. 
Part 2 (Optional Open-Label Extension): 
Part 2 of the study is an optional 96-week, open-label extension to assess the long-term safety 
and tolerability of AL001 in participants who have completed 96 weeks of treatment on Part 1 of 
the study. 
Continuation in the OLE is optional for Part 1 participants. A Part 1 participant may be excluded 
from continuing in the Part 2 OLE if, in the opinion of the investigator, continued treatment with 
AL001 at the conclusion of Part 1 is not beneficial or safe for the participant. 
Participants who complete the 96-week Part 1 treatment period are eligible for continued 
treatment with AL001 in Part 2, provided they are able to give informed consent to continue 
treatment with AL001, are able to comply with the OLE requirements, and have a study partner 
who can continue to assist with assessments throughout the OLE evaluation period. Part 1 
participants who have been admitted to a nursing home/assisted living facility, who have 
CDR® plus NACC FTLD global score >2, are not eligible for participation in the Part 2 OLE. 
Continued study treatment in the optional OLE will be IV AL001 60 mg/kg, q4w (i.e., same dose 
and treatment regimen as in Part 1). An individual participant may continue to receive AL001 in 
the OLE portion of the study for up to 25 doses over a 96-week dosing period, or until AL001 is 
commercially available in the country where the participant is being treated, whichever is earlier. 
In the event that an individual's participation in the OLE will extend beyond 96 weeks because 
AL001 is not commercially available AL001 in their country, they may be eligible to continue to 
receive AL001 under another Alector protocol or program. 
Evaluation of MRI, biofluid sampling for PK and PD biomarker measurements, and several 
COAs will continue during the optional OLE (the full Schedules of Assessments is provided in 
Table 4 and Table 5).  


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Participants will be discontinued from the OLE in the event of long-term placement in a skilled 
nursing facility; a CDR® plus NACC FTLD global score >2; if, in the opinion of the investigator 
and Alector, they are unable to follow protocol procedures; or if they develop intercurrent illness 
that would confound the interpretation of safety and efficacy data. 
Figure 1: 
Overview of Study Schema 
 
Abbreviations: COA, clinical outcome assessment; CSF, cerebrospinal fluid; GRN, granulin; IV, intravenous; MRI, 
magnetic resonance imaging; PD, pharmacodynamic; q4w, every 4 weeks. 
r 
'-
I 
/' 
\.. 
'I 
r 
GRN Mutation Carriers Cohort N=20 
C9orl72 Mutation Carriers Cohort N=20 
Asymptomatic carriers from AL 001-1 
New symptomatic caniers 
Symptomatic can iers from ALO0 1-1 
New symptomatic caniers 
. . . . 
• 
• 
Patt 1: Screening 
(Within 6 weeks prior to Day I) 
• 
Part 1: Baseline & 96-Week Open-Label Treatment 
25 doses of60 mg/kg IV AL00I, q4w 
CO As at baseline and every 12 weeks after Day I 
Blood samples collection at Baseline and throughout the study 
CSF samples at Baseline and throughout the study 
Brain MRI at Baseline and evety 24 weeks after Day I 
Participants who complete 96-week 
Part 1 treatment period and do not 
continue to Part 2 (Optiona l OLE): 
Part 1: EOS Visit (at the scheduled 
Week 97 timepoint) 
Safety Follow-up 
/' 
\.. 
/ 
Participants who complete 96-week Part 1 
treatment pe1·iod and continue to Part 2 
(Optional OLE): 
Continuation from Week 97 to Week 101 
visit 
• 
Patt 2: 96-Week Optional OLE 
(10-week follow-up period after last dose) 
Perfonn final safety assessments 
. 
25 doses of 60 mg/kg IV AL00I, q4w 
CO As every 24 weeks 
. Blood sample collection evety 12 weeks 
. 
'-
Brain MRI evety 48 weeks • 
Part 2: EOS Visit (at the scheduled Week 
197 timepoint) 
• 
Safety Follow-up 
( 10-week follow-up period after last dose) 
Perfon n fmal safety assessments 
'I 
,J 
I 
" 
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" 


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3.2. 
Study Duration 
Part 1 (Treatment Period): 
• A screening period (within 6 weeks prior to Day 1). 
• A treatment period (96 weeks, Day 1 through Week 97). 
• Participants who discontinue study drug prior to completing the 96-week Part 1 
treatment period should be encouraged to complete all remaining scheduled 
assessment visits through Part 1 (including COAs, MRI, and CSF evaluations). 
− A Part 1 End of Treatment (EOT) visit will be completed by participants who 
discontinue study drug but remain in the study and continue to perform 
assessments. Part 1 EOT assessments should be completed as soon as possible 
after the decision is made. A Safety Follow-Up visit will be performed 10 weeks 
after their last study drug administration. The Safety Follow-up visit may be 
substituted by a scheduled visit if it occurs within the same window. 
− A Part 1 End of Study (EOS) visit will be completed by participants who 
discontinue study drug and all assessments. Part 1 EOS assessments should be 
completed as soon as possible after the decision is made. A Safety Follow-Up 
visit will be performed 10 weeks after their last study drug administration. 
• At Week 97, participants who complete the Part 1 96-week treatment period will have 
the option to continue to receive AL001 in Part 2 (OLE) of the study. 
− Participants who do not continue in Part 2 will complete a Part 1 EOS visit at the 
scheduled Week 97 timepoint. A Safety Follow-up visit will be performed 10-
weeks after their last study drug administration. 
− Participants who continue in Part 2 will complete the Week 97 visit and continue 
to Part 2 (Week 101). 
Part 2 (Open-Label Extension) 
• OLE eligibility confirmation (prior to Week 101 study drug administration). 
• A treatment period (96 weeks, Day 101 through Week 197), or until AL001 is 
commercially available in the country where the participant is being treated, 
whichever is earlier. 
• Participants who discontinue study drug and/or all assessments prior to completing 
the 96-week Part 2 treatment period will complete a Part 2 EOS visit as soon as 
possible after the decision is made. A Safety Follow-Up visit will be performed 10 
weeks after their last study drug administration. 
• At Week 197, participants who complete the Part 2 96-week OLE period will 
complete a Part 2 EOS visit at the scheduled Week 197 timepoint. A Safety Follow-
up visit will be performed 10-weeks after their last study drug administration. 


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3.3. 
Description of Study Periods 
3.3.1. 
Part 1 – Treatment Period 
Screening 
Participants may be consented and screened within 6 weeks prior to Day 1 to determine 
eligibility. 
Treatment Period and Follow-up Period 
The planned study treatment period will be a total of 96 weeks. AL001 60 mg/kg will be 
administered intravenously q4w for a total of 25 doses (up to and including Week 97). Cognitive 
and functional testing (Section 6.9), which may include input from the participant and study 
partner (study partner is described in Section 4.1.1), will be performed during screening and then 
every 12 weeks. Imaging will be performed during screening and then every 24 weeks. Lumbar 
puncture for CSF collection will be performed at screening and then every 24 weeks. Accepted 
windows for treatment, clinical assessments, and imaging are provided in the Schedules of 
Assessments (Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9). 
Every effort will be made to follow all enrolled participants for the full 96-week treatment 
period, irrespective of whether they discontinue study treatment. All participants will be 
followed for safety at 10 weeks after the last dose of AL001. 
Upon completion of the 96-week treatment period, participants who are eligible and provide 
consent will continue in Part 2 (Optional OLE) of the study (Continuation from Week 97 to 
Week 101). Participants who do not continue in Part 2 (Optional OLE) will return to the 
investigational site 10 weeks after their last dose of AL001 for final safety assessments. 
In this protocol (Study AL001-2), the term “study drug” refers to AL001. 
3.3.2. 
Part 2 – Optional OLE 
Eligibility Confirmation 
There is no Screening period for participants that opt-in to continue receiving AL001 in Part 2 
(Optional OLE) of the study. Participants who, after completing the 96-week treatment period in 
Part 1 (Week 97), and who provide informed consent to participate in Part 2 (optional OLE) and 
meet all the eligibility criteria for the OLE (prior to Week 101 study drug administration), may 
continue to receive their next regularly scheduled dose of AL001 according to the OLE 
administration schedule (continuation from Week 97 to Week 101). 
Treatment Period and Follow-Up Period 
The Part 2 OLE period will be up to 96 weeks. Study treatment (AL001 60 mg/kg) will be 
administered IV q4w for a total of up to 25 doses. Blood sampling for safety will be performed 
approximately every 12 weeks. Clinical outcome assessments, including those performed by the 
participant and their study partner, will be conducted approximately every 24 weeks. Imaging 
will be performed approximately every 48 weeks. 


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Participants who discontinue study treatment early (e.g., due to participant decision, withdrawal 
criteria, AL001 commercial availability in the country where the participant in being treated) will 
be followed for safety at 10 weeks after the last dose of AL001. 


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4. 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Part 1 Study Population 
Approximately 40 participants will be enrolled at approximately 13 investigational sites in North 
America and Europe. Two cohorts will be enrolled in Part 1 (Treatment Period): 
• GRN mutation Cohort (up to 20 asymptomatic and symptomatic participants), 
including: 
− All asymptomatic and symptomatic participants in Study AL001-1 may be 
enrolled. 
− New symptomatic GRN mutation carriers may be enrolled. 
• C9orf72 mutation Cohort (up to 20 new symptomatic participants). 
4.1.1. 
Inclusion Criteria – Part 1 (Treatment Period) 
Prospective participants must meet all of the following criteria during the pre-study evaluation in 
order to be eligible to enroll in the study: 
Part 1 (Treatment Period) Participant Category Inclusion Criteria: 
1. Prospective participant meets all of the following criteria specific to their applicable 
participant category: 
Participant Category 1: GRN Mutation Carriers, Symptomatic, from AL001-1 
• Completed Study AL001-1 through the Day 57 visit and did not experience AEs that 
the investigator deems would prevent safe participation in Study AL001-2. 
− All previous participants in the AL001-1 study must be rescreened and meet all 
inclusion/exclusion criteria applicable to this study. 
• Meets 1 or more of the 6 behavioral/cognitive symptoms required for a diagnosis of 
possible behavioral variant frontotemporal dementia (bvFTD; Rascovsky 2011), or 
has a diagnosis of PPA (Gorno-Tempini 2011). 
Participant Category 2: GRN Mutation Carriers, Asymptomatic, from AL001-1 
• Prospective participant completed Study AL001-1 through the Day 43 visit and did 
not experience AEs that the investigator deems would prevent safe participation in 
Study AL001-2. 
− All previous participants in the AL001-1 study must be rescreened and meet all 
inclusion/exclusion criteria applicable to this study. If a participant becomes 
symptomatic during or after Study AL001-1, they will be screened under 
Category 3 (symptomatic). 


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Participant Category 3: GRN Mutation Carriers, Symptomatic, New 
• Is a carrier of a loss-of-function GRN mutation causative of FTD and knows their 
mutation status. 
• Has a CDR® plus NACC FTLD global score of 0.5, 1, or 2; and 1 or more of the 
6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD 
(Rascovsky 2011), or a diagnosis of PPA (Gorno-Tempini 2011). 
Participant Category 4: C9orf72 Mutation Carriers, Symptomatic, New 
• Is a carrier of a hexanucleotide repeat expansion C9orf72 mutation causative of FTD 
and knows their mutation status. 
• Has a CDR® plus NACC FTLD global score of 0.5, 1, or 2; and 1 or more of the 
6 behavioral/cognitive symptoms required for a diagnosis of possible bvFTD 
(Rascovsky 2011), or a diagnosis of PPA (Gorno-Tempini 2011). 
Part 1 (Treatment Period) General Inclusion Criteria: 
2. 18 to 85 years of age, inclusive, at screening. 
3. At screening, female prospective participants must be nonpregnant and nonlactating, and 
at least one of the following conditions must apply: 
a. Not a woman of childbearing potential (WOCBP) (either surgically sterilized or 
physiologically incapable of becoming pregnant, or at least 1-year postmenopausal 
[amenorrhea duration of 12 consecutive months with no identified cause other than 
menopause]). 
b. Is a WOCBP and using an acceptable contraceptive method from screening until 
10 weeks after the last dose of study drug. Acceptable contraception is defined as 
using hormonal contraceptives or an intrauterine device combined with at least 1 of 
the following forms of contraception: a diaphragm or cervical cap, or a condom. In 
addition, total abstinence, in accordance with the lifestyle of the participant, is 
acceptable. 
c. A WOCBP must have a serum pregnancy test conducted at screening. Additional 
requirements for pregnancy testing during and after the final dose of study treatment 
are located in the Schedules of Assessments (Table 4, Table 5, Table 7, and Table 9). 
4. Male prospective participants, if not surgically sterilized, must agree to use acceptable 
contraception and not donate sperm from Day 1 until 10 weeks after the last dose of study 
drug. Acceptable contraception for the male participant when having sexual intercourse 
with a WOCBP who is not currently pregnant is defined as using a condom. In addition, 
WOCBP partners must use hormonal contraceptives (e.g. combined oral contraceptive 
pill) or an intrauterine device combined. In addition, total abstinence, if in accordance 
with the usual lifestyle of the prospective participant, is acceptable. Vasectomized male 
participants should have received medical assessment of surgical success. 
5. Agrees not to donate blood or blood products for transfusion for the duration of the study 
and for 1 year after final dose of study drug. 


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6. Is willing and has the ability to comply with the study protocol requirements, in the 
opinion of the investigator. 
7. Is willing and able to give informed consent. If the study participant is not competent, a 
legally authorized representative must provide informed consent on their behalf, and the 
participant must provide assent, in accordance with the local regulations, guidelines, and 
institutional review board (IRB) or independent ethics committee (IEC). 
8. Has availability of a person (“study partner”) who has frequent and sufficient contact 
with the participant (at least 5 hours per week of in-person contact), can provide accurate 
information regarding the participant’s cognitive and functional abilities as well as their 
health throughout the study, agrees to provide information at site visits that require 
partner input for COA completion, and signs the necessary consent form. (Note: 
asymptomatic participants require the study partner at the COA visits only; symptomatic 
participants require the study partner at each visit). 
• The study partner must have sufficient cognitive capacity to accurately report upon 
the participant’s behavior, cognitive, and functional abilities in the opinion of the 
investigator. The study partner should be in sufficiently good general health to have a 
high likelihood of maintaining the same level of interaction with the participant, and 
participation in study procedures throughout the study duration. 
• The same study partner should participate throughout the duration of Part 1 of the 
study. If a change in study partners during Part 1 is necessary, the Medical Monitor 
must be contacted. 
Part 1 (Treatment Period) – Inclusion criteria applicable to those UK, US, or Canadian 
participants participating in the optional Winterlight Labs Speech Assessment (WLA) only: 
1. Has available and willing study partner to administer the WLA. 
2. Has WiFi access in their residence or WiFi access in a private area where the testing can 
take place. 
3. US, UK, or Canadian participants and study partners must be proficient in English in the 
investigator’s opinion. 
4.1.2. 
Exclusion Criteria - Part 1 (Treatment Period) 
Prospective participants who meet any of the following criteria during the pre-study evaluation 
will be excluded from enrolling in the study: 
1. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, 
human, or humanized antibodies or fusion proteins. 
2.  History of substance use disorder (drug or alcohol) within 2 years prior to the first study 
drug administration, with the exception of nicotine, as defined by the Diagnostic and 
Statistical Manual of Mental Disorders, fifth edition criteria (American Psychiatric 
Association 2013). 


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3. Current acute illness or active infection requiring oral or IV antibiotics within 30 days 
prior to the first study drug administration that may affect safety assessments. 
4. History of surgery or hospitalization during the 30 days prior to first study drug 
administration. 
5. History of cancer within the last 5 years with the exception of basal cell or squamous cell 
carcinoma.  
6. History or presence of intracranial tumor that is clinically relevant (e.g., glioma, cerebral 
metastasis). 
7. Positive for hepatitis B surface antigen, hepatitis C virus antibodies, or human 
immunodeficiency virus-1 and -2 antibodies or antigen, or history of spirochetal infection 
of the CNS (e.g., syphilis or borreliosis). 
8. Significant kidney disease as indicated by a screening creatinine clearance <30 mL/min 
as calculated by the central laboratory using the Cockcroft-Gault formula, which remains 
<30 mL/min if retested. 
9. Impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) ≥2.5 × the upper limit of normal (ULN) or total bilirubin 
≥1.5 × ULN, which remains above either of these limits if retested or other abnormalities 
in synthetic function that are clinically significant. Note: Participants with Gilbert's 
syndrome are eligible to participate if approved by the Medical Monitor. 
10. Unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, 
angina pectoris, New York Heart Association Class III or more cardiac failure) within the 
last 2 years. 
11. Uncontrolled hypertension, defined as an average systolic blood pressure ≥150 mmHg or 
an average diastolic blood pressure ≥95 mmHg, in an individual with hypertension. 
12. History of or current abnormal ECG that is clinically significant, including atrial 
fibrillation, complete left bundle branch block, second- or third-degree atrioventricular 
block, or evidence of acute or subacute myocardial infarction or ischemia. 
13. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular 
hypertrophy) or clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia). Note: Participants with premature ventricular 
contractions are eligible to participate. 
14. Contraindication to lumbar dural puncture, including coagulopathy, concomitant 
anticoagulation (except for a platelet inhibitor such as aspirin), thrombocytopenia, or 
other factor that precludes safe lumbar puncture. 
15. Dementia or a milder, symptomatic syndrome (e.g., mild cognitive impairment, mild 
behavioral impairment, or mild motor impairment) due to a condition other than FTD, 


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including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia with 
Lewy bodies, Huntington disease, or vascular dementia. 
16. History or presence of clinically evident vascular disease potentially affecting the brain 
(e.g., clinically significant carotid or vertebral artery stenosis or plaque; cerebral 
hemorrhage or infarct greater than 1 cm3; 3 or more lacunar infarcts in any location); 
cerebral contusion; encephalomalacia; intracranial aneurysm; arteriovenous 
malformation; subdural hematoma; hydrocephalus; space occupying lesions (e.g., abscess 
or brain tumor such as meningioma) that has the potential to affect cognitive function; or 
intracranial tumor that is clinically relevant (e.g., glioma, cerebral metastasis). 
17. History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) CNS trauma. 
18. Prospective participant resides in a skilled nursing facility, convalescent home, or 
long-term care facility at screening and requires continuous nursing care (i.e., >3 
months). Participants from the Phase 1 study (AL001-1) who have since moved to one of 
these facilities and require continuous nursing care are not eligible to continue to this 
study (AL001-2). 
19. Unable to tolerate MRI procedures (e.g., due to anxiety or claustrophobia) or has a 
contraindication to MRI, including, but not limited to, the presence of pacemakers, 
aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, 
skin, or body that are not compatible with an MRI scan; or any other clinical history or 
examination finding that would pose a potential hazard in combination with MRI. 
20. Prospective participant has a medical condition or extenuating circumstance that, in the 
opinion of the investigator, might compromise his or her ability to comply with the 
protocol-required testing or procedures or compromise the participant's well-being, 
safety, or clinical interpretability. 
Part 1 (Treatment Period) – Medication-Related Exclusion Criteria: 
The following medications are prohibited for a prespecified duration prior to study start, as 
indicated, and during the entire period of study participation (participants who start these 
medications during the study may be withdrawn from study drug): 
21. Cannabinoids, benzodiazepines, and tricyclic antidepressants are prohibited, unless 
prescribed as a stable regimen for at least 30 days prior to study drug administration or 
used as premedication prior to lumbar puncture or MRI procedures; however, use is not 
permitted within 8 hours before any COA. 
22. Any stimulant medication (e.g., amphetamine, dextroamphetamine, dexmethylphenidate, 
lisdexamfetamine, methylphenidate) is prohibited unless prescribed as a stable regimen 
for at least 90 days prior to study drug administration. 
23. Any passive immunotherapy (immunoglobulin) or other long-acting biologic agent that is 
under evaluation to prevent or postpone cognitive decline within 1 year of screening 
(participation in Study AL001-1 does not apply to this criterion). 


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24. Any experimental vaccine or gene therapy; routinely recommended vaccinations are 
allowed as well as any vaccine against SARS-CoV-2 administered under an Emergency 
Use Authorization. 
25. A drug from a clinical study (other than AL001-1) within 30 days prior to drug 
administration in the current study (study drug administration); use of any experimental 
oral therapy within 30 days or 5 half-lives prior to study drug administration, whichever 
is greater; use of any biologic therapy within 90 days or 5 half-lives prior to study drug 
administration, whichever is greater; or any other investigational treatment within 
5 half-lives or 90 days prior to study drug administration, whichever is longer. 
26. Typical antipsychotic or neuroleptic medication within 6 months of study drug 
administration except as brief treatment for a nonpsychiatric indication (e.g., emesis). 
a. Use of atypical antipsychotic medications or use of pimavanserin is allowed if treated 
with a stable regimen for at least 90 days prior to study drug administration. 
27. Anti-coagulation (e.g., coumadin, heparinoids, apixaban) medications within 90 days of 
study drug administration. Note: Use of aspirin or antiplatelet medication is allowed. 
28. Systemic immunosuppressive therapy or anticipated to be needed during the study. 
a. Use of prednisone of ≤10 mg/day or an equivalent corticosteroid is allowed if stable 
for at least 90 days prior to study drug administration and hemoglobin >9 g/dL, white 
blood cell (WBC) count >3000/mm3, absolute neutrophil count >1500 /mm3, and 
platelet count >100 000/mm3. 
29. Chronic use of opiates or opioids (including long-acting opioid medication) within 90 
days of study drug administration. 
a. Intermittent short-term use (<1 week) of short-acting opioid medications for pain is 
permitted except within 2 days or 5 half-lives (whichever is longer) prior to any 
COA.  
30. Chronic use of barbiturates, or hypnotics from 90 days prior to study drug administration. 
a. Intermittent short-term (<1 week) use of buspirone or short-acting hypnotic 
medication for sleep or anxiety is allowed except within 2 days or 5 half-lives 
(whichever is longer) prior to any clinical outcome assessment. 
Part 1 (Treatment Period) – Exclusion criteria applicable to those US, UK, or Canadian 
participants participating in the optional WLA only: 
1. Has clinically significant vision impairment (corrected vision is acceptable). 
2. Has clinically significant hearing impairment (use of hearing aids is acceptable). 
4.2. 
Part 2 Study Population 
Up to approximately 40 participants from Part 1 of the study will be eligible to enroll in Part 2 of 
the study (Optional OLE). Enrollment in Part 2 is optional for the participant, and at the 
discretion of the investigator. 


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4.2.1. 
Inclusion Criteria - Part 2 (Optional OLE)  
The OLE is optional for participants who complete Part 1 of the study. Participants who 
complete Week 97 of Part 1 of the study are eligible for continued treatment with AL001, 
provided that all of the following criteria are met: 
1. Participant is willing and able to give informed consent to continue treatment with 
AL001. If the study participant is not competent, a legally authorized representative must 
provide informed consent on their behalf, and the participant must provide assent, in 
accordance with the local regulations, guidelines, and institutional review board (IRB) or 
independent ethics committee (IEC). 
2. Is willing and has the ability to comply with OLE requirements, in the opinion of the 
investigator. 
3. Has availability of a person (“study partner”) who can continue to assist with assessments 
throughout the OLE evaluation period. The study partner must have frequent and 
sufficient contact with the participant (at least 5 hours per week of in-person contact), 
have the ability to provide accurate information regarding the participant’s cognitive and 
functional abilities as well as their health throughout the study, agree to provide 
information at site visits that require partner input for COA completion, and sign the 
necessary consent form. (Note: asymptomatic participants require the study partner at the 
COA visits only; symptomatic participants require the study partner at each visit). 
• The study partner must have sufficient cognitive capacity to accurately report upon 
the participant’s behavior, cognitive, and functional abilities. The study partner 
should be in sufficiently good general health to have a high likelihood of maintaining 
the same level of interaction with the participant, and participation in study 
procedures throughout the study duration. 
• The Part 2 study partner can be the same individual as in Part 1, or it can be a 
different individual, but the same Part 2 study partner should participate throughout 
the duration of Part 2. If a change in study partner during Part 2 is necessary, the 
Medical Monitor must be contacted. 
4.2.2. 
Exclusion Criteria - Part 2 (Optional OLE) 
Part 1 participants are not eligible for continued treatment with AL001 OLE if any of the 
following apply: 
1. Part 1 participant has been admitted to a skilled nursing facility, convalescent home, or 
long-term care facility at screening and requires continuous nursing care (i.e., >3 
months). 
2. Part 1 participant has a CDR® plus NACC FTLD global score >2 during Part 1. 
3. Part 1 participant has a medical condition or extenuating circumstance that, in the opinion 
of the investigator, continued treatment with AL001 at the conclusion of Part 1 is not 
beneficial or safe for the participant. 


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4.3. 
Withdrawal of Participants from Study Drug and/or the Study 
The duration of the study is defined for each participant as the date signed written informed 
consent is provided through the End of Study Visit (Part 1 or Part 2)/Safety Follow-up Visit, 
whichever is later. A Study Discontinuation section of the electronic case report form (eCRF) 
must be completed for all enrolled participants only. 
4.3.1. 
Part 1 (Treatment Period) 
4.3.1.1. 
Withdrawal from Study Drug (Part1) 
A participant may be discontinued from study drug at any time if the participant or the 
investigator feels that it is not in the participant’s best interest to continue. The following is a list 
of possible reasons for study drug discontinuation: 
1. Participant is noncompliant with the protocol 
2. Participant is lost to follow-up 
3. Participant withdraws consent 
4. Participant has a serious or intolerable AE that, in the investigator’ opinion, requires 
withdrawal from the study drug 
5. Serum aminotransferase levels (ALT or AST) >3 × ULN AND total bilirubin >2 × ULN 
without an alternative explanation 
6. Anaphylaxis 
7. Infusion-related or injection-related reaction despite adequate premedication for an initial 
occurrence of a moderate to severe infusion-related reaction (Section 5.1.2) or if the 
participant experiences any of the following events: mucosal tissue involvement, airway 
compromise, or symptomatic hypotension with systolic blood pressure <90 mm Hg 
measured in the supine position 
8. Occurrence of an intercurrent illness that, in the investigator’s opinion, will affect 
assessments of clinical status or safety to a significant degree 
9. Use of a nonpermitted concomitant medication per Section 4.1.2 (as appropriate) 
10. Pregnancy 
11. Discretion of the investigator 
If a participant is withdrawn from study drug due to an AE or SAE, the participant will be 
followed up by the investigator until the abnormal parameter or symptom has resolved or 
stabilized (if applicable). The investigator has the responsibility for all decisions regarding 
participant safety. It is recommended that the investigator consult with the Medical Monitor prior 
to removing the participant from study drug for any reason except participant withdrawal of 
consent and in case of medical emergency. If a participant is discontinued because of an AE or 
SAE, the event will be followed up until it is resolved. Any participant may withdraw his or her 
consent at any time. 


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All participants who discontinue study drug prior to the completion of the Part 1 96-week 
treatment period should be encouraged to complete all remaining scheduled assessment visits 
through the Part 1 treatment period (Week 97). Study staff will follow-up to aid in this goal. 
The reason for the participant’s early discontinuation of study drug will be specified in the 
participant’s source documents and on the eCRF. A Part 1 End of Treatment (EOT) visit will be 
completed by participants who discontinue the study drug but remain in the study and continue 
to perform assessments. Part 1 EOT assessments should be completed as soon as possible after 
the decision is made. A Safety Follow-Up visit will be performed 10 weeks after their last study 
drug administration. The Safety Follow-up visit may be substituted by a scheduled visit if it 
occurs within the same window. 
4.3.2. 
Withdrawal From Study (Part 1) 
A participant may be discontinued from the study (including study drug and all assessments) at 
any time if the participant or the investigator feels that it is not in the participant’s best interest to 
continue. The following is a list of possible reasons for study discontinuation: 
1. Participant withdrawal of consent 
2. Lost to follow-up 
3. Discretion of the investigator 
4. Administrative or other reasons (e.g., premature termination of the study by Alector) 
All Part 1 participants who discontinue the study drug and all assessments prior to the scheduled 
Week 97 visit should be encouraged to return to the site for a Part 1 EOS visit. Part 1 EOS 
assessments should be completed as soon as possible after the decision is made. A Safety 
Follow-Up visit will be performed 10 weeks after the participant’s last study drug administration. 
Reasonable attempts will be made by the investigator to obtain reasons for participant 
withdrawals (e.g., 2 documented telephone calls on different days, followed by 1 registered 
letter). The reason for the participant’s withdrawal from the study will be specified in the 
participant’s source documents and in the eCRF. 
4.4. 
Part 2 (Optional OLE) 
4.4.1. 
Criteria for Withdrawal of Participants in Part 2 
A participant may be discontinued from Part 2 of the study (including study drug and all 
assessments) at any time if the participant or the investigator feels that it is not in the 
participant’s best interest to continue. The following is a list of possible reasons for Part 2 study 
discontinuation: 
1. Long-term placement in a skilled nursing convalescent home, or long-term care facility at 
screening and requires continuous nursing care. (i.e., >3 months) 
2. If, in the opinion of the investigator and Alector, they are unable to follow protocol 
procedures 


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3. If they develop intercurrent illness that would confound the interpretation of safety and 
efficacy data 
4. CDR® plus NACC FTLD global score >2 during Part 2 
5. AL001 is commercially available in the country where the participant is being treated 
6. Participant withdrawal of consent  
7. Lost to follow-up 
8. Discretion of the investigator 
9. Administrative or other reasons (e.g., premature termination of the study by Alector) 
10. Participant is noncompliant with the protocol 
11. Participant has a serious or intolerable AE that, in the investigator’ opinion, requires 
withdrawal from the study drug 
12. Serum aminotransferase levels (ALT or AST) >3 × ULN AND total bilirubin >2 × ULN 
without an alternative explanation 
13. Anaphylaxis 
14. Infusion-related or injection-related reaction despite adequate premedication for an initial 
occurrence of a moderate to severe infusion-related reaction (Section 5.1.2) or if the 
participant experiences any of the following events: mucosal tissue involvement, airway 
compromise, or symptomatic hypotension with systolic blood pressure <90 mm Hg 
measured in the supine position 
15. Occurrence of an intercurrent illness that, in the investigator’s opinion, will affect 
assessments of clinical status or safety to a significant degree 
16. Use of a nonpermitted concomitant medication per Section 4.1.2 (as appropriate) 
17. Pregnancy 
All Part 2 participants who discontinue the study drug and/or all assessments prior to the 
scheduled Week 197 visit should be encouraged to return to the site for a Part 2 EOS visit. Part 2 
EOS assessments should be completed as soon as possible after the decision is made. A Safety 
Follow-Up visit will be performed 10 weeks after the participant’s last study drug administration. 
Reasonable attempts will be made by the investigator to obtain reasons for participant 
withdrawals (e.g., 2 documented telephone calls on different days, followed by 1 registered 
letter). The reason for the participant’s withdrawal from the study will be specified in the 
participant’s source documents and in the eCRF. 
4.5. 
Replacements (Part 1 Only) 
Participants who do not meet all eligibility criteria at screening or who qualify at screening but 
are not enrolled within the screening period may be reconsented, assigned a new screening 
number, and rescreened (see Section 6.2). 


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Participants who withdraw from the study may be replaced at the discretion of Alector and in 
consultation with the investigator. 
Note: the optional OLE (Part 2 of the study) is open to any eligible participant from Part 1; thus, 
replacing participants who leave the OLE is not applicable. 


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5. 
STUDY TREATMENTS 
This is an open-label study; all participants will receive AL001 (Part 1 treatment period and Part 
2 optional OLE).  
Each participant who provides informed consent will be assigned a screening number that 
uniquely identifies the participant. It is the responsibility of the investigator to ensure each 
participant is eligible for the study prior to enrollment. Participants who complete Part 1 will 
retain their unique screening number if they participate in Part 2. Alector will maintain a central 
screening log and utilize an electronic data capture (EDC) and Interactive Response Technology 
(IRT) systems to implement enrollment, to assess current inventories of AL001, to initiate 
necessary resupply of drug and to document discontinuation of drug. 
5.1. 
Treatments Administered 
Part 1(Treatment Period) 
All participants will receive AL001 (60 mg/kg IV) on Day 1, and then q4w for a total of 25 doses 
over a 96-week period. 
Part 2 (Optional OLE) 
Participants in the OLE will receive AL001 60 mg/kg IV q4w. An individual participant may 
continue to receive AL001 on the OLE portion of the study for up to 25 doses over a 96-week 
dosing period, or until commercial availability of AL001 in the country where the participant is 
being treated, whichever is earlier. 
5.1.1. 
Administration Instructions 
AL001 will be administered intravenously over approximately 60 minutes at the investigational 
site by study-trained clinic staff under the supervision of the investigator or their designee, or by 
a home health service, as applicable (See Appendix 3). Dosing solution preparation instructions 
will be provided separately in a Pharmacy Manual. 
Documentation of study drug administration will be recorded in the source documentation and 
documented in the eCRF. 
The investigator is responsible for the education of study staff in the correct administration of the 
study drug. 
Participants will be monitored for at least 60 minutes after the end of infusion (Section 5.1.2) and 
completion of all activities scheduled for that visit day and discharged at the discretion of the 
investigator. 
5.1.2. 
Infusion-Related and Injection-Related Reactions 
All participants will be monitored for infusion-related reactions or injection-related reactions 
during the infusion/injection and immediately afterwards for at least 60 minutes. 
Injection-related reactions can be localized at the site of the injection or systemic and should be 
treated per institutional guidelines. If a participant experiences a mild infusion-related reaction, 


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the infusion should be halted. Once the reaction has resolved, the infusion rate will be resumed at 
half the most recently used rate (e.g., from 60 mL/hr [1.0 mL/min] to 30 mL/hr [0.5 mL/min]). 
The infusion should be stopped immediately for any participant who experiences a moderate to 
severe infusion-related reaction (e.g., fever or chills), and the participant should receive 
aggressive symptomatic treatment. The infusion should not be restarted before all symptoms 
have disappeared, and then it should be restarted at half of the initial rate. The infusion should 
not be resumed if there is a second occurrence or if the participant experiences any of the 
following events: mucosal tissue involvement, airway compromise, or symptomatic hypotension 
with systolic blood pressure <90 mm Hg measured in the supine position. 
In addition, in the event of an infusion-related reaction, a sample of blood should be obtained for 
PK serum and ADA assessment of AL001, and testing should be performed for C-reactive 
protein, tryptase, and Interleukin 6 (IL-6). Further details regarding infusion-related reactions are 
provided in the IB. 
5.2. 
Identity of Investigational Product 
5.2.1. 
Study Drug Formulation 
The study drug (AL001) is provided as a liquid solution formulated at a concentration of 
50 mg/mL in an aqueous solution containing AL001 (human recombinant anti-human Sortilin 
IgG1 monoclonal antibody) in 20 mM histidine / histidine HCL, 7.5% (w/v) sucrose and 0.02% 
(w/v) polysorbate-80 at pH 5.5. 
5.2.2. 
Study Drug Packaging and Labeling 
The container closure system for AL001 study drug consists of a 20R Type I (EP-compliant) 
clear glass vial, with a coated bromobutyl rubber stopper and an aluminum crimp seal with blue 
flip-off cap. Each single-use vial will contain at least 0 mL of a 0 mg/mL solution of AL001 
study drug. 
AL001 will be labeled to meet applicable requirements of the Food and Drug Administration 
(FDA) as well as the EU Guideline for Good Manufacturing Practice for Investigational 
Medicinal Products (Annex 13), and other local requirements. 
5.3. 
Management of Clinical Supplies 
Specific instructions about the storage, preparation, and administration of AL001 are provided in 
the Pharmacy Manual. Additional information about AL001 is provided in the IB and on the 
Certificate of Analysis. 
5.3.1. 
Study Drug Supply 
Alector will supply AL001 to the investigational sites, as detailed in the Pharmacy Manual. 
5.3.2. 
Study Drug Storage 
Study drug will be shipped at a temperature of 2°C to 8°C. 


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Upon receipt at the investigational site, the study drug shall be stored securely under controlled 
conditions until use, in a refrigerator, set to maintain 2°C to 8°C. From preparation of dosing 
solution to administration at the investigational site, dosing solution storage time will be limited 
to 4 hours at ambient temperature and no more than 24 hours at 2°C to 8°C. 
The investigators will be fully responsible for the security, accessibility, and storage of the study 
drug while they are at their investigational facility. 
5.3.3. 
Study Drug Accountability 
The investigational site will maintain accurate records of receipt of all study drug, including 
dates and condition of receipt. In addition, accurate records will be kept (including the initials of 
the person dispensing the study drug) regarding when and how much study drug is dispensed and 
used by each participant in the study. Reasons for departure from the expected dispensing 
regimen must also be recorded. At the completion of the study, to satisfy regulatory requirements 
regarding drug accountability, all study drug will be reconciled and retained or destroyed 
according to applicable regulations. 
5.3.4. 
Study Drug Return or Disposal 
Study product supplies, including partially used or empty vials, should be disposed of at the site 
per local standard operating procedures. If study product supplies cannot be destroyed on-site, 
they may be shipped back to the return depot. Please see Pharmacy Manual for additional 
instructions. 
5.4. 
Misuse for Illegal Uses 
AL001 is supplied for use only in this clinical study and should not be used for any other 
purpose. 
5.5. 
Blinding 
This is an open-label study where all participants will receive AL001, and doses are not 
concealed; blinding, therefore, is not required. 
5.6. 
Prior and Concomitant Therapy 
All concomitant medications used by a participant from informed consent through the Part 1/Part 
2 EOS or Safety Follow-up visit, whichever is later, will be recorded in the participant’s eCRF 
and coded using the World Health Organization Drug Dictionary (WHO-DD), March 2019 or 
later. The minimum requirement is that drug name, total daily dose, route, frequency of dosing, 
indicated use, and the dates of administration are to be recorded. This will include all 
prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-
the-counter medications. Any changes in concomitant medications also will be recorded in the 
participant’s eCRF. 
During the course of the study, participants are anticipated to continue the use of accepted 
prescribed medications identified during the screening procedures, in accordance with study 


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inclusion and exclusion criteria. Participants should be advised against taking any new 
medication, both prescribed or over-the-counter, without consulting the investigator, unless the 
new medication is required for emergency use. 
Any concomitant medication deemed necessary for the welfare of the participant during the 
study may be given at the discretion of the investigator. However, it is the responsibility of the 
investigator to ensure that details regarding the medication are recorded in full in the eCRF.  
Any restricted medication must have been stopped as required by the study inclusion and 
exclusion criterion (Section 4.1.1 and Section 4.1.2, respectively); participants who start these 
medications during the study may be withdrawn from study drug at the discretion of the Medical 
Monitor. 


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6. 
STUDY ASSESSMENTS AND PROCEDURES 
Before performing any study procedures, all potential participants and study partners will sign an 
informed consent form (ICF). If the study participant is not competent, a legally authorized 
representative must provide informed consent on their behalf, and the participant must provide 
assent, in accordance with the local regulations, guidelines, and IRB/IEC. Participants and study 
partners will have the opportunity to have any questions answered before signing the ICF. The 
investigator must address all questions raised by the participants. The investigator or designee 
will also sign the ICF. Further details of informed consent are provided in Section 10.3. 
Timing and frequency of all assessments and procedures for Part 1 are presented in the 
Schedules of Assessments (Table 4,Table 5) and Schedule of PK, Immunogenicity, and PD 
Biomarker Sample and Imaging Assessments (Table 6).Timing and frequency of all assessments 
and procedures for Part 2 are presented in the Schedules of Assessments (Table 7 and Table 8) 
and Schedule of PK, Immunogenicity, and PD Biomarker Sample and Imaging Assessments 
(Table 9). Asymptomatic participants require the study partner at the COA visits only; 
symptomatic participants require the study partner at each visit. 
Adaptations to visits and procedures under the exceptional circumstance of COVID-19 pandemic 
are detailed in Appendix 3. 
6.1. 
Timing of Study Drug Administration 
Pre-dose Study Procedures and Assessments: 
• Perform COAs prior to any potentially stressful procedure (e.g., blood collections, 
lumbar punctures, imaging) 
• PE, or limited or symptom-directed examination 
• Neurological examination, or limited or symptom-directed examination 
• Vital signs and weight, including blood pressure (BP), pulse, body temperature, and 
respiratory rate 
• Triplicate 12-lead ECG 
• Obtain blood and urine samples for chemistry, hematology, coagulation, serology, 
pregnancy testing, and urinalysis. 
• Obtain blood samples for ADAs 
• Obtain blood samples for PK and PD 
• Obtain blood sample for whole genome sequencing (WGS) (Part 1 only) 
• Collect CSF samples via lumbar puncture for PK and PD (Part 1 only) 
• Perform MRI 
• Perform Sheehan Suicidality Tracking Scale (Sheehan-STS) 
• Review of concomitant medication(s) 


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• Record any AEs and SAEs 
Dosing Procedures: 
• AL001 will be administered to participants per institutional practice (Section 5.1). 
Post-dose Procedures: 
• Obtain serum samples for PK 
• Triplicate 12-lead ECG 
• Vital signs, including BP, pulse, body temperature, and respiratory rate 
• Review of concomitant medication(s) 
• Record any AEs and SAEs 
6.2. 
Rescreening Criteria 
Part 1 participants who are not enrolled within the screening period will be screen failed. 
Rescreening may be allowed after approval from the Medical Monitor. Participants who rescreen 
after the screening period must be reconsented with a new screening number, and the screening 
assessments must be repeated. The participant may not be required to repeat the MRI imaging or 
CSF screening assessment, if performed within 3 months prior to screening. Clinical outcome 
assessments performed within 8 weeks prior to screening may not be required to be repeated 
after approval from the Medical Monitor. 
Those aFTD-GRN and FTD-GRN participants who have completed Study AL001-1 (described in 
Section 1.2.2) may enroll in this study. Participants must be rescreened after completion of 
Study AL001-1 and meet all inclusion/exclusion criteria applicable to this study. The participant 
may not be required to repeat the imaging (MRI) or CSF baseline assessment if performed within 
3 months prior to screening. The participant may not be required to repeat the safety and 
tolerability assessments, if performed within 6 weeks prior to screening. 
All participants are not required to report WGS results, and there is no time restriction for 
reporting. 
Rescreening is not applicable for Part 2 of the study. 
6.3. 
Sample Collections 
Specific information on clinical laboratory, ADAs, PK, PD, exploratory PD biomarker, and 
WGS sample collection, processing, storage, and shipment will be provided in separate manuals. 
Unused portions of PK, PD, and/or exploratory PD biomarker samples remaining after all 
applicable protocol-defined tests have been performed may be retained and maintained, for up to 
10 years, if the participant agrees and provides consent separately as described in Section 10.3. 
These samples may be used for future testing not described in this protocol. 
For participants who have provided consent, the samples may be used for testing including the 
following: further evaluation of PD biomarkers (e.g., associated with efficacy, AEs, or disease 


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progression), further clarification or characterization of the disease, further evaluation of the 
study drug’s effects, and/or development of assays (e.g., PD biomarker or diagnostic assays). 
6.4. 
Cerebrospinal Fluid Sampling 
Cerebrospinal fluid samples will be collected in Part 1 only via lumbar puncture prior to study 
drug administration (if applicable) at Screening, Week 25, Week 49, and Week 97 (or the Part 1 
EOT/EOS Visit) to evaluate PK, PD, and exploratory PD biomarker measures. The Week 25 
lumbar puncture may be adjusted as determined by Alector’s review of exploratory PD 
biomarkers. 
Specific information on the collection, processing, storage, and shipment of CSF samples will be 
provided in a separate manual. 
6.5. 
Safety and Tolerability Assessments 
Safety and tolerability assessments include monitoring AEs; PEs; neurological examinations; 
vital signs and weight; ECGs; clinical laboratory analyses in blood and urine; MRIs; 
Sheehan-STS; and ADAs. 
6.5.1. 
Adverse Events 
All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur 
after the participant signs informed consent and through the Part 1/Part 2 EOS or Safety Follow-
up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through 
satisfactory clinical resolution. Additionally, SAEs considered related to study drug which occur 
at any time should be reported by the investigator regardless of the AE/SAE collection window. 
Definitions describing what is and is not considered an AE are provided in Section 7.1. 
6.5.2. 
Concomitant Medications 
All medication history and use of concomitant medications will be collected and recorded in the 
eCRF as detailed in Section 5.6. 
6.5.3. 
Demographics 
Demographic information (year of birth, age, sex, race, ethnicity) will be recorded at screening, 
unless disallowed by local regulatory agencies. 
For US, UK, and Canadian participants who will be performing the optional WLA, additional 
demographic information will be collected (ethnicity, number of years of education, first 
language, when they learned English [if English is not their first language], how long they have 
been speaking English consistently [if English is not their first language], country of birth, and 
year of immigration to Canada/United States/United Kingdom [if applicable]). 
Alector is collaborating with the GENFI study, a group of research centers across Europe and 
Canada with expertise in familial FTD, and the ARTFL LEFFTDS Longitudinal Frontotemporal 
Lobar Degeneration (AllFTD) study, a study in the United States and Canada targeting most 
varieties of frontotemporal lobar degeneration (FTLD). As part of the GENFI and AllFTD 


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studies, all clinical trial participants will have the option of having a National Institute on Aging 
(NIA) Global Unique Identifier (GUID) generated. The GUID is a secure, random alphanumeric 
identifier. It can be used to match participants across studies and datasets without disclosing 
participants’ Personal Identifying Information or Personal Health Information. The purpose of 
this GUID is to allow for the sharing of deidentified data and biospecimens between sponsors 
and GENFI and AllFTD. 
For AL001-2 study participants who are also participating in the GENFI or AllFTD, they will 
have the option to have their NIA GUID collected by the investigational site personnel and 
recorded in the AL001-2 EDC system. For AL001-2 study participants who are not participating 
in GENFI or AllFTD, they will have the option for the investigational site personnel to assign a 
NIA GUID and recorded it in the AL001-2 EDC system. 
6.5.4. 
Medical History 
All relevant medical history, including history of current disease, other pertinent history, and 
information regarding underlying diseases will be recorded at screening prior to study drug 
administration in the eCRF. 
A diagnostic characterization form will be completed in an EDC system for symptomatic 
participants only at screening, week 97 and week 197 (if applicable for symptomatic participants 
in the optional Part 2 OLE). It will also be completed for any asymptomatic participant who 
becomes symptomatic during the course of the study; for these participants, the diagnostic 
characterization form will be completed only at the first visit in which they exhibit clinical 
symptomatology and at all remaining study timepoints. 
6.5.5. 
Physical Examinations 
A complete PE includes evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, and gastrointestinal systems. 
Breast, genital, and rectal examinations are not required, unless warranted in the opinion of the 
health care provider. Limited examinations should include cardiovascular, respiratory, and 
gastrointestinal systems. Symptom‑directed PEs may also include any other pertinent system as 
required. The examination will be performed by a physician or by a nurse practitioner or 
physician’s assistant under the supervision of a physician. 
Complete or limited or symptom-directed examinations will be performed at time points 
indicated in the Schedule of Assessments. For visits with study drug administration, this should 
be completed prior to the study drug infusion. Additional examinations may be completed as 
clinically indicated. 
Record abnormalities observed at screening on the General Medical History and Baseline 
Conditions page of the eCRF. At subsequent visits, record new or worsened clinically significant 
abnormalities on the AE eCRF. 
Height (cm) will be measured at screening. 


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6.5.6. 
Neurological Examinations 
A complete neurologic examination should include the evaluation of consciousness, orientation, 
cranial nerves, motor and sensory system, coordination and gait, and reflexes. Limited or 
symptom-directed examinations will be performed at all other specified time points. A symptom-
directed neurological examination should focus on the affected organ system or body area. 
For visits with study drug administration, this should be completed prior to study drug infusion. 
Additional examinations may be completed as clinically indicated. 
Record abnormalities observed at screening on the General Medical History and Baseline 
Conditions page of the eCRF. At subsequent visits, record new or worsened clinically significant 
abnormalities as AEs on the AE eCRF. 
6.5.7. 
Vital Signs and Weight 
Supine systolic and diastolic BP, pulse, body temperature, and respiratory rate will be recorded 
after the participant has been resting for ≥5 minutes in the supine position. 
Pulse rate, BP, body temperature, and respiratory rate should be obtained per institutional 
practices. 
Record abnormalities observed at screening on the General Medical History and Baseline 
Conditions eCRF. At subsequent visits, record new or worsened clinically significant 
abnormalities on the AE eCRF. 
Weight (kg) will be collected at the same visits that vital signs are taken. 
6.5.8. 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for 
≥5 minutes.  
Additional ECG monitoring must be performed during the treatment period if clinically 
indicated. 
All ECGs will be analyzed from a clinical safety basis (without intensive QT analysis). The 
clinical significance of ECG changes will be determined by the investigator after review of the 
ECG report in relation to the participant’s medical history, PE, and concomitant medications and 
documented in the eCRF.  
6.5.9. 
Laboratory Assessments 
Blood and urine samples that will be collected for clinical safety laboratory tests (chemistry, 
coagulation, hematology, urinalysis, serology, and pregnancy testing) are indicated in Table 3. 
For any laboratory test value outside the reference range that the investigator considers clinically 
significant, the investigator will follow the instructions in Section 7.3. 
Laboratory assessment analysis will be performed at a central laboratory, with the exception of 
urine pregnancy testing or medically indicated emergency laboratory tests which will be done at 
local laboratories. 


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Table 3: 
Laboratory Assessments 
Chemistry 
Coagulation 
Hematology 
Serology 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
gammaGT 
AST 
ALT 
LDH 
Creatine kinase 
Creatinine a 
Urea 
Uric acid 
Cholesterol 
HDL 
LDL 
Triglycerides 
Total protein 
Albumin 
Glucose 
Bicarbonate 
Inorganic phosphate 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Lipase 
Apolipoprotein B100 
PT 
INR 
aPTT 
HbA1c  
Leukocytes 
Erythrocytes 
Hemoglobin 
Hematocrit 
Thrombocytes (platelets) 
MCV 
MCH 
MCHC 
 
Partial automated 
differentiation: 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Neutrophils b 
ANC b 
anti-HCV 
anti-HIV  
HIV antigen 
HBsAg 
Total hepatitis B core 
antibody 
Urinalysis 
Pregnancy Test 
Hemoglobin (blood urine) 
Ketones 
Glucose 
Protein 
Leukocyte esterase 
Nitrite 
pH 
Specific gravity 
Microscopic analysis d (sediment, erythrocytes, leukocytes, 
casts, crystals, epithelial cells, and bacteria) 
Serum β-hCG or urine 
pregnancy test c 
Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; aPTT, activated partial 
thromboplastin time; AST, aspartate aminotransferase; β-hCG, β-human chorionic gonadotropin; gammaGT, 
gamma glutamyl transferase; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDL, high-density 
lipoprotein-cholesterol; HIV, human immunodeficiency virus; INR, international normalized ratio; LDH, lactate 
dehydrogenase; LDL, low-density lipoprotein-cholesterol; MCH, mean corpuscular haemoglobin; MCHC, mean 
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PT, prothrombin time. 
a 
Creatinine (and calculation of glomerular filtration rate). 
b 
ANC will be calculated at Screening only. Neutrophils will be assessed at all other time points. 
c  All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be 
performed at specified subsequent visits prior to study drug administration. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
d 
Microscopic examination of the sediment if blood, protein, leukocytes esterase, or nitrite are positive on the 
dipstick. 


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6.5.10. 
Sheehan Suicidality Tracking Scale 
The Sheehan-STS (described in Appendix 2) is a brief scale designed to assess and monitor over 
time the core phenomena of suicidality. Any change in the Sheehan-STS score indicating the 
presence of suicidality should be immediately evaluated by the investigator and reported to the 
Medical Monitor. An AE should only be recorded if the investigator makes an evaluation and 
deems there to be suicidal ideation or behavior. 
6.5.11. 
Anti-Drug Antibodies 
Blood serum samples will be collected for determination of ADAs. 
Additional ADA samples should be collected in participants with signs and symptoms of 
infusion-related reactions (Section 5.1.2 and Section 7.9). A sample of blood should be obtained 
for serum PK and ADA assessment of AL001, and testing should be performed for C-reactive 
protein, tryptase, and Interleukin 6 (IL-6). 
6.6. 
Pharmacokinetic Assessments 
6.6.1. 
Serum Pharmacokinetic Samples 
Blood serum samples will be collected for assessment of serum concentrations of AL001. All PK 
samples should be collected from the arm that is not used for the infusion on day of study drug 
administration. 
6.6.2. 
Cerebrospinal Fluid Pharmacokinetic Samples 
Cerebrospinal fluid samples will be assessed for concentration of AL001 in Part 1 only. See 
Section 6.4 for details of CSF sampling. 
6.7. 
Pharmacodynamic Biomarker Assessments 
6.7.1. 
Progranulin Plasma Samples 
Blood PGRN plasma samples will be collected for evaluation of levels of PGRN. 
6.7.2. 
Cerebrospinal Fluid Pharmacodynamic Samples 
Cerebrospinal fluid samples will be evaluated for levels of PGRN in Part 1 only. See Section 6.4 
for details of CSF sampling. 
6.7.3. 
Whole Blood Samples 
Whole blood samples will be collected for evaluation of levels of Sortilin in WBCs and for 
evaluation of other analytes in Part 1 only. 


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6.7.4. 
Exploratory Pharmacodynamic Biomarker Assessments 
6.7.4.1. 
Other Exploratory Pharmacodynamic Biomarker Samples 
Exploratory whole blood, plasma, and CSF PD biomarker samples will be collected for 
evaluation for neurodegeneration (e.g., neurofilament light chain [NfL], 
), lysosomal 
function (e.g., cathepsins), and glial activity (e.g., YKL-40, IL-6), evaluation of messenger 
ribonucleic acid (mRNA) expression in peripheral cells, and to potentially evaluate levels of 
other analytes relevant to disease biology and response to AL001. CSF PD biomarker samples 
will be collected in Part 1 only. 
6.7.4.2. 
Magnetic Resonance Imaging 
MRI scans of the brain will be performed and centrally reviewed for assessment of safety, and 
for evaluation of global and regional brain volumes, volume of white matter hyperintensities, 
brain perfusion (measured by a
g MRI), fractional anisotropy, 
, 
). 
Specific information regarding the collection and processing of MRI images will be provided in 
a separate manual. 
6.8. 
Pharmacogenomic Assessments 
A blood sample will be collected during Part 1 at screening for DNA extraction to enable 
analysis via WGS to identify common and rare genetic variants that are predictive of response to 
study drug, are associated with progression to a more severe disease state, are associated with 
susceptibility to developing AEs, or can increase the knowledge and understanding of disease 
biology. 
Genomics is increasingly informing researchers' understanding of disease pathobiology. Whole 
genome sequencing provides a comprehensive characterization of the genome and, along with 
clinical data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but will also be explored in 
aggregate with data from other studies. The availability of larger datasets will assist in 
identification of important pathways, guiding the development of new targeted agents. 
6.9. 
Clinical Outcome Assessments – Neurocognitive and Functional 
Tests 
The following neurocognitive and functional tests (described in Appendix 2) will be performed. 
Neurocognitive and functional tests will be performed prior to study drug administration (if 
applicable) and prior to any stressful procedures (e.g., blood collections, imaging).  
• Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s 
Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and 
Language Domains (CDR® plus NACC FTLD) 
• Frontotemporal Dementia Rating Scale (FRS) 


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• Clinical Global Impression of Improvement (CGI-I) 
• Clinical Global Impression of Severity (CGI-S) 
• Color Trails Test (CTT) Part 2 
• Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
• WLA (US, UK, and Canadian participants who are proficient in English and who 
agree and are eligible to participate in the optional assessments only, refer to 
Appendix 2). 
A tablet will be used to collect data for the electronic COAs. A few COAs will be completed on 
paper and entered into the eCRF. Specific information on the collection and data entry of 
neurocognitive and function tests will be provided in a separate manual. Adaptations to visits and 
procedures under the exceptional circumstance of COVID-19 pandemic are detailed in 
Appendix 3. 
Restrictions on when to stop the use of medications known to impair consciousness or cognition 
prior to COAs are provided in Section 4.1.2. 
6.10. 
Unscheduled Visits 
Unscheduled visits may occur at any time while the participant is enrolled in the study. 
6.11. 
Part 1 End of Treatment Visit 
Participants who discontinue study drug prior to completing the 96-week Part 1 treatment period 
should be encouraged to complete all remaining scheduled assessment visits through Part 1 
(including COAs, MRI, and CSF evaluations). 
A Part 1 EOT visit will only be completed by participants who discontinue study drug but remain 
in Part 1 of the study and continue to perform all assessments (Section 4.3.1.1). Part 1 EOT 
assessments should be completed as soon as possible after the decision is made. 
The EOT visit may be substituted by a scheduled study visit if it occurs within the same window.  
6.12. 
End of Study Visit 
6.12.1. 
Part 1 End of Study Visit 
Participants who discontinue study drug and all assessments prior to completing the 96-week 
Part 1 treatment period (Section 4.3.2) will complete a Part 1 EOS visit as soon as possible after 
the decision is made. The Part 1 EOS visit may be substituted by a scheduled study visit if it 
occurs within the same window. 
Participants who complete the 96-week Part 1 treatment period, at Week 97, will have the option 
to continue to receive AL001 in Part 2 (OLE) of the study. Participants who do not continue in 
Part 2 will complete a Part 1 EOS visit at the scheduled Week 97 timepoint. Participants who 
continue in Part 2 will complete the Week 97 visit and continue to Part 2 (Week 101). 


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6.12.2. 
Part 2 End of Study Visit 
Participants who discontinue study drug and/or all assessments prior to completing the 96-week 
Part 2 treatment period (Section 4.4.1) will complete a Part 2 EOS visit as soon as possible after 
the decision is made. The Part 2 EOS visit may be substituted by a scheduled study visit if it 
occurs within the same window. 
At Week 197, participants who complete the 96-week Part 2 OLE period will complete a Part 2 
EOS visit at the scheduled Week 197 timepoint. 
6.13. 
Safety Follow-up Visit 
A Safety Follow-up visit will be performed 10-weeks following the last dose of AL001. The 
Safety Follow-up visit may be substituted by a scheduled visit if it occurs within the same 
window. 


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7. 
ADVERSE EVENTS 
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
7.1. 
Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to study drug. Participants will be instructed to contact the 
investigator at any time after informed consent signature if any symptoms develop. Study 
participants should be instructed to report all AEs to the investigator. All AEs must be 
appropriately documented in the participant’s original source documents and on the eCRFs. 
Investigators should report the diagnosis rather than list symptoms, whenever possible. 
An AE does not include the following:  
• Elective medical or surgical procedures planned prior to the start of study treatment 
(e.g., hip replacement surgery) that did not result from a worsening of a previous 
condition. The condition that led to the procedure may be an AE and must be 
reported. 
• Pre-existing diseases, conditions, or laboratory abnormalities present or detected at 
the screening visit that do not worsen. 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for study drug administration per institutional guidelines, elective 
surgery, social and/or convenience admissions).  
• Overdose without clinical sequelae. 
• Any medical condition or clinically significant laboratory abnormality that has an 
onset date before the consent form is signed and that is not related to a 
protocol-associated procedure is not an AE. It is considered to be a pre-existing 
medical condition and should be documented on the medical history eCRF. However, 
deterioration of a medical condition or new or worsened clinically significant 
abnormality during the study should be reported as an AE. 
• Any AE that began during the Phase 1 study (AL001-1) and was ongoing at the time 
of enrolling in this study (AL001-2) will not be considered an AE, but medical 
history. 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported in the established 
time frames. 


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A treatment emergent adverse event (TEAE) is defined as any event not present before exposure 
to study drug, or any event already present that worsens in either intensity or frequency after 
exposure. 
7.2. 
Serious Adverse Events 
An SAE is defined as any AE that fulfills one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event that may jeopardize the participant or may require 
medical intervention to prevent one of the outcomes listed above 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the participant or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
An AE is considered “life-threatening” if, in the opinion of either the Investigator or the Sponsor, 
its occurrence places the participant at immediate risk of death. It does not include an AE that, 
had it occurred in a more severe form, might have caused death. 
Social hospitalization, defined as inadequate family support or care at the participant’s primary 
residence resulting in participant hospitalization, will not be considered an SAE. 
7.3. 
Eliciting and Documenting Adverse Events 
At every study visit, participants will be asked a standard, nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
regimens (prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, 
and over-the-counter medications). 
Laboratory test values or investigational findings (e.g., findings on ECGs, imaging, or 
examination) outside the normal reference range that meets the following criteria should be 
reported as an AE: (1) is confirmed and the investigator considers clinically significant, or 
(2) requires a participant to be discontinued from the study, or (3) requires a participant to 
receive treatment. Abnormal laboratory test values or investigational findings reported as AEs 


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should be followed until satisfactory clinical resolution, participant withdrawal of consent, loss 
to follow-up, or death, whichever comes first. 
7.4. 
Assessment of Causality 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Relationship to Study Drug  
Comment 
Related 
There is reasonable possibility that the event may have been caused 
by the study drug (e.g., confirmation by positive rechallenge test). 
Not Related 
The event can be readily explained by the participant’s underlying 
medical condition, concomitant therapy, or other causes, and 
therefore, the investigator believes no relationship exists between the 
event and the study drug. 
The investigator should assess causality by answering either "related” or “not related” to the 
question “Is there a reasonable possibility that the event may have been caused by the study 
drug?” 
The following factors may be used in consideration of causality assessment: 
• Challenge/rechallenge: Did the event abate after study treatment was reduced or 
interrupted? Did the event reappear after study treatment was reintroduced? 
• Temporal relationship and time to onset plausibility. 
• Confounding risk factors. 
• Amount and duration of study treatment exposure. 
• Concomitant medications. 
7.5. 
Reporting Adverse Events 
All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur 
after the participant signs informed consent through the Part1/Part 2 EOS or Safety Follow-up 
visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory 
clinical resolution. Additionally, SAEs considered related to study treatment that occur at any 
time should be reported by the investigator regardless of the AE/SAE collection window. 
Definitions describing what is and is not considered an AE are provided in Section 7.1. 
Information to be collected includes the following: 
• Event term 
• Time and date of onset 
• Investigator-specified assessment of severity and relationship to study drug  
• Time of resolution of the event 


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• Seriousness 
• Any required treatment or evaluations 
• Outcome 
The Medical Dictionary for Regulatory Activities (MedDRA) Version 21.1 or later will be used 
to code all AEs. 
7.6. 
Reporting Serious Adverse Events 
In the event of any SAE reported or observed during the study, the investigational site is 
immediately required to complete the AE eCRF within the EDC system, indicating the AE is 
serious, and at least within 24 hours of becoming aware of the event or aware of new information 
relating to the event. In the event that the EDC system is not available, a paper SAE Report Form 
should be used and emailed to 
, according to the instructions provided in 
the Study-Specific Regulatory Binder
The participant’s condition will be followed up by the investigator or designated sub-investigator 
until resolution of the condition, as described in Section 7.8. If additional visits are required, the 
participant will be asked to return to the investigational site for further follow-up. As additional 
information becomes available, such as hospital discharge notes and participant medical records, 
the investigator will be notified and provided with all relevant information. 
It is the investigator’s responsibility to report all SAEs to Alector (covered in Section 11.6), and 
it is Alector’s responsibility to ensure that all safety reporting obligations are carried out in 
compliance with current legislation for expedited reporting of SAEs (including Suspected 
Unexpected Serious Adverse Reaction (SUSARS)). 
7.6.1. 
Protocol-Specific Disease Progression Adverse Event and Serious Adverse Event 
Reporting Requirements 
Disease progression in this study is measured via the CDR® plus NACC FTLD and other 
cognitive and functional assessments. Changes in these scores that are consistent with the 
expected rate of progression of the underlying disease should not be recorded as AEs. 
However, symptomatic deterioration or events that are judged by the investigator to be 
inconsistent with normal disease progression or are considered related to study treatment should 
be reported as AEs, and if any of the “serious” criteria are met, it must be reported as an SAE.  
Please note that the term “disease progression” should not be reported, but rather the clinical 
manifestation(s) with applicable descriptors should be captured on the Adverse Event eCRF 
page. 
7.7. 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the participant’s 
daily activities. Severity will be graded according to the World Health Organization (WHO) 


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Toxicity Grading Scale, March 2019 or later. If an AE is not specified within the WHO Toxicity 
Grading Scale, then the AE will be graded according to the following definitions:  
Grade 
Severity  
Description 
1 
Mild  
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The participant may be aware of the sign 
or symptom but tolerates it reasonably well. 
2 
Moderate 
Mild to moderate limitation in activity; no or minimal medical 
intervention/therapy required. 
3 
Severe  
Marked limitation in activity; medical intervention/therapy required; 
hospitalizations possible. 
4 
Life-
threatening  
The participant is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically might 
have caused death if it were more severe. 
5 
Death 
Any AE where the outcome is death. 
It should be pointed out that the term “severe” is a measure of intensity and that a severe AE is 
not necessarily serious. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of onset and duration of each episode. When the 
intensity of an AE changes more than once a day, the maximum severity for the event should be 
listed. If the intensity changes over a number of days, these changes should be recorded 
separately (e.g., as having distinct onset dates). 
7.8. 
Follow-up of Participants Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF. The investigator should 
follow each AE and SAE through satisfactory clinical resolution. 
All AEs and SAEs that have not resolved by the end of the study or that have not resolved upon 
discontinuation of the participant’s participation in the study must be followed up until any of the 
following occurs: 
• The event resolves. 
• The event stabilizes. 
• The event returns to baseline, if a baseline value is available. 
• The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct. 
• It becomes unlikely that any additional information can be obtained (participant or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts). 


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After the protocol-defined follow-up period, Alector (or designee) should be notified if the 
investigator becomes aware of any SAE that is believed to be related to prior study drug. 
7.9. 
Infusion Reactions 
Signs or symptoms of AEs during the infusion will be carefully monitored and treated according 
to institutional guidelines. Further details regarding infusion-related reactions are provided in 
Section 5.1.2 of this protocol and in the IB. 
7.10. 
Anaphylaxis 
Signs or symptoms of anaphylaxis will be carefully monitored and treated according to 
institutional guidelines. Emergency crash cart equipment and medications, including multiple 
doses of epinephrine, pressors, and bronchodilators, will be available at all times during the 
infusion portions of the study. 
7.11. 
Special Situations 
Special situations are non-standard medical conditions that provide valuable information about 
an investigational product (IP) even when they do not occur in association with an AE or medical 
condition, and therefore should be reported. All special situations should be reported using a 
paper Serious Adverse Event Report Form and emailed to d
, according to 
the instructions provided in the Study-Specific Regulatory Binder. 
Special situations are defined as below: 
• Overdose: This refers to the administration of a quantity of IP given per 
administration or cumulatively, which is above the maximum recommended dose 
according to the authorized product information. Clinical judgment should always be 
applied. 
• Misuse: This refers to situations where the IP is intentionally and inappropriately used 
not in accordance with the prescribed or authorized dose, route of administration, 
and/or the indication(s) or within legal status of its supply. 
• Abuse: This corresponds to the persistent or sporadic, intentional excessive use of IP, 
which is accompanied by harmful physical or psychological effects. 
• Medication error: A medication error is any dose of study treatment given to a subject 
or taken by a subject that differs from the dose described in the protocol. Any 
medication error, with or without associated AEs, must be promptly recorded in the 
eCRF. Medication errors without signs or symptoms do not need to be recorded as 
AEs; in case of any AEs associated with the medication error, these should be 
reported on relevant AE/SAE sections in the eCRF. Medication errors are not likely 
in the study, as the study treatment is administered by IV infusion by trained 
personnel under the supervision of the investigator or their designee. 


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• Occupational exposure: This corresponds to an IP for human use as a result of one’s 
occupation. 
7.12. 
Pregnancy 
Female participants must be instructed to discontinue all study drugs and inform the investigator 
immediately if they become pregnant during the study. 
The investigator must report any pregnancy that occurs in a female participant or partner of a 
male participant within 24 hours of becoming aware of the event by submitting the Pregnancy 
Report Form. Follow-up information documenting the pregnancy outcome should be reported on 
the Pregnancy Report Form. The investigational site should email the Pregnancy Report Form to 
 according to the instructions provided in the Study-Specific Regulatory 
Binder. 
All pregnancies must be reported on the appropriate page in the eCRF. 
An uncomplicated pregnancy will not be considered an AE or SAE, but all pregnancies will be 
followed up through term. 
Pregnancies are captured if they occur in female participants or in the sexual partners of male 
participants from the time the participant is first exposed to the study drug until Part1/Part 2 EOS 
or Safety Follow-up visit, whichever is later. 
Any congenital abnormalities noted at birth in the offspring of a participant who received study 
drug or in the sexual partner of a male participant who received study drug will be reported as an 
SAE. The outcome of any pregnancy and the presence or absence of any congenital abnormality 
will be recorded in the source documentation and reported using the Pregnancy Report Form. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after 
the participant has completed the study, and considered by the investigator as possibly related to 
the study drug, must be promptly reported to Alector (or designee). 


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8. 
STATISTICAL METHODS AND CONSIDERATIONS 
This section describes the statistical methods to be used for the analysis of the data from the 
study. Additional information is provided in the Statistical Analysis Plan (SAP). 
8.1. 
Sample Size Estimations 
Part 1 (Treatment Period) 
The primary objective of Part 1 of the study is to assess the safety profile of repeat dosing of 
AL001 in asymptomatic and symptomatic participants. Descriptive statistics will be used to 
assess clinically significant associated findings (for example, study drug related AEs leading to 
study drug discontinuation or study drug-related SAEs). The Part 1 sample size of 40 participants 
was chosen based on feasibility; however, the probability of detecting at least 1 clinically 
significant associated finding will be explored. When the probability of a clinically significant 
associated finding for a single participant is 0.1%, 1%, 5%, and 10%, then with a sample size of 
40 participants, the probability of detecting at least 1 clinically significant associated finding 
across all participants is 3.9%, 33.1%, 87.1% and 98.5% respectively. 
Part 2 (Optional OLE) 
It is estimated that up to 40 participants from Part 1 of the study will be eligible to continue with 
Part 2 of the study. Part 2 is optional for participants, and at the discretion of the investigator. 
8.2. 
Analysis Populations 
Part 1 (Treatment Period) 
The following analysis sets will be used in the statistical analyses: 
Enrolled Population: The enrolled population will consist of all participants who signed the ICF. 
Safety Analysis Population: The safety analysis population will consist of all participants who 
received at least 1 dose of AL001. The safety analysis population will be used for safety 
summaries. 
PK Analysis Population: The PK analysis population will include all participants in the safety 
population who had adequate assessments for determination of at least 1 PK parameter. The PK 
analysis population will be used for PK summaries. 
Full Analysis Population: The full analysis population will include all participants in the safety 
analysis population who had both a baseline and at least 1 post-dose assessment. The full 
analysis population will be used for all PD and PD biomarker summaries. 
Part 2 (Option OLE) 
Part 2 analyses will include all participants who received at least 1 dose administration in Part 2. 


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8.3. 
Description of Subgroups to be Analyzed 
Except for safety endpoints, all other study endpoints specified above will be summarized by 
GRN mutation carriers vs C9orf72 mutation carriers. Additional subgroups may be summarized 
as exploratory. 
8.4. 
Statistical Analysis Methodology 
The main statistical analysis will be performed on Part 1. The statistical analysis will be 
performed using SAS software Version 9.4 or later (SAS Institute Inc., Cary, North Carolina, 
USA). The statistical methods for this study will be described in a detailed Statistical Analysis 
Plan (SAP), which will be finalized before locking of the database. Changes from analyses 
planned in this protocol will be documented in the SAP. Any deviations from the planned 
analysis as described in the SAP will be justified and recorded in the final clinical study report 
(CSR). 
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarized using descriptive statistics (number of participants, mean, standard deviation 
[SD], median, minimum, maximum, and 95% confidence interval [CI] where applicable). All 
summaries will be presented by combined participant status and dementia type at baseline 
(aFTD-GRN, FTD-GRN [bvFTD and PPA], FTD-C9orf72 [bvFTD and PPA], and All Patients). 
Part 1 (Treatment Period) 
In Part 1, data collected for participants who failed screening and were not enrolled will not be 
presented in any summaries or data listings. All other data will be listed in data listings. Baseline 
will be defined as the last non-missing assessment, including repeated and unscheduled 
measurements, prior to the start of first study drug administration. 
In Part 1, all CIs will be 2-sided and performed using a 5% significance level, except for PK 
parameters, for which 90% CI and geometric mean will be used. As the objectives of the study 
are exploratory in nature no adjustments for multiplicity will be made. 
No formal significance testing will be performed. 
Part 2 (OLE) 
For Part 2, no formal statistical testing will be performed. Descriptive statistics will be presented 
for Part 2 separately from Part 1. The purpose of the OLE is to collect continued long-term (up to 
96 weeks) safety and tolerability data from participants who have completed Part 1 of the study. 
As the objectives of the OLE are exploratory in nature no adjustments for multiplicity will be 
made. 
8.4.1. 
Study Population 
All study population summaries will be presented using the enrolled population. 


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8.4.1.1. 
Disposition of Participants 
Participant disposition will be summarized. The number of participants and reasons for study 
discontinuation, reasons for study drug discontinuation, and the number of participants in each 
analysis population will be presented. 
8.4.1.2. 
Protocol Deviations 
A protocol deviation occurs when the participant, investigator, or Alector fails to adhere to 
protocol requirements. Major protocol deviations for this study are described in Section 12.4.2. 
Major protocol deviations will be summarized, and all protocol deviations will be presented in a 
data listing, including the categorization of the deviation as major or minor. 
8.4.2. 
 
Analysis of Primary Safety Endpoints 
All safety summaries will be presented using the safety analysis population. 
8.4.2.1. 
Demographic, Baseline, and Background Characteristics 
Demographics (including but not limited to age, sex, and race, if allowable per local regulatory 
authorities) and baseline and background characteristics will be presented in summary tables. 
Qualitative data (e.g., medical history, diagnostic characterization) will be summarized in 
contingency tables, and quantitative data (e.g., age) will be summarized using quantitative 
descriptive statistics. 
All genotype data will be presented in a summary table. 
8.4.2.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO-DD, March 2019 or later. 
A medication will be considered as concomitant if the end date and time of administration is 
after start of administration of study drug. If the date and time of administration contains partial 
information such that the attribution of concomitant administration cannot be ruled out, then it 
will be considered as concomitant. A medication will be considered as prior if the start and stop 
date and time of administration is prior to the start of administration of study drug. A medication 
started prior to study drug and continuing during the study will be considered as concomitant. 
All prior and concomitant medications data will be summarized by anatomical therapeutic 
chemical classes and generic names. Separate summaries will be presented for prior and 
concomitant medications. 
8.4.2.3. 
Study Drug Administration 
Study drug administration data will be summarized by number of doses received and total dose 
received. The overall treatment compliance will be calculated based on dose 
interruptions/discontinuations. 


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8.4.2.4. 
Adverse Events 
Adverse events will be recorded as described in Section 7.7 and will be coded to system organ 
class and preferred term according to MedDRA, Version 21.1 or later. A TEAE is defined as 
described in Section 7.1. The following AE summaries will be reported by system organ class, 
preferred term, and combined participant status and dementia type at baseline: 
• TEAEs 
• Treatment-related TEAEs 
• TEAEs by relationship to study drug 
• TEAEs by severity 
• SAEs 
• TEAEs leading to study drug discontinuation 
• TEAEs leading to study discontinuation 
For safety reporting, any clinically significant changes in MRI after dosing relative to baseline 
will be evaluated by the investigator and will be included in the eCRF as AEs. A separate 
analysis of AEs identified through MRI will not be conducted. 
8.4.2.5. 
Physical and Neurological Examinations 
Separate shift tables for physical and neurological examinations will be generated by the 
categorical interpretation of findings and will be presented by body system. 
8.4.2.6. 
Vital Signs Analysis 
Actual values and changes from baseline for vital signs and weight will be summarized at each 
time point using descriptive statistics. 
8.4.2.7. 
Electrocardiogram Analysis 
Actual values and changes from baseline for quantitative ECG results will be summarized at 
each time point using descriptive statistics. A shift table will be generated for the categorical 
interpretation of ECGs. Any grade 3 or higher QTcF prolongation will be listed. 
8.4.2.8. 
Clinical Laboratory Analysis 
Actual values and changes from baseline for clinical laboratory test results will be summarized at 
each time point using descriptive statistics. Shift tables will be generated for clinical laboratory 
test results. 
8.4.2.9. 
Sheehan Suicidality Tracking Scale 
A summary table for Sheehan-STS Total Score will be presented by time point using descriptive 
statistics. 


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8.4.2.10. Immunogenicity Analysis 
Immunogenicity test results for ADA to AL001 will be summarized by time point. 
8.4.3. 
Analysis of Pharmacokinetic and Pharmacodynamic Biomarker Endpoints 
8.4.3.1. 
Analysis of Secondary Pharmacokinetic Endpoints 
All PK summaries will be presented using the PK analysis population. 
Individual and mean serum AL001 concentration-time data will be tabulated and plotted by 
study day and mutation carriers. As applicable, the serum PK of AL001 will be summarized by 
estimation of maximum observed concentration (Cmax), trough concentration (Ctrough), and area 
under the concentration-time curve (AUCss) on the basis of results obtained following multiple 
doses of AL001 by study day and cohort.  
The individual serum concentration versus actual time data for AL001 will be used to derive PK 
parameters by standard noncompartmental methods using Phoenix® WinNonlin® (Certara USA 
Inc., Princeton, New Jersey, USA) Version 6.4 or higher. The individual PK parameters will be 
presented in listings. PK parameters will be summarized in tables using the following descriptive 
statistics: n, arithmetic mean, SD, coefficient of variation (CV), geometric mean, geometric 
mean CV, minimum, median, and maximum. Geometric mean and geometric mean, 90% CI, and 
CV will only be included for Cmax, Ctrough, and AUCss (if data permit). 
Potential correlations of relevant PK parameters with demographics, safety (including QT 
changes), and PD measures may be explored, as data allow. Additional modeling, including 
population PK analysis, to characterize these correlations may be performed. The results of such 
additional analyses may be reported separately from the CSR. 
8.4.3.2. 
Analysis of Secondary and Exploratory Pharmacodynamic Endpoints  
All PD summaries will be presented using the PD analysis population. 
PD endpoints will be described and summarized by study day and mutation carriers at baseline 
and each time point specified in the Schedules of Assessments (Table 4, Table 5, Table 6, 
Table 7,Table 8, and Table 9), as will the percent change from baseline for each PD endpoint. 
Pharmacodynamic endpoints to be evaluated in plasma and CSF samples will include but are not 
limited to PGRN, Sortilin, and NfL. 
Summary statistics for PD endpoints and their corresponding changes from baseline (e.g., percent 
change from baseline) will be tabulated by study day and cohort. The time course of PD 
endpoints will be presented graphically for both observed values and percent change from 
baseline values. In addition, a mixed model of repeated measures (MMRM) may be used to 
summarize the mean percent changes in PD endpoints from baseline with 95% CIs. Association 
between PD endpoints and clinical response may also be explored. 
The PK-PD relationship may be modeled by population PK/PD model using nonlinear mixed 
effects modeling. Baseline exploratory PD biomarkers may also be explored as potential 


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predictors of response to AL001, including baseline serum or CSF PGRN levels and GRN or 
C9orf72 genotyping. 
8.4.3.3. 
Analyses of Exploratory Pharmacodynamic Biomarker Endpoints 
All exploratory PD biomarker summaries will be presented using the PD biomarker population. 
Correlations among fluid PD biomarker levels, imaging PD measures, and clinical outcome 
measures will be evaluated, and details will be provided in the SAP. 
8.4.3.3.1. Magnetic Resonance Imaging 
Actual results and percent change from baseline values for quantitative MRI parameters will be 
summarized by visit using descriptive statistics. Mean percent change from baseline values, plus 
or minus the SD, will also be presented in a plot. 
8.4.3.3.2. Other Exploratory Pharmacodynamic Biomarkers 
Actual results and change from baseline values for other exploratory PD biomarker parameters 
will be summarized by visit using descriptive statistics. Mean change from baseline values, plus 
or minus the SD, will also be presented in a plot. 
8.4.4. 
 
Analyses of Exploratory Clinical Outcome Assessment Endpoints 
All COA summaries will be presented using the safety population. The full details of analysis for 
COA will include total and subscale scores and will be provided in the SAP. 
Actual results and change from baseline values for COA total and/or subscale scores will be 
summarized by visit using descriptive statistics. Mean change from baseline values, plus or 
minus the SD, will also be presented in a plot. 
The COA endpoint will be assessed using MMRM methodology. The dependent variable will be 
the change from baseline score to each postbaseline visit assessment. The fixed effects will 
include the participant mutation type, and time point will be the repeated measure. Covariates 
including but not limited to baseline PGRN level, sex, and age may be explored. 
8.4.5. 
 
Interim Analyses 
An iDMC will review safety data during the course of the study to provide recommendations to 
Alector on study conduct. The details of the iDMC are provided in Section 12.1 and in a separate 
charter. 


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9. 
DATA QUALITY ASSURANCE 
This study will be conducted according to the ICH E6(R2) risk and quality processes described 
in the applicable procedural documents. The quality and risk management approach to be 
implemented in this study will be documented and will comply with the current ICH guidance on 
quality and risk management. 
All aspects of the study will be monitored for compliance with applicable government regulatory 
requirements, current Good Clinical Practice (GCP), the protocol, and applicable standard 
operating procedures. The monitor will maintain current personal knowledge of the study 
through observation, review of study records and source documentation, and discussion of the 
conduct of the study with the investigator and investigational site personnel. Electronic case 
report forms (CRFs) and electronic data capture will be utilized. The electronic data capture 
(EDC) system is validated and compliant with local regulatory requirements. Each person 
involved with the study will have an individual identification code and password that allows for 
record traceability. There may be an internal quality review audit of the data and additional 
reviews by the clinical monitor. 
9.1. 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator will 
maintain adequate case histories for the participants treated as part of the research under this 
protocol. The investigator will maintain accurate eCRFs and source documentation as part of the 
case histories. These source documents may include laboratory reports, recorded data from 
automated instruments, medical progress notes, email correspondence, and ECG strips. In 
addition, electronic COA devices will be used to capture some COAs, whereas others will be 
performed on paper and entered into the eCRF. This will be part of the source. 
A separate device will be used for the WLAs (optional; UK, US, or Canadian participants only). 
All data collected by the Winterlight application will be stored securely on the device and 
queued for upload to Winterlight’s secure servers. 
The investigator will adhere to Good Documentation Practice, and investigative site personnel 
will enter participant data into the eCRF. The analysis datasets will be a combination of these 
data and data from other sources (e.g., laboratory data). 
Clinical data management will be performed in accordance with applicable standards and will 
include data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 
inconsistencies in the data. Adverse Event terms will be coded using the MedDRA Version 21.1 
or later and an internal validated medical dictionary, and concomitant medications will be coded 
using the WHO-DD, March 2019 or later. 
After database lock, each investigational site will receive a digital file containing all of their 
site-specific eCRF data as entered into the EDC system for the study, including full discrepancy 
and audit history. Additionally, a digital copy of all of the investigational site’s data from the 
study will be created and sent to Alector for storage. Alector will maintain a duplicate digital file 


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copy for their records. In all cases, participant initials will not be collected or transmitted to 
Alector. 


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10. 
ETHICS 
10.1. 
Independent Ethics Committee or Institutional Review Board 
Local regulation and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human participants in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study participants, and any 
other written information regarding this study to be provided to the participant or the 
participant’s legally authorized representative must be approved by the IRB/IEC. Documentation 
of all IRB/IEC approvals and of the IRB/IEC compliance with ICH harmonised tripartite 
guideline E6(R2): GCP will be maintained by the site and will be available for review by Alector 
(or designee). 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator 
must promptly supply Alector (or designee), the IRB/IEC, and, where applicable, the institution, 
with written reports on any changes significantly affecting the conduct of the study or increasing 
the risk to participants. 
10.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
10.3. 
Participant Information and Consent 
A written informed consent in compliance with US Title 21 CFR (Part 50) and applicable 
regulatory authority regulations shall be obtained from each participant before enrolling in the 
Part 1 treatment period of the study, before continuation of treatment in the optional Part 2, or 
before performing any unusual or nonroutine procedure that involves risk to the participant. An 
informed consent template may be provided by Alector to investigational sites. If any site-
specific modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by Alector (or designee) or both before IRB/IEC submission. Once 
reviewed, the consent will be submitted by the investigator to his or her IRB/IEC for review and 
approval before the start of the study. If the ICF is revised during the course of the study, all 
active participating participants must sign the revised form. 
Before recruitment and enrollment into Part 1 and Part 2, each prospective participant and study 
partner will be given a full explanation of the study and be allowed to read the approved ICF. 
Once the investigator is assured that the participant understands the implications of participating 
in the study, the participant will be asked to give consent to participate in the study by signing 
the ICF. The participant’s study partner will also be asked to give consent to participate in the 
study by signing an ICF. 


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If the study participant is not competent, a legally authorized representative must provide 
informed consent on their behalf, and the participant must provide assent, in accordance with the 
local regulations, guidelines, and IRB/IEC. If the study participant becomes incompetent over 
the course of the study, a legally authorized representative will need to be identified and the 
participant will need to provide assent, in accordance with the local regulations, guidelines, and 
the IRB/IEC. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the participant, legally authorized representative, or study partner. 
Consent for Optional Future Research 
Prior to agreeing to samples being retained for future testing outside of the main study, 
participants will provide informed consent in accordance with the standard operating procedures 
of the investigational sites. 
Consent for Optional National Institutes on Aging (NIA) Global Unique Identifier (GUID) 
Prior to the investigational site collecting/assigning the optional NIA GUID as described in 
Section 6.5.4, participants will provide informed consent in accordance with the standard 
operating procedures of the investigational sites. 
Consent for Optional WLA Assessments (optional, US, UK, and Canadian participants only) 
Prior to participating in the optional WLAs, participants and study partners will provide 
informed consent in accordance with the standard operating procedures of the investigational 
sites. 


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11. 
INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB/IEC 
but will not result in protocol amendments. 
11.1. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant (or the participant’s legally authorized representative), except as 
necessary for monitoring and auditing by Alector, its designee, the FDA/European Medicines 
Agency (EMA), or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from Alector (or designee) must be obtained for the disclosure of any said 
confidential information to other parties. 
11.2. 
Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow Alector to submit 
the complete and accurate certification or disclosure statements required under 21 CFR 54. 
In addition, the investigator must provide to Alector a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study. 
Alector (or designee) is not financially responsible for further testing or treatment of any medical 
condition that may be detected during the screening process. In addition, in the absence of 
specific arrangements, Alector (or designee) is not financially responsible for further treatment 
of the participant’s disease. 
11.3. 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 and 
Title 21 of the CFR by providing the following essential documents, including but not limited to: 
• IRB/IEC approval 
• Original investigator-signed investigator agreement page of the protocol. 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572, or an equivalent form capturing this information. 
• Curriculum vitae for the investigator and each sub-investigator listed on Form 
FDA 1572 or equivalent.  


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• Financial disclosure information to allow Alector to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to Alector a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the participant or legally authorized representative. 
• Laboratory certifications and normal ranges for any local laboratories used by the site 
for this study, in accordance with 42 CFR 493. 
11.4. 
Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations. Study information from this protocol will be posted on 
publicly available clinical trial registers before enrollment of participants begins. 
11.5. 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) and all applicable guidelines and regulations. 
11.6. 
Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to Alector and/or 
IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the investigational site IRB/IEC as appropriate. 
After the protocol-defined follow-up period, Alector (or designee) should be notified if the 
investigator becomes aware of any SAE that is believed to be related to prior study drug. 
11.7. 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and Alector and regulatory authority(ies) with any reports required. 
11.8. 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with Alector. It is the responsibility of Alector to inform the investigator/institution as to when 


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these documents no longer need to be retained. The trial master file will be created during the 
implementation phase of a study, maintained on an ongoing basis throughout the duration of the 
project, and collated at the end of the study. 
11.9. 
Publications 
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, Alector will be responsible for these 
activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. Alector has final approval authority over all such issues. 
Data are the property of Alector and cannot be published without prior authorization from 
Alector, but data and publication thereof will not be unduly withheld. 


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12. 
STUDY MANAGEMENT 
12.1. 
Independent Data Monitoring Committee (iDMC) 
An iDMC will review Part 1 safety data during the course of Part 1 of the study to provide 
recommendations to Alector on study conduct. The iDMC will be comprised of two physicians 
(including one with disease area expertise) and a statistician, each of which are independent from 
the Sponsor. Data reviews will be conducted after the first 6 participants complete approximately 
12 weeks of study drug, and then every 6 months thereafter until the last participant completes 
Part 1 the study. The details of the iDMC are provided in a separate charter. 
12.2. 
Monitoring of the Study 
The clinical monitors, as representatives of Alector, have the obligation to follow the study 
closely. In doing so, the monitors will visit the investigator and investigational site at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The monitors will 
maintain current personal knowledge of the study through observation, review of study records 
and source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored, by Alector or its designee, for compliance 
with applicable government regulation with respect to current GCP and current standard 
operating procedures. 
12.3. 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the investigator agrees to allow Alector, representatives of Alector, or a 
regulatory agency access to all study records. 
The investigator should promptly notify Alector (or designee) of any audits scheduled by any 
regulatory authorities. Dependent upon the scope of the regulatory authority audit, Alector may 
elect to assist the site in preparation or support. The investigation should promptly forward 
copies of any audit reports received to Alector. 
12.4. 
Management of Protocol Amendments and Deviations 
12.4.1. 
 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the participant, must be reviewed and approved by Alector (or designee). Amendments 
to the protocol must be submitted in writing to the investigator’s IRB/IEC for approval before 
participants can be enrolled into an amended protocol. 


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12.4.2. 
Protocol Deviations 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
participants without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to Alector for agreement, and to the 
regulatory authorities, if required. 
A protocol deviation occurs when the participant, investigator, or Alector (or designee) fails to 
adhere to protocol requirements. Major protocol deviations are the ones that affect the 
participants' safety or the study endpoints. Major protocol deviations for this study include, but 
are not limited to, the following: 
• Failure to meet inclusion/exclusion criteria 
• Failure to comply with GCP guidelines will result in a major protocol deviation; 
Alector will determine if a major protocol deviation will result in withdrawal of a 
participant. 
12.5. 
Study Termination 
Although Alector has every intention of completing the study, Alector reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last participant completes the last visit 
(includes Safety Follow-up visit). 
12.6. 
Final Report 
Whether the study is completed or prematurely terminated, Alector will ensure that the CSR is 
prepared and provided to the regulatory agency(ies) as required by the applicable regulatory 
requirement(s). Alector will also ensure that the CSR in marketing applications meet the 
standards of the ICH harmonised tripartite guideline E3: Structure and content of the CSR. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the CSR, Alector will provide the investigator with the full summary of the 
study results. The investigator is encouraged to share the summary results with the study 
participants, as appropriate. The study results will be posted on publicly available clinical trial 
registers. 


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13. 
REFERENCE LIST 
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5th ed. Washington (DC): American Psychiatric Publishing; 2013. 947 p. 
2. Ayala YM, Zago P, D’Ambrogio A, et al. Structural determinants of the cellular 
localization and shuttling of TDP-43. J Cell Sci. 2008;121(22):3778-85. 
3. Boxer AL, Gold M, Huey E, et al. Frontotemporal degeneration, the next therapeutic 
frontier: molecules and animal models for frontotemporal degeneration drug 
development. Alzheimers Dement. 2013a;9(2):176-88.  
4. Boxer AL, Gold M, Huey E, et al. The advantages of frontotemporal degeneration drug 
development (part 2 of frontotemporal degeneration: the next therapeutic frontier). 
Alzheimers Dement. 2013b;9(2):189-98.  
5. Busch JI, Unger TL, Jain N, et al. Increased expression of the frontotemporal dementia 
risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol 
Genet. 2016;25(13):2681-97. 
6. Carrasquillo MM, Nicholson AM, Finch N, et al. Genome-wide screen identifies 
rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am J Hum 
Genet. 2010;87(6):890-7. 
7. Chitramuthu BP, Kay DG, Bateman A, et al. Neurotrophic effects of progranulin in vivo 
in reversing motor neuron defects caused by over or under expression of TDP-43 or FUS. 
PLoS One. 2017;12(3):e0174784. 
8. Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for 
neurodegenerative brain diseases. Hum Mutat 33:1340-4, 2012 doi:10.1002/humu.22117 
(PubMed ID: 22581678). 
9. De Muynck L, Herdewyn S, Beel S, et al. The neurotrophic properties of progranulin 
depend on the granulin E domain but do not require sortilin binding. Neurobiol Aging. 
2013;34(11):2541-7. 
10. Deleon J, Miller BL. Frontotemporal dementia. Handb Clin Neurol. 2018;148:409-30. 
11. European Medicines Agency (EMA). Committee for Orphan Medicinal Products. Public 
summary of opinion on orphan designation (EU/3/16/1614). Tolfenamic acid for the 
treatment of behavioural variant frontotemporal dementia. London, 31 March 2016. 
EMA/COMP/75479/2016 [cited 2019 Feb 12]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2016/04/
WC500204476.pdf. 
12. Gallagher MD, Suh E, Grossman M, et al. TMEM106B is a genetic modifier of 
frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta 
Neuropathol. 2014;127(3):407-18. 
13. Galvin JE, Howard DH, Denny SS, et al. The social and economic burden of 
frontotemporal degeneration. Neurology. 2017;89(20):2049-56. 


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14. Gass J., Cannon A., Mackenzie I.R., Boeve B., Baker M., Adamson J., Crook R., 
Melquist S., Kuntz K., Petersen R., et al. Mutations in progranulin are a major cause of 
ubiquitin-positive frontotemporal lobar degeneration. Hum. Mol. Genet. 2006;15:2988–
3001. 
15. Gass J, Lee WC, Cook C, et al. Progranulin regulates neuronal outgrowth independent of 
sortilin. Mol neurodegener. 2012;7:33. 
16. Ghidoni R, Paterlini A, Benussi L. Circulating progranulin as a biomarker for 
neurodegenerative diseases. Am J Neurodegener Dis. 2012;1(2):180-90. 
17. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive 
aphasia and its variants. Neurology. 2011;76(11):1006-1014.  
18. Hu F, Padukkavidana T, Vaegter CB, et al. Sortilin-mediated endocytosis determines 
levels of the frontotemporal dementia protein, progranulin. Neuron. 2010;68(4):654-67. 
19. Mann DMA, Snowden JS. Frontotemporal lobar degeneration: Pathogenesis, pathology 
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20. Meeter LH, Patzke H, Loewen G, et al. Progranulin Levels in Plasma and Cerebrospinal 
Fluid in Granulin Mutation Carriers. Dement Geriatr Cogn Dis Extra. 2016;6(2): 330-40.  
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22. O'Bryant SE, Lacritz LH, Hall J, et al. Validation of the new interpretive guidelines for 
the clinical dementia rating scale sum of boxes score in the national Alzheimer’s 
coordinating center database. Arch Neurol. 2010;67(6):746-9. 
23. Onyike CU, Diehl-Schmid J. The epidemiology of frontotemporal dementia. Int Rev 
Psychiatry. 2013;25(2):130-7. 
24. O’Rourke JG, Bogdanik L, Yanez A, et al. C9orf72 is required for proper macrophage 
and microglial function in mice. Science. 2016;351(6279):1324-29. 
25. Perry DC, Brown JA, Possin KL, et al. Clinicopathological correlations in behavioral 
variant frontotemporal dementia. Brain. 2017;140(12):3329-45. 
26. Pottier C, Zhou X, Perkerson III RB, et al. Potential genetic modifiers of disease risk and 
age at onset in patients with frontotemporal lobal degeneration and GRN mutations: a 
genome-wide association study. Lancet Neurol. 2018;17(6):548-58. 
27. Rademakers R, Neumann M, Mackenzie IR. Advances in understanding the molecular 
basis of frontotemporal dementia. Nat Rev Neurol. 2012;8(8):423-34. 
28. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for 
the behavioural variant of frontotemporal dementia. Brain. 2011;134(9):2456-2477.  
29. Rohlfing FW, Tu RK. Genetics of Frontotemporal Dementia. AJNR Am J Neuroradiol. 
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30. Tanaka Y, Matsuwaki T, Yamanouchi K, et al. Increased lysosomal biogenesis in 
activated microglia and exacerbated neuronal damage after traumatic brain injury in 
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31. Tatton N. FTD Research and Drug Development Landscape. The Association for 
Frontotemporal Degeneration, 2014. Available from: https://www.theaftd.org/wp-
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03 Apr 2019] 66 p. 
32. Tsai RM, Boxer AL. Treatment of frontotemporal dementia. Curr Treat Options Neurol. 
2014;16(11):319. 
33. Valdez C, Wong YC, Schwake M, et al. Progranulin-mediated deficiency of cathepsin D 
results in FTD and NCL-like phenotypes in neurons derived from FTD patients. Hum 
Mol Genet. 2017;26(24):4861-72. 
34. van Blitterswijk M, Mullen B, Nicholson AM, et al. TMEM106B protects C9orf72 
expansion carriers against frontotemporal dementia. Acta Neuropathol. 
2014;127(3):397-406. 
35. Zhang Y, Xu Y, Dickey CA, et al. Progranulin mediates caspase-dependent cleavage of 
TAR DNA binding protein-43. J Neurosci. 2007;27(39):10530-4. 
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14. 
APPENDICES 


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APPENDIX 1. SCHEDULES OF ASSESSMENTS 
Table 4: 
Schedule of Assessments for Part 1, Treatment Period (Through Week 53) 
Proceduresm 
Screening 
Treatment Period 
Visits 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Study week 
-6 
1 
2 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Study day 
 
1 
10 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Visit window (days) 
42 
Total 
0 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsa 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history review 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
xb 
x 
x 
x 
x 
x 
x 
x 
xb 
x 
x 
x 
x 
x 
xb 
x 
Neurological examinationc 
xc 
x 
 
x 
x 
x 
x 
x 
xc 
x 
x 
x 
x 
x 
xc 
x 
Vital signs and weightd,f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECGe,f 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Clinical chemistry, hematologyg 
x 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
Coagulationg,h 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
Urinalysisg 
x 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Serologyg,i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testg,j 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PK samplesf,g,k 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PGRN Plasma samplesf,g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Whole blood for WBCf,g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Whole blood for WGS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum ADA samplesf,g,k 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Exploratory plasma PD biomarker 
samples f,g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Exploratory whole blood PD 
biomarker samples f,g 
 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Lumbar puncture/CSFl 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 


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Proceduresm 
Screening 
Treatment Period 
Visits 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Study week 
-6 
1 
2 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Study day 
 
1 
10 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Visit window (days) 
42 
Total 
0 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Brain MRIn 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Diagnostic characterizationo 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COAsp 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Winterlight-A Labs Speech 
Assessment (Optional)q 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Winterlight-B Labs Speech 
Assessment (Optional)q 
 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
Review of AEs and concomitant 
medicationsr 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sheehan-STS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug administration 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; CSF, 
cerebrospinal fluid; ECG, electrocardiogram; eCRF, electronic case report form; IL-6, Interleukin 6; MRI, magnetic resonance imaging; PD, pharmacodynamic; 
PE, physical examination; PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, Sheehan Suicidality Tracking Scale; V, visit; WBC, white blood cell; WGS, 
whole genome sequencing. 
a 
Demographic information (year of birth, age, sex, race, ethnicity) will be recorded at screening, unless disallowed by local regulatory agencies. 
b 
A complete PE will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, and includes evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, genital, and 
rectal examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a physician, or a nurse 
practitioner or physician’s assistant under the supervision of a physician. Limited or symptom-directed examinations is required at all other specified time 
points, prior to study drug administration (if applicable). A limited examination or symptom-directed examination should focus on the affected organ system 
or body area. Record abnormalities observed at screening on the General Medical History and Baseline Conditions page of the eCRF. At subsequent visits, 
record new or worsened clinically significant abnormalities on the AE eCRF. Height (cm) will be measured at screening. 
c 
A complete neurological examination will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, and 
includes the evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. Limited or symptom-
directed examinations are required at all other specified time points, prior to study drug administration (if applicable). A limited examination or symptom-


Clinical Study Protocol AL001-2, Version 4.0 
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Alector, Inc. 
Confidential 
Page 96 
directed examination should focus on the organ system or affected body area. Record abnormalities observed at screening on the General Medical History 
and Baseline Conditions page of the eCRF. At subsequent visits, record new or worsened clinically significant abnormalities as AEs on the AE eCRF.  
d 
Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be recorded 
prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight (kg) will be 
collected at the same visits that vital signs are taken. 
e 
Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days ECG will be obtained 
prior to study drug administration and within 60 minutes after the end of infusion, and once at all other specified time points as indicated. Additional ECG 
monitoring must be performed during the treatment period if clinically indicated. 
f 
Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, exploratory plasma PD biomarker 
samples, whole blood samples for WBC analysis, and exploratory whole blood PD biomarker samples are provided in Table 6. 
g 
Samples will be collected prior to study drug administration (if applicable).  
h 
If the lumbar puncture is moved to a different visit, the coagulation panel will be moved to the visit immediately preceding the new lumbar puncture visit. 
i 
Serology testing will include anti-HCV, anti-HIV, HIV antigen, HBsAg, and total hepatitis B core antibody. 
j 
All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at specified subsequent visits. If 
a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
k 
Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should be 
collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA assessment of 
AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 
l 
Cerebrospinal fluid samples will be collected via lumbar puncture prior to study drug administration (if applicable). The timing of lumbar punctures may be 
adjusted as determined by Alector’s review of exploratory PD biomarkers. GRN mutation carriers previously treated in Study AL001-1 may not be required 
to repeat the CSF assessment if it has been performed within 3 months prior to screening. 
m 
If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-site visit 
with approval from the medical monitor. Refer to Appendix 3 for additional details on trial adaptations due to COVID-19. 
n 
During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. GRN mutation carriers previously treated in 
Study AL001-1 may not be required to repeat the imaging screening assessment if it has been performed within 3 months prior to screening.  
o 
A diagnostic characterization form will be completed in an electronic data capture system at screening, week 97, and EOT/EOS for symptomatic participants 
only. It will also be completed for any asymptomatic participant who becomes symptomatic during the course of the study; for these participants, the 
diagnostic characterization form will be completed only at the first visit in which they exhibit clinical symptomatology. 
p 
The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center 
Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical Global 
Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. The Clinical Global 
Impression of Improvement is not administered at baseline. Neurocognitive and functional tests will be performed prior to study drug administration 
(if applicable) and prior to any stressful procedures (e.g., blood collections, imaging). 


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q 
Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) will be 
conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only (WLA-B) or 
both (WLA-A and WLA-B). Assessments are conducted at home within ±7 days of the visit and will be supervised by the study partner. The study partner 
will be asked to complete a questionnaire online within ±7 days of the EOS visit. 
r 
All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and through the 
Part1/Part 2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory clinical resolution. 
Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator regardless of the AE/SAE 
collection window. At every study visit, participants will be asked a standard nonleading question to elicit any medically related changes in their well-being. 
They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed concomitant medication regimens 
(prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter medications). Review of AEs and concomitant 
medications will be performed before and after study drug administration (when applicable). 


Clinical Study Protocol AL001-2, Version 4.0 
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Table 5: 
Schedule of Assessments for Part 1, Treatment Period (Through Week 97) 
Proceduresm 
Treatment Period (continued) 
Part 1 
EOT/EOSs,t 
Safety 
Follow-upb,s 
Visits 
V16 
V17 
V17Aa 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26s 
 
 
Study week 
57 
61 
61 
65 
69 
73 
77 
81 
85 
89 
93 
97b 
 
 
Study day 
393 
421 
422 
449 
477 
505 
533 
561 
589 
617 
645 
673 
 
 
Visit window (days) 
±7 
±7 
±7a 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
±7 
Physical examinationc 
x 
x 
 
x 
x 
xc 
x 
x 
x 
x 
x 
xc 
xc 
xc 
Neurological examinationd 
x 
x 
 
x 
x 
xd 
x 
x 
x 
x 
x 
xd 
xd 
xd 
Vital signs and weighte,g 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECGf,g 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
Clinical chemistry, hematologyh 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Coagulationh,i 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Urinalysish 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Pregnancy testh,j 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PK samplesg,h,k 
 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x  
PGRN Plasma samplesg,h 
 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Whole blood for WBCg,h 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Serum ADA samplesg,h,k 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Exploratory plasma PD biomarker samplesg,h 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Exploratory whole blood PD biomarker 
samplesg,h 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Lumbar puncture/CSFl 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Brain MRIn 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
 
Diagnostic characterizationo 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
COAsp 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Winterlight-A Labs Speech Assessments 
(Optional)q 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Winterlight-B Labs Speech Assessments 
(Optional)q 
x 
 
 
x 
x 
 
x 
x 
 
x 
     x 
 
 
 
Review of AEs and concomitant medicationsr 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sheehan-STS 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug administration 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 


Clinical Study Protocol AL001-2, Version 4.0 
AL001 
Alector, Inc. 
Confidential 
Page 99 
Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; CSF, 
cerebrospinal fluid; ECG, electrocardiogram; eCRF, electronic case report form; EOS, End of Study; EOT, End of Treatment; IL-6, Interleukin 6; MRI, magnetic 
resonance imaging; PD, pharmacodynamic; PE, physical examination; PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, Sheehan Suicidality Tracking 
Scale; V, visit; WBC, white blood cell; WGS, whole genome sequencing. 
a 
Visit 17A should occur the following day after Visit 17. 
b 
A Safety Follow-up visit will be performed 10 weeks following the last dose of AL001. The Safety Follow-up visit may be substituted by a scheduled visit if 
it occurs within the same window. 
c 
A complete PE will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, and includes evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, genital, and 
rectal examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a physician, or a nurse 
practitioner or physician’s assistant under the supervision of a physician. Limited or symptom-directed examination are required at all other specified time 
points, prior to study drug administration (if applicable). A limited examination or symptom-directed examination should focus on the organ system or 
affected body area. Record abnormalities observed at screening on the General Medical History and Baseline Conditions page of the eCRF. Height (cm) will 
be measured at screening. At subsequent visits, record new or worsened clinically significant abnormalities on the AE eCRF. 
d 
A complete neurological examination will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, and 
includes the evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. Limited or symptom-
directed examinations are required at all other specified time points, prior to study drug administration (if applicable). A limited examination or symptom-
directed examination should focus on the affected organ system or body area. Record abnormalities observed at screening on the General Medical History 
and Baseline Conditions page of the eCRF. At subsequent visits, record new or worsened clinically significant abnormalities as AEs on the AE eCRF.  
e 
Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be recorded 
prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight (kg) will be 
collected at the same visits that vital signs are taken. 
f 
Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days ECG will be obtained 
prior to study drug administration and within 60 minutes after the end of infusion, and once at all other specified time points as indicated. Additional ECG 
monitoring must be performed during the treatment period if clinically indicated. 
g 
Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, exploratory plasma PD biomarker 
samples, whole blood samples for WBC analysis, and exploratory whole blood PD biomarker samples are provided in Table 6. 
h 
Samples will be collected prior to study drug administration (if applicable).  
i 
If the lumbar puncture is moved to a different visit, the coagulation panel will be moved to the visit immediately preceding the new lumbar puncture visit. 
j 
All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at specified subsequent visits. If 
a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
k 
Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should be 
collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA assessment of 
AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 


Clinical Study Protocol AL001-2, Version 4.0 
AL001 
Alector, Inc. 
Confidential 
Page 100 
l 
Cerebrospinal fluid samples will be collected via lumbar puncture prior to study drug administration (if applicable). The timing of lumbar puncture may be 
adjusted as determined by Alector’s review of exploratory PD biomarkers. GRN mutation carriers previously treated in Study AL001-1 may not be required 
to repeat the CSF assessment if it has been performed within 3 months prior to screening. 
m 
If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-site visit 
with approval from the medical monitor. Refer to Appendix 3 for additional details on trial adaptations due to COVID-19. 
n 
During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. GRN mutation carriers previously treated in 
Study AL001-1 may not be required to repeat the imaging screening assessment if it has been performed within 3 months prior to screening. 
o 
A diagnostic characterization form will be completed in an electronic data capture system at screening, week 97, and EOT/EOS for symptomatic participants 
only. It will also be completed for any asymptomatic participant who becomes symptomatic during the course of the study; for these participants, the 
diagnostic characterization form will be completed only at the first visit in which they exhibit clinical symptomatology. 
p 
The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center 
Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical Global 
Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. The Clinical Global 
Impression of Improvement is not administered at baseline. Neurocognitive and functional tests will be performed prior to study drug administration (if 
applicable) and prior to any stressful procedures (e.g., blood collections, imaging). 
q 
Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) will be 
conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only (WLA-B) or 
both (WLA-A and WLA-B). Assessments are conducted at home within +/- 7 days of the visit and will be supervised by the study partner. The study partner 
will be asked to complete a questionnaire online within +/- 7 days of the Study Completion visit. 
r 
All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and through the 
Part 1/Part 2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory clinical resolution. 
Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator regardless of the AE/SAE 
collection window. At every study visit, participants will be asked a standard nonleading question to elicit any medically related changes in their well-being. 
They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed concomitant medication regimens 
(prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter medications). Review of AEs and concomitant 
medications will be performed before and after study drug administration (when applicable). 
s 
Participants who complete the Part 1 96-week treatment period (Week 97), who provide informed consent to participate in Part 2 (optional OLE) and meet 
all the eligibility criteria for the Part 2 OLE (prior to Week 101 study drug administration), will complete the Week 97 visit and continue to Part 2 (Week 
101) to receive their next regularly scheduled dose of AL001 according to the OLE administration schedule (continuation from Week 97 to Week 101). All 
other participants who complete the Part 1 96-week treatment period and who do not continue in Part 2 will complete a Part 1 EOS visit at the scheduled 
Week 97 timepoint. A Safety Follow-up visit will be performed 10-weeks after their last study drug administration (Week 107, +/- 7 days).   
t 
A Part 1 EOT visit will be completed by participants who discontinue study drug but remain in the study and continue to perform assessments. Part 1 EOT 
assessments should be completed as soon as possible after the decision is made. A Part 1 EOS visit will be completed by participants who discontinue study 
drug and all assessments. Part 1 EOS assessments should be completed as soon as possible after the decision is made.   


Clinical Study Protocol AL001-2, Version 4.0 
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Table 6: 
Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker Sample and Imaging 
Assessments – Part 1, Treatment Period 
Timepoint 
Vital 
Signs 
Serum 
PK 
sample a 
Triplicate 
ECG 
Serum 
ADA 
sample 
Progranulin 
plasma 
sample 
Exploratory 
plasma PD 
biomarker 
samples b 
Whole 
blood 
for 
WBC 
Exploratory 
whole blood 
PD biomarker 
samples c 
Screening 
x 
 
x 
 
 
 
 
 
V1 (Week 1): Pre-dose 
x 
x 
x 
x 
x 
x 
x 
x 
V1 (Week 1): End of infusion  
x 
x 
x 
 
 
 
 
 
V2 (Week 2) 
x 
x 
 
x 
x 
x 
x 
x 
V3 (Week 5): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V3 (Week 5): End of infusion  
x 
x 
 
 
 
 
 
 
V4 (Week 9): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V4 (Week 9): End of infusion  
x 
x 
 
 
 
 
 
 
V5 (Week 13): Pre-dose  
x 
x 
 
x 
x 
x 
x 
x 
V5 (Week 13): End of infusion  
x 
x 
 
 
 
 
 
 
V6 (Week 17): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V6 (Week 17): End of infusion  
x 
x 
 
 
 
 
 
 
V7 (Week 21): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V7 (Week 21): End of infusion  
x 
x 
 
 
 
 
 
 
V8 (Week 25): Pre-dose  
x 
x 
x 
x 
x 
x 
x 
x 
V8 (Week 25): End of infusion  
x 
x 
x 
 
 
 
 
 
V9 (Week 29): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V9 (Week 29): End of infusion  
x 
x 
 
 
 
 
 
 
V10 (Week 33): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V10 (Week 33): End of infusion  
x 
x 
 
 
 
 
 
 
V11 (Week 37): Pre-dose  
x 
x 
 
x 
x 
x 
x 
x 
V11 (Week 37): End of infusion  
x 
x 
 
 
 
 
 
 
V12 (Week 41): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V12 (Week 41): End of infusion  
x 
x 
 
 
 
 
 
 
V13 (Week 45): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 
V13 (Week 45): End of infusion  
x 
x 
 
 
 
 
 
 
V14 (Week 49): Pre-dose 
x 
x 
x 
x 
x 
x 
x 
x 
V14 (Week 49): End of infusion 
x 
x 
x 
 
 
 
 
 
V15 (Week 53): Pre-dose  
x 
x 
 
x 
x 
x 
x 
 


Clinical Study Protocol AL001-2, Version 4.0 
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Alector, Inc. 
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Timepoint 
Vital 
Signs 
Serum 
PK 
sample a 
Triplicate 
ECG 
Serum 
ADA 
sample 
Progranulin 
plasma 
sample 
Exploratory 
plasma PD 
biomarker 
samples b 
Whole 
blood 
for 
WBC 
Exploratory 
whole blood 
PD biomarker 
samples c 
V15 (Week 53): End of infusion  
x 
x 
 
 
 
 
 
 
V16 (Week 57): Pre-dose  
x 
 
 
 
 
 
 
 
V16 (Week 57): End of infusion  
x 
 
 
 
 
 
 
 
V17 (Week 61): Pre-dose  
x 
x 
 
x 
x 
x 
x 
x 
V17 (Week 61): End of infusion  
x 
x 
 
 
 
 
 
 
V17 (Week 61): 3 hr ± 90 minutes post end of infusion 
 
x 
 
 
 
 
 
 
V17A (Week 61): The next day after V17 
 
x 
 
 
x 
 
 
 
V18 (Week 65): Pre-dose  
x 
 
 
 
 
 
 
 
V18 (Week 65): End of infusion  
x 
 
 
 
 
 
 
 
V19(Week 69): Pre-dose  
x 
 
 
 
 
 
 
 
V19 (Week 69): End of infusion  
x 
 
 
 
 
 
 
 
V20 (Week 73): Pre-dose  
x 
x 
x 
x 
x 
x 
x 
x 
V20 (Week 73): End of infusion  
x 
x 
x 
 
 
 
 
 
V21 (Week 77): Pre-dose  
x 
 
 
 
 
 
 
 
V21 (Week 77): End of infusion  
x 
 
 
 
 
 
 
 
V22 (Week 81): Pre-dose  
x 
 
 
 
 
 
 
 
V22 (Week 81): End of infusion  
x 
 
 
 
 
 
 
 
V23 (Week 85): Pre-dose  
x 
x 
 
x 
x 
x 
x 
x 
V23 (Week 85): End of infusion  
x 
x 
 
 
 
 
 
 
V24 (Week 89): Pre-dose  
x 
 
 
 
 
 
 
 
V24 (Week 89): End of infusion  
x 
 
 
 
 
 
 
 
V25 (Week 93): Pre-dose  
x 
 
 
 
 
 
 
 
V25 (Week 93): End of infusion  
x 
 
 
 
 
 
 
 
V26 (Week 97): Pre-dose  
x 
x 
x 
x 
x 
x 
x 
x 
V26 (Week 97): End of infusion  
x 
x 
x 
 
 
 
 
 
Safety Follow-up) 
x 
x 
x 
x 
x 
 
  
 
Part 1 EOT/EOS 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: ADA, anti-drug antibody; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; hr, hour; PD, pharmacodynamic; PK, 
pharmacokinetic; V, visit; WBC, white blood cell. 
a 
The window for serum PK samples is within 15 minutes after the end of the infusion. 
b 
Exploratory PD biomarkers include Neurofilament Light chain, t
u in plasma and other analytes.  
c 
Exploratory whole blood biomarkers include mRNA and other analytes.  


Clinical Study Protocol AL001-2, Version 4.0 
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Table 7: 
Schedule of Assessments for Part 2 (Optional OLE) (Through Week 161) 
Proceduresj 
OLE Part 2 Treatment Period 
Visits 
V27a V28 
V29 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Study week 
101 
105 
109 
113 
117 
121 
125 
129 
133 
137 
141 
145 
149 
153 
157 
161 
Study day 
701 
729 
757 
785 
813 
841 
869 
897 
925 
953 
981 1009 1037 1065 1093 1121 
Visit window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consenta 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
Xb 
Xb 
Neurological examinationc 
Xc 
Xc 
Vital signs and weightd,f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECGe,f 
x 
x 
Clinical chemistry, hematologyg 
x 
x 
x 
x 
x 
Urinalysisg 
x 
x 
Pregnancy testg,h 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PK samplesf,g,i 
x 
x 
PGRN Plasma samplesf,g 
x 
x 
Serum ADA samplesf,g,i 
x 
x 
Exploratory plasma PD biomarker samples f,g 
x 
x 
Brain MRIk 
x 
Diagnostic characterizationl 
COAsm 
x 
x 
Winterlight-A Labs Speech Assessment 
(Optional)n 
x 
x 
x 
x 
x 
Winterlight-B Labs Speech Assessment 
(Optional)n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Review of AEs and concomitant medicationso 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sheehan-STS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; ECG, 
electrocardiogram; eCRF, electronic case report form; IL-6, Interleukin 6; MRI, magnetic resonance imaging; PD, pharmacodynamic; PE, physical examination; 
PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, Sheehan Suicidality Tracking Scale; V, visit. 
a 
There is no Screening period for participants that opt-in to continue receiving AL001 in Part 2 (Optional OLE) of the study. Participants who complete the 
Part 1 96-week treatment period (Week 97), who provide informed consent to participate in Part 2 (optional OLE) and meet all the eligibility criteria for the 
Part 2 OLE (prior to Week 101 study drug administration), will complete the Week 97 visit and continue to Part 2 (Week 101) to receive their next regularly 
scheduled dose of AL001 according to the OLE administration schedule (continuation from Week 97 to Week 101). Visit 27/Week 101 of Part 2 (Optional 
OLE) will be conducted 4 weeks after Visit 26/Week 97 of the Part 1 Treatment Period for those participants who are eligible to participate. 
b 
A complete PE will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, genital, and rectal 
examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a physician, or a nurse 
practitioner or physician’s assistant under the supervision of a physician. If applicable, limited or symptom-directed examinations will be performed at all 
other specified time points, prior to study drug administration. A limited examination or symptom-directed examination should focus on the affected organ 
system or body area. Record new or worsened clinically significant abnormalities on the AE eCRF. Height (cm) does not need to be collected in Part 2 OLE. 
c 
A complete neurological examination will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes the 
evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. If applicable, limited or symptom-
directed examinations will be performed at all other specified time points, prior to study drug administration. A limited examination or symptom-directed 
examination should focus on the organ system or affected body area. Record new or worsened clinically significant abnormalities as AEs on the AE eCRF. 
d 
Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be recorded 
prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight (kg) will be 
collected at the same visits that vital signs are taken. 
e 
Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days, ECG will be 
obtained prior to study drug administration and within 60 minutes after the end of the infusion, and once at all other specified time points as indicated. 
Additional ECG monitoring must be performed during treatment period if clinically indicated. 
f 
Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, and exploratory plasma PD 
biomarker samples, are provided in Table 9. 
g 
Samples will be collected prior to study drug administration (if applicable). 
h 
All women of childbearing potential will have urine pregnancy tests at specified visits. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
i 
Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should be 
collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA assessment of 
AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 
j 
If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-site visit 
with approval from the medical monitor. Refer to Appendix 3 for additional details on trial adaptations due to COVID-19. 
k 
During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. 


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l 
A diagnostic characterization form will be completed for symptomatic patients at Week 197/Part 2 EOS. It will also be completed for any asymptomatic 
participant who becomes symptomatic during the course of the study; for these participants, the diagnostic characterization form will be completed only at 
the first visit in which they exhibit clinical symptomatology. 
m 
The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center 
Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical Global 
Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. Neurocognitive and 
functional tests will be performed prior to study drug administration (if applicable) and prior to any stressful procedures (e.g., blood collections, imaging). 
n 
Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) will be 
conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only (WLA-B) or 
both (WLA-A and WLA-B). Assessments are conducted at home within ±7 days of the visit and will be supervised by the study partner. The study partner 
will be asked to complete a questionnaire online within ±7 days of the EOS visit. 
o 
All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and through the 
Part1/Part2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory clinical resolution. 
Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator regardless of the AE/SAE 
collection window. At every study visit, participants will be asked a standard non-leading question to elicit any medically related changes in their well-being. 
They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed concomitant medication regimens 
(prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter medications). Review of AEs and concomitant 
medications will be performed before and after study drug administration (when applicable). 


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Table 8: 
Schedule of Assessments for Part 2 (Optional OLE) (Through Week 197) 
Proceduresi 
OLE Part 2 Treatment Period (continued) 
Part 2 
EOSo,p 
Safety 
Follow-upq 
Visits 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51o 
 
 
Study week 
165 
169 
173 
177 
181 
185 
189 
193 
197 
 
 
Study day 
1149 
1177 
1205 
1233 
1261 
1289 
1317 
1345 
1373 
 
 
Visit window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
±7 
Physical examinationa 
 
xa 
 
 
 
 
 
 
xa 
xa 
xa 
Neurological examinationb 
 
xb 
 
 
 
 
 
 
xb 
xb 
xb 
Vital signs and weightc,e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
ECGd,e 
 
x 
 
 
 
 
 
 
x 
X 
x 
Clinical chemistry, hematologyf 
 
x 
 
 
x 
 
 
 
x 
X 
x 
Urinalysisf 
 
x 
 
 
 
 
 
 
x 
X 
x 
Pregnancy testf,g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
Serum PK samplese,f,h 
 
x 
 
 
 
 
 
 
x 
X 
x 
PGRN Plasma samplese,f 
 
x 
 
 
 
 
 
 
x 
X 
x 
Serum ADA samplese,f,h 
 
x 
 
 
 
 
 
 
x 
X 
x 
Exploratory plasma PD biomarker 
samplese,f 
 
x 
 
 
 
 
 
 
x 
X 
 
Brain MRIj 
 
 
 
 
 
 
 
 
x 
X 
 
Diagnostic characterizationk 
 
 
 
 
 
 
 
 
x 
X 
 
COAsl 
 
x 
 
 
 
 
 
 
x 
X 
 
Winterlight-A Labs Speech 
Assessment (Optional)m 
 
x 
 
 
x 
 
 
 
x 
x 
 
Winterlight-B Labs Speech 
Assessment (Optional)m 
x 
 
x 
x 
 
x 
x 
x 
 
 
 
Review of AEs and concomitant 
medicationsn 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
Sheehan-STS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
Study drug administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; ECG, 
electrocardiogram; eCRF, electronic case report form; IL-6, Interleukin 6; MRI, magnetic resonance imaging; PD, pharmacodynamic; PE, physical examination; 
PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, Sheehan Suicidality Tracking Scale; V, visit. 


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a 
A complete PE will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes evaluation of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, genital, and rectal 
examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a physician, or a nurse 
practitioner or physician’s assistant under the supervision of a physician. If applicable, limited or symptom-directed examinations will be performed at all 
other specified time points, prior to study drug administration. A limited examination or symptom-directed examination should focus on the affected organ 
system or body area. Record new or worsened clinically significant abnormalities on the AE eCRF. Height (cm) does not need to be collected in Part 2 OLE. 
b 
A complete neurological examination will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes the 
evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. If applicable, limited or symptom-
directed examinations will be performed at all other specified time points, prior to study drug administration. A limited examination or symptom-directed 
examination should focus on the organ system or affected body area. Record new or worsened clinically significant abnormalities as AEs on the AE eCRF. 
c 
Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be recorded 
prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight (kg) will be 
collected at the same visits that vital signs are taken. 
d 
Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days, ECG will be obtained 
prior to study drug administration and within 60 minutes after the end of the infusion, and once at all other specified time points as indicated. Additional 
ECG monitoring must be performed during treatment period if clinically indicated.  
e 
Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, and exploratory plasma PD 
biomarker samples, are provided in Table 9. 
f 
Samples will be collected prior to study drug administration (if applicable). 
g 
All women of childbearing potential will have urine pregnancy tests at specified visits. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
h 
Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should be 
collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA assessment of 
AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 
i 
If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-site visit 
with approval from the medical monitor. Refer to Appendix 3 for additional details on trial adaptations due to COVID-19. 
j 
During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. 
k 
A diagnostic characterization form will be completed for symptomatic patients at Week 197/Part 2 EOS. It will also be completed for any asymptomatic 
participant who becomes symptomatic during the course of the study; for these participants, the diagnostic characterization form will be completed only at 
the first visit in which they exhibit clinical symptomatology.   
l 
The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center 
Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical Global 
Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. Neurocognitive and functional 
tests will be performed prior to study drug administration (if applicable) and prior to any stressful procedures (e.g., blood collections, imaging). 


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m 
Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) will be 
conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only (WLA-B) or 
both (WLA-A and WLA-B). Assessments are conducted at home within ±7 days of the visit and will be supervised by the study partner. The study partner 
will be asked to complete a questionnaire online within ±7 days of the EOS visit. 
n 
All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and through the 
Part1/Part2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory clinical resolution. 
Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator regardless of the AE/SAE 
collection window. At every study visit, participants will be asked a standard non-leading question to elicit any medically related changes in their well-being. 
They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed concomitant medication regimens 
(prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter medications). Review of AEs and concomitant 
medications will be performed before and after study drug administration (when applicable). 
o 
At Week 197, participants who complete the Part 2 96-week OLE period will complete a Part 2 EOS visit at the scheduled Week 197 timepoint. Participants 
who complete Visit 51/Week 197 will return for a Safety Follow-up visit 10 weeks after their last AL001 administration (Week 207, +/- 7 days). 
P 
Participants who discontinue study drug and/or all assessments prior to completing the 96-week Part 2 treatment period will complete a Part 2 EOS visit as 
soon as possible after the decision is made. 
q 
A Safety Follow-up visit will be performed 10 weeks following the last dose of AL001. The Safety Follow-up visit may be substituted by a scheduled visit if 
it occurs within the same window. 


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Table 9: 
Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker Sample and Imaging 
Assessments – Part 2 (Optional OLE) 
Timepoint 
Vital 
Signs 
Serum PK 
sample a 
Triplicate 
ECG 
Serum 
ADA 
sample 
Progranulin 
plasma sample 
Exploratory 
plasma PD 
biomarker 
samples b 
V27 (Week 101): Pre-dose 
x 
 
 
 
 
 
V27 (Week 101): End of infusion  
x 
 
 
 
 
 
V28 (Week 105): Pre-dose 
x 
 
 
 
 
 
V28 (Week 105): End of infusion 
x 
 
 
 
 
 
V29 (Week 109): Pre-dose 
x 
 
 
 
 
 
V29 (Week 109): End of infusion 
x 
 
 
 
 
 
V30 (Week 113): Pre-dose 
x 
 
 
 
 
 
V30 (Week 113): End of infusion 
x 
 
 
 
 
 
V31 (Week 117): Pre-dose 
x 
 
 
 
 
 
V31 (Week 117): End of infusion 
x 
 
 
 
 
 
V32 (Week 121): Pre-dose 
x 
x 
x 
x 
x 
x 
V32 (Week 121): End of infusion  
x 
x 
x 
x 
x 
x 
V33 (Week 125): Pre-dose 
x 
 
 
 
 
 
V33 (Week 125): End of infusion 
x 
 
 
 
 
 
V34 (Week 129): Pre-dose 
x 
 
 
 
 
 
V34 (Week 129): End of infusion 
x 
 
 
 
 
 
V35 (Week 133): Pre-dose 
x 
 
 
 
 
 
V35 (Week 133): End of infusion 
x 
 
 
 
 
 
V36 (Week 137): Pre-dose 
x 
 
 
 
 
 
V36 (Week 137): End of infusion 
x 
 
 
 
 
 
V37 (Week 141): Pre-dose 
x 
 
 
 
 
 
V37 (Week 141): End of infusion 
x 
 
 
 
 
 
V38 (Week 145): Pre-dose  
x 
x 
x 
x 
x 
x 
V38 (Week 145): End of infusion  
x 
x 
x 
x 
x 
x 
V39 (Week 149): Pre-dose 
x 
 
 
 
 
 
V39 (Week 149): End of infusion 
x 
 
 
 
 
 
V40 (Week 153): Pre-dose 
x 
 
 
 
 
 
V40 (Week 153): End of infusion 
x 
 
 
 
 
 
V41 (Week 157): Pre-dose 
x 
 
 
 
 
 


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Timepoint 
Vital 
Signs 
Serum PK 
sample a 
Triplicate 
ECG 
Serum 
ADA 
sample 
Progranulin 
plasma sample 
Exploratory 
plasma PD 
biomarker 
samples b 
V41 (Week 157): End of infusion 
x 
 
 
 
 
 
V42 (Week 161): Pre-dose 
x 
 
 
 
 
 
V42 (Week 161): End of infusion 
x 
 
 
 
 
 
V43 (Week 165): Pre-dose 
x 
 
 
 
 
 
V43 (Week 165): End of infusion 
x 
 
 
 
 
 
V44 (Week 169): Pre-dose  
x 
x 
x 
x 
x 
x 
V44 (Week 169): End of infusion  
x 
x 
x 
x 
x 
x 
V45 (Week 173): Pre-dose 
x 
 
 
 
 
 
V45 (Week 173): End of infusion 
x 
 
 
 
 
 
V46 (Week 177): Pre-dose 
x 
 
 
 
 
 
V46 (Week 177): End of infusion 
x 
 
 
 
 
 
V47 (Week 181): Pre-dose 
x 
 
 
 
 
 
V47 (Week 181): End of infusion 
x 
 
 
 
 
 
V48 (Week 185): Pre-dose 
x 
 
 
 
 
 
V48 (Week 185): End of infusion 
x 
 
 
 
 
 
V49 (Week 189): Pre-dose 
x 
 
 
 
 
 
V49 (Week 189): End of infusion 
x 
 
 
 
 
 
V50 (Week 193): Pre-dose 
x 
 
 
 
 
 
V50 (Week 193): End of infusion 
x 
 
 
 
 
 
V51 (Week 197): Pre-dose  
x 
x 
x 
x 
x 
x 
V51 (Week 197): End of infusion  
x 
x 
x 
x 
x 
x 
Safety Follow-up  
x 
x 
x 
x 
x 
 
Part 2: EOS 
x 
x 
x 
x 
x 
x 
Abbreviations: ADA, anti-drug antibody; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; hr, hour; PD, pharmacodynamic; PK, 
pharmacokinetic; V, visit; 
a 
The window for serum PK samples is within 15 minutes after the end of the infusion. 
b 
Exploratory PD biomarkers include Neurofilament Light chain, tau, and p-tau in plasma and other analytes. 


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APPENDIX 2. CLINICAL OUTCOME ASSESSMENTS – 
NEUROCOGNITIVE AND FUNCTIONAL TESTS 
Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s 
Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language 
Domains (CDR® plus NACC FTLD): 
The CDR® plus NACC FTLD assessment is the CDR® plus the Frontotemporal Dementia 
Behavior and Language Domain scores from the NACC FTLD module. Data for this scale will 
be captured through completion of the standard CDR and a domain-specific container form 
labeled Frontotemporal Dementia Behavior and Language Domains (FTD-BLD). The necessary 
information to rate these domains is obtained through a semi-structured interview of the 
participant and a reliable informant or collateral source (e.g., a caregiver). 
Clinical Dementia Rating Scale (CDR®): 
Washington University’s CDR is a global assessment instrument that yields global scores 
(CDR-GS). The sum of boxes (CDR-SB) score is a detailed quantitative general index that 
provides more information than the CDR-GS in participants with mild dementia 
(O'Bryant 2010). The CDR characterizes 6 domains of cognitive and functional performance 
applicable to Alzheimer’s disease and related dementias: Memory, Orientation, Judgment and 
Problem Solving, Community Affairs, Home and Hobbies, and Personal Care. The necessary 
information to make each rating is obtained through a semi-structured interview of the 
participant and a reliable informant or collateral source (e.g., a caregiver). 
Frontotemporal Dementia Rating Scale (FRS): 
The FRS is a 30-item scale designed to assess the frequency of problematic behaviors and 
difficulties with activities of daily living such as shopping, chores, telephone use, management of 
finances and medications, meal preparation and eating, self-care and mobility. 
Clinical Global Impression of Severity (CGI-S): 
The CGI-S is a 7-point Likert scale that is used by a clinician to rate the severity of a 
participant’s disease relative to the clinician’s past experience with patients who have the same 
diagnosis. 
Clinical Global Impression of Improvement (CGI-I): 
The CGI-I is a 7-point Likert scale that is used by a clinician to rate how much a participant’s 
disease has improved or worsened relative to baseline. The CGI-I will be administered in this 
study to assess (a) total improvement/worsening, (b) total improvement/worsening of behavior, 
motivation, and social cognition symptoms, and (c) total improvement/worsening of language 
abilities. 


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Color Trails Test (CTT): 
The CTT is a language-free version of the Trail Making Test that was developed to allow for 
broader cross-cultural assessment of sustained attention and divided attention in adults. In the 
CTT, numbered circles are printed with vivid pink or yellow backgrounds. For Part 1, the 
respondent uses a pencil to rapidly connect circles numbered 1 to 25 in sequence. For Part 2, the 
respondent rapidly connects numbered circles in sequence, but alternates between pink and 
yellow. The length of time to complete each study is recorded. Part 2 of the CTT will only be 
assessed in this study. 
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): 
The RBANS is a collection of 12 subtests representing 5 neurocognitive domains: Immediate 
Memory, Visuospatial/Constructional, Language, Attention, and Delayed Memory. The raw 
scores from each subtest within a domain are converted to a summary score, or Index Score, for 
the domain by consulting normative data tables. The RBANS also provides an overall Index 
Score that summarizes the patient’s overall level of performance on this measure. 
Sheehan Suicidality Tracking Scale (Sheehan-STS): 
The Sheehan-STS is a brief scale designed to assess and monitor over time the core phenomena 
of suicidality. The Sheehan-STS is a sensitive psychometric tool to prospectively assess for 
treatment-emergent suicidal thoughts and behaviors. The Sheehan-STS is a 16-item scale that 
will be administered either by a clinician or participant through self-report. Each item in the 
Sheehan-STS is scored on a 5-point Likert scale (0=not at all, 1=a little, 2=moderately, 3=very, 
and 4=extremely). Any change in the Sheehan-STS score indicating the presence of suicidality 
should be immediately evaluated by the investigator and reported to the Medical Monitor. 
Optional Winterlight Labs Speech Assessments (WLA) 
The optional Winterlight Lab Speech Assessments (WLA) are for US, UK, and Canadian 
participants who are proficient in English and who agree and are eligible to participate in these 
optional assessments. 
If the participant and study partner are eligible, agree to, and provide consent for this optional 
assessment, WLA procedures will be performed at home, as detailed in the Schedules of 
Assessments (Appendix 1). 
Winterlight Labs Speech Assessment (WLA) Overview 
The WLA was developed to evaluate speech, language, and cognition using short samples of 
speech. Winterlight’s software decomposes a speech sample into over 500 individual markers. 
These markers quantify both the acoustic and linguistic properties of the speech. Acoustic 
markers describe properties of the sound wave itself such as tone, speaking rate, pausing (both 
filled and unfilled), pitch, and spectral power. Linguistic markers are extracted from the content 
of speech (e.g., transcripts) and include the frequency of different parts of speech (such as nouns, 
verbs, pronouns, and prepositions) as well as more global measures of discourse coherence and 
the complexity of syntax and grammar. 


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To standardize the content of each speech sample and ensure that sufficient speech is collected, 
the WLA records participants’ responses to a series of standard speech and language tasks. 
To allow for a greater range of free speech collection, the WLA also includes open-ended 
questions and journaling in place of structured neuropsychological tasks. While these tasks 
provide consistent subject matter, they also provide their own task-specific indices of 
performance. The WLA leverages both these task-specific outcomes as well as task-independent 
markers to evaluate an individual’s cognitive performance. 
The WLA is administered using a tablet that presents assessment questions and records audio of 
the participant. It is composed of various established aspects from paper/interview-based 
assessments, including picture description, story recall, and object recognition as well as open-
ended questions and journaling. 
Participants will have the option to complete the WLA after assessment visits only (WLA-A), 
after treatment visits only (WLA-B) or both (WLA-A and WLA-B). These assessments are 
conducted at home within ±7 days of a treatment assessment visit. Assessments will be 
supervised by the study partner. 


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APPENDIX 3. ADAPTATION OF TRIAL PROTOCOL DURING COVID-
19 PANDEMIC 
Background 
The COVID-19 pandemic has caused significant disruption globally and is a public health 
emergency that has an impact on the conduct of global clinical research activities. The safety of 
patients and site staff continues to be paramount, and Alector has made the decision to continue 
patient participation in the AL001-2 study at the discretion of the investigator, and in accordance 
with each site’s regional or country health authority guidelines and recommendations regarding 
the COVID-19 pandemic. 
Alector, in collaboration with the clinical research organization (CRO), is committed to 
performing pandemic-related risk reviews of study procedures and mitigating the effect of the 
pandemic on the conduct of this study. These ongoing collaborative risk reviews include analysis 
of COVID-19 restrictions as they impact patient safety, study, and data integrity, and the impact 
on program timelines continues to be assessed. The review has been and will continue to be 
conducted regularly and will take into consideration any new information regarding the 
pandemic, including continuous assessment of adverse events reported in the study. 
Implementation of COVID-19 Appendix 
The implementation of adaptations to study visits and procedures detailed described in this 
appendix applies only to the exceptional circumstances of the COVID-19 pandemic. Procedure 
adaptations apply to those sites that have been impacted by the pandemic through restrictions to 
movement/trave, study site restrictions, and where the safety of the patient may be adversely 
impacted by on-site visits. 
The implementation of these adaptations will be determined on a site-by-site basis dependent on 
local requirements, and will be reviewed on a regular basis with Alector to confirm the continued 
need for implementation. 
Essential On-Site Assessments and Remote Visits (Via Phone or Video) 
Continuation of the study during the pandemic does, and will continue, to impact the ability of 
some sites to conduct all protocol assessments per the Schedules of Events detailed in 
Appendix 1). This is due to reduced time for on-site visits, limited or no availability of some 
services at site, or the need to conduct visits remotely via telephone or via televisit (if approved 
locally). 
The primary objective with any change to the study schedule is to ensure ongoing monitoring of 
patient safety. 


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On-site Essential Assessments 
Where possible, all protocol assessments and treatments should be completed. 
To accommodate reduced time on-site during study visits, the following reduced assessments 
schedule should be completed as a minimum: 
• Vital signs, weight, physical, and neurological examinations 
• Phlebotomy and urinalysis, including pregnancy test 
• ECGs 
• Collection of AEs and concomitant medications 
• Sheehan-STS 
• Study drug administration 
Remote Essential Assessments 
If participants or raters are not able to come to the hospital for a visit, the following assessments 
should be completed by telephone or video (if locally approved/allowed): 
• Review of AEs and concomitant medications 
• Review of medical history 
• The following Clinical Outcome Assessments (COAs) listed below can be completed 
remotely: 
1. Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s 
Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and 
Language Domains (CDR® plus NACC FTLD) 
While it is strongly preferred that participants and caregivers receive 
administration of the CDR® plus NACC FTLD in person, it is understood that 
remote administration might be required due to extenuating circumstances. The 
CDR NACC FTLD can be administered telephonically or by locally approved video 
conference capabilities. 
• Recommendation: Although the full CDR® plus NACC FTLD administration has 
not been validated for remote (i.e. phone or video conferencing) administration, 
remote administration by phone has been validated for 6 of the domains (Randolph, 
C., et al, TELEPHONE ADMINISTRATION OF THE CDR: EXCELLENT 
AGREEMENT WITH FACE-TO-FACE ADMINISTRATION, 2014). Scoring 
anchors can be reliably differentiated for the remaining CDR® plus NACC FTLD two 
domains (language and behavior) via phone, however video conferencing would yield 
more reliable data for scoring these domains and eliminate the need to rely on the 
caregiver for observations (e.g., the rater can evaluate subject appearance, facial 
expression, and ask them to name objects in the room). Given the incremental 


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differences between anchors, raters should be able to differentiate scores with 
adequate inquiry even if the rater, subject, and caregiver are not in the same room. 
• In the circumstance that the primary rater is remote, and the subject and back-up rater 
are on-site, scales can still be administered by the primary rater. The primary rater 
should call in to the visit to administer the CDR® plus NACC FTLD questions over 
the phone. The back-up rater should observe the subject while they are answering the 
questions, and then provide observations of the subject behavior to the primary rater. 
Missing data from direct observation, which cannot be provided by the primary rater, 
can be completed by the back-up rater, as long as they are appropriately trained on the 
scale. Final observational assessments should be made by the primary rater. 
2. Frontotemporal Dementia Rating Scale (FRS) 
• Recommendation: As a clinician-administered interview with the study partner, the 
FRS can be administered in person in the clinic, in home, telephonically, or via video 
conferencing. 
• In the circumstance that the primary rater is remote, and the subject and back-up rater 
are on-site, scales can still be administered by the primary rater. The primary rater 
should call in to the visit to administer the FRS questions over the phone. The back-
up rater should observe the subject while they are answering the questions, and then 
provide observations of the subject behavior to the primary rater. Missing data from 
direct observation, which cannot be provided by the primary rater, can be completed 
by the back-up rater, as long as they are appropriately trained on the scale. Final 
observational assessments should be made by the primary rater. 
3. CGI 
• Recommendation: A general, unstructured evaluation, discussion with an informant, 
as well as review of data collected from other scales (if not contraindicated by the 
protocol or study team instructions) may help ensure CGI raters have adequate 
information to score. Since the CGI is scored based on the CDR® plus NACC FTLD 
interview, a separate interview is not required. 
4. Sheehan-STS  
• Recommendation: This can be completed via phone. Per Dr. Sheehan, a copy of 
scale should be provided for the subject to view when they are being evaluated. 
Please note that some scales requiring subject performance, like drawing or writing, are not 
validated for remote administration and may not be administered via telephone (e.g., Color 
Trails Test [CTT] and Repeatable Battery for the Assessment of Neuropsychological Status 
[RBANS]). 


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Communication technologies to be used for remote COA administration are summarized in the 
following table: 
Scale 
Communication Technologies 
CDR® plus NACC 
FTLD 
Video Conference 
(Please note that a phone assessment might be done, however, the Language domain 
impairment should be taken into account and this should be approved by Alector) 
CGI-I 
NA 
CGI-S 
NA 
FRS 
Phone 
Sheehan-STS 
Phone 
RBANS 
Should not be administered remotely 
CTT 
Should not be administered remotely 
The following general guidelines for administering scales telephonically or by video conference 
should be followed: 
• Always record on the notes page of the scale or in your source documents when a 
certain assessment was administered remotely and describe any accommodations 
made. 
• Ensure that scale administration guidelines indicated in the scale manual and tutorial 
are carefully followed when adapted for use via telephone. 
• Raters are encouraged to consider and address possible distractions which could 
affect performance during an assessment. This includes forms of distraction that may 
not be obvious or visible (e.g., sight, sound, and smell). Consider the quality of the 
telecommunication technologies being used and the hardware requirements needed in 
order to conduct the specific assessment (e.g., a telephone with speakerphone). 
• Always use the speaker phone for the scales that should be recorded for Independent 
Review. 
• Scales should be administered as if informant and/or subject were face-to-face with 
the rater and should be administered in a quiet, distraction-free interview 
environment. 
• There may be situations in which study partners or raters are remote. In these cases, 
the following guidance should be followed: 
− If the study partner/caregiver is remote and the subject is on-site, scales can be 
administered per procedure, with study partner/caregiver providing answers to the 
site rater. 
− If the primary rater is remote, and the subject and back-up rater are on-site, scales 
can still be administered by the primary rater. The back-up rater can be used to 


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provide observational information to the primary rater, provided that they are 
trained on the scale. Refer to additional guidance under CDR® plus NACC FTLD 
and Frontotemporal Dementia Rating Scale (FRS) sections. 
On-site Assessments Unable to be Completed at Scheduled Visits 
In the event that a scheduled assessment is unable to be completed at site, e.g., limited 
availability/restriction of equipment (e.g., MRI), patient limited time on-site or because a remote 
visit was completed, the missed assessments may be completed at a future on-site visit as 
determined and approved by the medical monitor. 
The approval of the medical monitor must be obtained prior to completion of these moved 
assessments. 
COVID-19 Reporting 
In the event where a study subject is diagnosed with COVID-19 infection, the local health 
authority recommendations regarding treatment should be followed and the event should be 
reported as an AE/SAE depending on the severity of infection and diagnosis. Refer to Section 7 
of the protocol. 
Remote Consent 
Where it is allowed by country/site regulations, a remote eConsent will be provided that allows a 
patient to be remote from the site and participate in the consent process. 
Remote Source Document Verification 
Remote source document verification will be employed only in the following circumstance:  
• National law, Regulatory Authorities and IRB/Ethics Committee permit this process 
and approval is obtained.  
• On-site clinical research associate (CRA) visits are not permitted due to continued 
COVID-19 restrictions.  
• There is a need to complete source document verification for the following reasons: 
− Study Data assessment review of critical study milestones (e.g., database lock) 
− Patient safety 
− A significant backlog of data monitoring that could impact data integrity or 
patient safety. 
Prior to commencing remote source document verification, the following documentation must be 
completed:  
• The Site CRA will complete a confidentiality agreement committing to securely 
destroy any copies of documents received from sites (paper or electronic), nor take 
any recording during video access. 


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• Remote source data verification (SDV) will only be completed for subjects who have 
consented to allow access to their health records remotely. 
At Home Study Drug Administration 
In most instances, study drug should be administered at the investigational site. In the event the 
participant is unable to have study drug administered at the investigational site (i.e., due to 
participant or site restrictions related to Covid-19) study drug administration for the third and 
subsequent infusions may be performed “at home” (i.e., at the participant’s home or other 
suitable location) by a home healthcare provider who has appropriate training and expertise in IV 
administration. Study drug administration for the first and second infusion must be conducted at 
the investigational site, at home study drug administration for subsequent infusions may only be 
performed with Medical Monitor approval. 
The following procedures must be performed for each at home study drug administration: 
Before study drug administration: 
• Home healthcare provider will record vital signs, including systolic and diastolic BP, 
pulse, body temperature, and respiratory rate (recorded after the participant has been 
resting for at least 5 minutes in the supine position) 
• Home healthcare provider will conduct anassessment1,2 to include evaluation of 
general appearance, skin, EENT, head and neck, extremities, abdomen, and 
respiratory, cardiovascular, neurological, and musculoskeletal systems 
• Home healthcare provider will conduct a review of concomitant medication(s) 
• Home healthcare provider will record any AEs (signs and symptoms) which may 
have occurred since previous visit 
• Home healthcare provider will contact the investigative site by phone or video 
(investigator or designee) to review findings from the assessment, adverse events and 
concomitant medications 
• Home healthcare provider must receive email confirmation from the investigative site 
to proceed with study drug administration, prior to initiating study drug 
administration. 
During study drug administration: 
• Approximately 15 and 45 minutes after initiating study drug administration, monitor 
vital signs, including systolic and diastolic BP, pulse, body temperature, and 
respiratory rate2 
• Monitor for infusion-related reactions or injection-related reactions3 
• Record any AEs (signs and symptoms) 


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After study drug administration 
• Record vital signs, including systolic and diastolic BP, pulse, body temperature, and 
respiratory rate (recorded within 15 minutes after the end of infusion) 
• Monitor for infusion-related reactions or injection-related reactions for at least 90 
minutes post-infusion3 
• Conduct an assessment1,2 to include evaluation of general appearance, skin, EENT, 
head and neck, extremities, abdomen, and respiratory, cardiovascular, neurological, 
and musculoskeletal systems 
• Record any AEs (signs and symptoms) 
If any AEs are observed during or after study drug administration the home healthcare provider 
must contact the clinical site by phone or video (investigator or designee) to review findings and 
to take appropriate action(s), if directed by the investigator (or designee). 
If required, the site investigator may also conduct a tele visit prior to, during, or after study drug 
administration. 
1 The assessment will substitute for the protocol specified physical and neurological examination . 
2 Abnormalities identified during the assessment should be recorded as an AE and reported to the site in order to be 
entered in the EDC. 
3 Management of infusion-related and/or injection-related reactions is described in Protocol Section 5.1.2. 

SAP_001.pdf: 
Confidential 
Alector Inc. 
AL001-2 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of AL001 in Heterozygous 
Carriers of Granulin or C9orf72 Mutations Causative of Frontotemporal 
Dementia 
19MAR2024 
Final Statistical Analysis Plan 
Version 3.0 
Prepared by: 
Mario Langa Oropesa 
PPD 
3900 Paramount Parkway 
Morrisville, NC 27560 USA 


Statistical Analysis Plan (SAP) Client Approval Form 
 
Document Number: FORM-02894 v8.0 
Page 1 of 1 
Effective Date: 22 Nov 2021 
Printed on: 19 March 2024 
 
Client: 
Alector, Inc 
Protocol Number: 
AL001-2 
 
Document Description: 
Final Statistical Analysis Plan 
SAP Title: 
A Phase 2, Multicenter, Open-Label Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of AL001 in Heterozygous Carriers of 
Granulin or C9orf72 Mutations Causative of 
Frontotemporal Dementia 
SAP Version Number: 
3.0 
Effective Date: 
19MAR2023 
 
Author(s): 
For PPD: Mario Langa Oropesa, 
 
               Oluwakemi Oyeneyin, 
 
 
Approved by: 
 
 
 
 
 
Grace Chao 
 
 
Date (DD-MMM-YYYY) 
 
 
 
 
 
 
Lawrence Carter 
 
 
Date (DD-MMM-YYYY) 
 


Alector Inc. 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
Date Issued: 19MAR2024 
 
  
 
 
 1
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 3 
1. 
INTRODUCTION ............................................................................................................ 0 
1.1. 
OBJECTIVES AND ENDPOINTS .......................................................................................... 0 
1.2. 
STUDY DESIGN ................................................................................................................ 4 
2. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 6 
2.1. 
SAMPLE SIZE ................................................................................................................... 6 
2.2. 
RANDOMIZATION AND BLINDING .................................................................................... 7 
2.3. 
ANALYSIS POPULATIONS ................................................................................................. 7 
2.3.1. 
ENROLLED POPULATION .................................................................................................. 7 
2.3.2. 
SAFETY ANALYSIS POPULATION ..................................................................................... 7 
2.3.3. 
PK ANALYSIS POPULATION ............................................................................................. 7 
2.3.4. 
FULL ANALYSIS POPULATION ......................................................................................... 7 
3. 
PARTICIPANT DISPOSITION AND PROTOCOL DEVIATIONS .......................... 7 
3.1. 
DISPOSITION .................................................................................................................... 7 
3.2. 
PROTOCOL DEVIATIONS .................................................................................................. 8 
4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 8 
4.1. 
DEMOGRAPHICS .............................................................................................................. 8 
4.2. 
DIAGNOSTICS CHARACTERIZATION ................................................................................. 9 
4.3. 
MEDICAL HISTORY .......................................................................................................... 9 
4.4. 
ADMISSION CRITERIA DEVIATION ................................................................................... 9 
4.5. 
PHARMACOGENOMIC MEASUREMENTS ........................................................................... 9 
5. 
TREATMENTS AND MEDICATIONS ......................................................................... 9 
5.1. 
PRIOR AND CONCOMITANT MEDICATIONS ...................................................................... 9 
5.2. 
MEDICAL AND SURGICAL TREATMENT PROCEDURES .................................................... 10 
5.3. 
STUDY DRUG ADMINISTRATION .................................................................................... 10 
6. 
SAFETY ANALYSIS ..................................................................................................... 11 
6.1. 
ADVERSE EVENTS ......................................................................................................... 11 
6.1.1. 
INCIDENCE OF ADVERSE EVENTS .................................................................................. 12 
6.1.2. 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY DRUG ................................................. 12 
6.1.3. 
SEVERITY OF ADVERSE EVENT ...................................................................................... 12 
6.1.4. 
SERIOUS ADVERSE EVENTS ........................................................................................... 13 
6.1.5. 
ADVERSE EVENTS LEADING TO STUDY DRUG DISCONTINUATION ................................ 13 
6.2. 
CLINICAL LABORATORY EVALUATIONS ........................................................................ 13 
6.3. 
VITAL SIGNS AND WEIGHTS MEASUREMENTS ............................................................... 15 
6.4. 
TRIPLICATE 12-LEAD ELECTROCARDIOGRAMS ............................................................. 15 
6.5. 
PHYSICAL AND NEUROLOGICAL EXAMINATIONS ........................................................... 16 
6.6. 
SHEEHAN SUICIDALITY TRACKING SCALE (S-STS) ....................................................... 17 
6.7. 
IMMUNOGENICITY ......................................................................................................... 18 
6.8. 
MAGNETIC RESONANCE IMAGING ................................................................................. 18 


Alector Inc. 
 
Final Statistical Analysis Plan, Version 3.0 
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Date Issued: 19MAR2024 
 
  
 
 
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7. 
PHARMACOKINETICS ............................................................................................... 18 
7.1. 
SERUM PHARMACOKINETICS SAMPLES ......................................................................... 18 
7.2. 
CSF PHARMACOKINETIC SAMPLES................................................................................ 19 
7.3. 
SERUM PHARMACOKINETIC PARAMETERS ..................................................................... 19 
8. 
PHARMACODYNAMIC BIOMARKERS .................................................................. 20 
8.1. 
PROGRANULIN PLASMA SAMPLES ................................................................................. 20 
8.2. 
PROGRANULIN CEREBROSPINAL FLUID SAMPLES .......................................................... 20 
9. 
EXPLORATORY CLINICAL OUTCOME ASSESSMENTS................................... 21 
9.1. 
ANALYSIS VISIT WINDOWS ............................................................................................ 21 
9.2. 
CLINICAL DEMENTIA RATING DEMENTIA STAGING INSTRUMENT PLUS NATIONAL 
ALZHEIMER’S DISEASE COORDINATING CENTER FRONTOTEMPORAL LOBAR 
DEGENERATION BEHAVIOR AND LANGUAGE DOMAINS (CDR® PLUS NACC FTLD) .. 22 
9.3. 
FRONTOTEMPORAL DEMENTIA RATING SCALE (FRS) ................................................... 22 
9.4. 
CLINICAL GLOBAL IMPRESSION OF SEVERITY (CGI-S) AND OF IMPROVEMENT (CGI-I) 22 
9.5. 
COLOR TRAILS TEST (CTT) .......................................................................................... 23 
9.6. 
REPEATABLE BATTERY FOR THE ASSESSMENT OF NEUROPSYCHOLOGICAL STATUS 
(RBANS) ...................................................................................................................... 23 
9.7. 
NEUROPSYCHIATRIC INVENTORY (NPI), U
 
(
; PART III), DELIS-KAPLAN EXECUTIVE FUNCTION SYSTEM (D-KEFS), AND 
INTERPERSONAL REACTIVITY INDEX (IRI) .................................................................... 23 
9.8. 
OPTIONAL WINTERLIGHT LABS SPEECH ASSESSMENTS ................................................ 23 
10. 
EXPLORATORY PHARMACODYNAMIC BIOMARKERS .................................. 23 
10.1. 
ANALYSIS VISIT WINDOWS ............................................................................................ 24 
10.2. 
EXPLORATORY PHARMACODYNAMIC BIOMARKERS OF NEURODEGENERATION, 
LYSOSOMAL FUNCTION, AND GLIAL ACTIVITY ............................................................... 24 
10.3. 
BRAIN IMAGING ............................................................................................................ 26 
10.4. 
EXPLORATORY CORRELATION ANALYSES ..................................................................... 27 
11. 
INTERIM ANALYSIS ................................................................................................... 27 
12. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 27 
13. 
REFERENCES ................................................................................................................ 29 
14. 
APPENDICES ................................................................................................................. 32 
14.1. 
SCHEDULE OF ASSESSMENTS FOR PART 1, TREATMENT PERIOD (THROUGH WEEK 53) . 32 
14.2. 
APPENDICES SCHEDULE OF ASSESSMENTS FOR PART 1, TREATMENT PERIOD (THROUGH 
WEEK 97) ...................................................................................................................... 36 
14.3. 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND PHARMACODYNAMIC 
BIOMARKER SAMPLE AND IMAGING ASSESSMENTS – PART 1, TREATMENT PERIOD ..... 39 
14.4. 
SCHEDULE OF ASSESSMENTS FOR PART 2 (OPTIONAL OLE) (THROUGH WEEK 161) .... 41 
14.5. 
SCHEDULE OF ASSESSMENTS FOR PART 2 (OPTIONAL OLE) (THROUGH WEEK 197) .... 44 
14.6. 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND PHARMACODYNAMIC 
BIOMARKER SAMPLE AND IMAGING ASSESSMENTS – PART 2 (OPTIONAL OLE) ........... 47 


Alector Inc. 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
Date Issued: 19MAR2024 
 
  
 
 
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List of Abbreviations 
 
ADA
Antidrug antibody 
AE
Adverse event 
aFTD-GRN 
Asymptomatic frontotemporal dementia carriers heterozygous 
for granulin mutations
ALT 
Alanine aminotransferase
ANC
Absolute neutrophils count 
AST
Aspartate aminotransferase
ATC
Anatomical-Therapeutic-Chemical
AUCss
Area under the concentration-time curve at steady state
BP
Blood pressure
bvFTD
Behavioral variant frontotemporal dementia 
CDR
Clinical Dementia Rating Scale 
CGI-I
Clinical Global Impression of Improvement
CGI-S
Clincal Global Impression of Severity
CI
Confidence interval
Cmax
Maximum observed concentration
CNS
Central nervous system 
COA
Clinical outcome assessment
CSF 
Cerebrospinal fluid 
CSR
Clinical study report
Ctrough
Trough concentration 
CTT
Color Trails Test 
CV
Coefficient of variation 
D-KEFS
Delis-Kaplan Executive Function System 
DTI
Diffusion tensor imaging
ECG
Electrocardiogram
eCRF
Electronic case report form
FCRS
Frontotemporal Dementia Clinical Rating Scale 
FDA
US Food and Drug Administration 
FRS 
Frontotemporal Dementia Rating Scale
FTD
Frontotemporal dementia 
FTD-C9orf72 
Symptomatic frontotemporal dementia patients with C9orf72 
hexanucleotide repeat expansion mutations 
FTD-GRN 
Symptomatic frontotemporal dementia patients heterozygous for 
granulin mutations
FTLD
Frontotemporal lobar degeneration
FTLD-FUS 
Frontotemporal lobar degeneration – immunoreactive to the 
fused in sarcoma protein
FTLD-TDP 
Frontotemporal lobar degeneration – transactive response 
DNA-binding protein 43 
GCP
Good Clinical Practice
GRN
Granulin
ICF
Informed consent form
ICH
International Council for Harmonisation


Alector Inc. 
Final Statistical Analysis Plan, Version 3.0 
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IEC
Independent ethics committee
IRB
Institutional review board
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model of repeated measures
MMSE
Mini-Mental Status Exam
MRI
Magnetic resonance imaging
mRNA
messenger ribonucleic acid
NFL
Neurofilament-light
NPI
Neuropsychiatric Inventory
OLE
Open-Label Extension
PD
Pharmacodynamic(s)
PE
Physical examination
PGRN
Progranulin
PK
Pharmacokinetic(s)
PPA
Primary progressive aphasia
PT
Preferred term
q4w
Every 4 weeks
QTcF
QT interval corrected using Fridericia formula
RBANS 
Repeatable Battery for the Assessment of Neuropsychological 
Status
SAE
Serious adverse event
SAP
Statistical analysis plan
Sheehan-STS
Sheehan Suicidality Tracking Scale
SOC
System organ class
TDP-43
DNA-binding protein 43
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
S
WBC
White blood cell
WGS
Whole genome sequencing
WHO
World Health Organization
WHO-DD
WHO Drug Dictionary
WLA
Winterlight Lab Speech Assessment
WOCBP
Woman of childbearing potential


Alector Inc. 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
Date Issued: 19MAR2024 
 
  
 
 
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1. Introduction 
This document outlines the statistical methods to be implemented during the analysis of data 
collected within the scope of Alector Inc. protocol AL001-2 version 4.0, dated 04 Feb 2021 (A 
Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of AL001 in Heterozygous Carriers of Granulin or C9orf72 Mutations 
Causative of Frontotemporal Dementia) and the previous version 3.2 United Kingdom, dated 23 
November 2020, version 3.1, dated 13 July 2020, version 3.0, dated 02 June 2020, version 2.0, 
dated 26 September 2019 and the original protocol version 1.0, dated 09 April 2019. The purpose 
of this plan is to provide specific guidelines for the analyses. Any deviations from these 
guidelines will be documented in the clinical study report (CSR). The analyses described in this 
plan are considered a priori, in that they have been defined prior to database lock. Any analyses 
performed subsequent to database lock will be considered post-hoc and exploratory post-hoc 
analyses will be identified in the CSR. 
1.1. Objectives and Endpoints 
 
Table 1: Part 1 (Treatment Period): Study Objectives and Endpoints 
 
Objective(s) 
Endpoint(s) 
Primary 
The primary objective of the 
treatment period of the study is 
to evaluate the safety and 
tolerability of IV 
administration of AL001 over 
96 weeks in asymptomatic and 
symptomatic carriers of a GRN 
mutation causative of FTD and 
in symptomatic carriers of a 
C9orf72 mutation causative of 
FTD. 
Primary Safety Endpoints: 
To assess the potential effect of cumulative 
exposure on the safety profile of AL001, the 
following will be evaluated by dose, such as 
by using tertiles of the actual dose 
(normalized to weight) received: 
• Incidence, nature, and severity of AEs and 
SAEs 
• Incidence of treatment discontinuations and 
study discontinuations due to AEs 
• Physical examination abnormalities 
• Neurological examination abnormalities 
• Changes in vital signs from baseline over 
time 
• Changes in ECGs from baseline over time 
• MRI abnormalities after dosing relative to 
baseline 
• Changes in clinical laboratory tests from 
baseline over time 
• Sheehan Suicidality Tracking Scale 
(Sheehan-STS) 
• Incidence of ADAs to AL001
Secondary 
The secondary objectives of 
the treatment period of the 
 


Alector Inc. 
 
Final Statistical Analysis Plan, Version 3.0 
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Date Issued: 19MAR2024 
 
  
 
 
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study are to evaluate the effect 
of IV administration of AL001 
over 96 weeks in 
asymptomatic and 
symptomatic carriers of a GRN 
mutation causative of FTD and 
in symptomatic carriers of a 
C9orf72 mutation causative of 
FTD on the following:
Secondary PK Objective: 
• PK 
Secondary PK Endpoints: 
• Serum concentration of AL001 at specified 
time points 
• AL001 PK parameters (if data permit) 
o Cmax 
o Ctrough 
o AUCss 
Secondary PD Biomarker 
Objectives: 
• Longitudinal plasma and CSF 
PGRN concentration levels 
• Longitudinal levels of 
Sortilin in WBCs 
Secondary PD Biomarker Endpoints: 
• The overall change from baseline in PGRN 
in CSF 
• The overall change from baseline in PGRN 
in plasma 
• The overall change from baseline in 
Sortilin in WBCs in plasma
Exploratory 
The exploratory objectives of 
the treatment period of the 
study are to assess the effect of 
IV administration of AL001 
over 96 weeks in 
asymptomatic and 
symptomatic carriers of a GRN 
mutation causative of FTD and 
in symptomatic carriers of a 
C9orf72 mutation causative of 
FTD on the following:
 
Exploratory PD Biomarker 
Objectives: 
• Longitudinal blood, plasma, 
and CSF concentration levels 
of exploratory biomarkers of 
neurodegeneration, lysosomal 
function, and glial activity 
• MRI measures to evaluate 
changes in the brain 
• Global and regional brain 
MRI atrophy measures
Exploratory PD Biomarker Endpoints: 
• The overall change from baseline in 
exploratory biomarkers of 
neurodegeneration, lysosomal function, and 
glial activity in blood, plasma, and CSF 
• Global and regional brain MRI atrophy 
measures 
• Correlations among exploratory fluid 
biomarkers, imaging measures, and COAs 


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• Correlations among 
exploratory fluid PD 
biomarkers, imaging PD 
measures, and COAs
Exploratory Clinical 
Objectives: 
• Clinical progression as 
measured by COAs 
Exploratory Clinical Endpoints: 
The overall change from baseline on the 
scores of the instruments in the COAs 
• Clinical Dementia Rating Dementia 
Staging Instrument PLUS National 
Alzheimer’s Disease Coordinating Center 
Frontotemporal Lobar Degeneration 
Behavior and Language Domains (Clinical 
Dementia Rating (CDR®) plus NACC 
FTLD) 
• Frontotemporal Dementia Rating Scale 
(FRS) 
• Clinical Global Impression of Improvement 
(CGI-I) 
• Clinical Global Impression of Severity 
(CGI-S) 
• Color Trails Test (CTT) Part 2 
• Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS) 
• Winterlight Labs Speech Assessments 
(WLA; for participants who agree to 
participate in these optional assessments 
only)
 
 
Table 2: Part 2 (Optional Open-Label Extension (OLE)): Objectives and Endpoints 
 
Objective(s) 
Endpoint(s) 
Primary 
The primary objective of the 
OLE period of the study is to 
assess the long-term safety and 
tolerability of AL001 in 
participants who have 
completed 96 weeks of 
treatment on Part 1 of the 
study. 
• Incidence, nature, and severity of AEs and 
SAEs 
• Incidence of treatment discontinuations and 
study 
discontinuations due to AEs 
• Physical examination abnormalities 
• Neurological examination abnormalities 
• Changes in vital signs from baseline over 
time 
• Changes in ECGs from baseline over time 
• MRI abnormalities after dosing relative to 
baseline 
• Changes in clinical laboratory tests from 
baseline over time 
• Sheehan-STS


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Date Issued: 19MAR2024 
 
  
 
 
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• Incidence of ADAs to AL001 
Exploratory 
COAs, correlative assessments 
(e.g., biomarker) and other 
efficacy assessments 
conducted during the OLE are 
considered exploratory. 
The exploratory objectives of 
the OLE period of the study 
are to assess the long-term 
effect of AL001 in participants 
who have completed 96 weeks 
of treatment on Part 1 of the 
study on the following: 
• PK 
 
 
 
 
 
 
• Longitudinal plasma and CSF 
PGRN concentration levels 
• Longitudinal blood, plasma, 
and CSF concentration levels 
of exploratory biomarkers of 
neurodegeneration, lysosomal 
function, and glial activity 
 
• Magnetic resonance imaging 
(MRI) measures to evaluate 
changes in the brain 
 
 
 
 
 
 
 
 
 
 
 
 
Serum concentration of AL001 at specified 
time points 
• AL001 PK parameters (if data permit) 
o Cmax 
o Ctrough 
o AUCss 
 
• The overall change from baseline in PGRN 
in plasma 
• The overall change from baseline in 
exploratory biomarkers of 
neurodegeneration, lysosomal function, and 
glial activity in blood, plasma, and CSF 
 
 
• Global and regional brain MRI atrophy 
measures 
• Correlations among 
exploratory fluid PD 
biomarkers, imaging PD 
measures, and clinical outcome 
assessments (COAs)
• Correlations among exploratory fluid 
biomarkers, imaging measures, and COAs 
• Clinical progression as 
measured by COAs 
The overall change from baseline on the 
scores of the instruments in the COAs 
• CDR® plus NACC FTLD 
• FRS 
• CGI-I 
• CGI-S 
• CTT Part 2 
• RBANS


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• Winterlight Labs Speech Assessments (for 
participants who agree to participate in these 
optional assessments only)
 
1.2. Study Design 
This is a Phase 2, multicenter, open label study evaluating the safety, tolerability, PK, PD, and 
effect on COAs of AL001 administered intravenously (60 mg/kg, q4w) in asymptomatic and 
symptomatic carriers of loss-of-function GRN mutations causative of FTD and in symptomatic 
carriers of C9orf72 hexanucleotide repeat expansion mutations causative of FTD. This study has 
two parts: A phase 2 open-label treatment period (Part 1), followed by an optional open-label 
extension (OLE) period (Part 2). 
Part 1 is a 96-week evaluation of the safety, tolerability, PK, PD, and clinical effect of AL001 
administered intravenously (60 mg/kg, every 4 weeks [q4w]), for a total of 25 doses (96-week 
dosing period), in asymptomatic and symptomatic carriers of loss-of-function GRN mutations 
causative of FTD, and in symptomatic carriers of C9orf72 hexanucleotide repeat expansion 
mutations causative of FTD. 
Part 2 is an optional OLE for eligible participants who have completed the 96-week Part 1 
treatment period. The OLE period will evaluate the long-term safety and tolerability of AL001 
administered at the same dose and regimen as Part 1 (60 mg/kg, q4w), for up to a total of 25 
doses (96-week optional OLE period). 
 
 
 


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Figure 1-1 
Overview of Study Schema 
 
 
Abbreviations: COA, clinical outcome assessment; CSF, cerebrospinal fluid; GRN, granulin; IV, intravenous; MRI, 
magnetic resonance imaging; PD, pharmacodynamic; q4w, every 4 weeks. 


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2. General Statistical Considerations 
All data collected from enrolled participants, excluding screen failures, will be presented in data 
listings. Data from participants excluded from an analysis set will be presented in the data 
listings but not included in the calculation of summary statistics for the corresponding analysis 
set. 
Data from Part 1 and Part 2 will be combined and will not be analyzed separately. 
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarized using descriptive statistics (number of participants, mean, standard deviation 
[SD], median, minimum, maximum, and 90% or 95% confidence interval [CI] where 
applicable). All summaries will be presented by the three cohorts [asymptomatic FTD-GRN 
(aFTD-GRN), symptomatic FTD-GRN (FTD-GRN), symptomatic FTD-C9orf72 (FTD-C9orf72)] 
and All Participants.  
Baseline will be defined as the last non-missing assessment, including repeated and unscheduled 
measurements, prior to the start of first study drug administration.  
Due to the high rate of participant attrition over the study duration and small FTD cohort sizes, 
time points beyond week 49 will not be included in the cohort level summary of the figures.  
All CIs will be 2-sided and performed using a 5% significance level except for PK parameters 
for which, 90% CI and geometric mean will be used. All p-values will be presented to 3 decimal 
places and values less than 0.001 or greater than 0.999 will be presented as <0.001 and >0.999, 
respectively. As the objectives of the study are exploratory in nature no adjustments for 
multiplicity will be made. 
No formal significance testing will be performed.  
Analysis visit windows will be applied for COA and Biomarker analysis. A detailed explanation 
about the analysis visit windows will be described in the specific section of each analysis, 
2.1.  Sample Size 
 
Part 1 (Treatment Period) 
The primary objective of Part 1 of this study is to assess the safety profile of repeat dosing of 
AL001 in three FTD cohorts: aFTD-GRN, FTD-GRN, and FTD-C9orf72 participants. 
Descriptive statistics will be used to assess clinically significant associated findings (for 
example, study-drug related AEs leading to study drug discontinuation or study-drug related 
SAEs). The Part 1 sample size of 40 participants was chosen based on feasibility; however, the 
probability of detecting at least 1 clinically significant associated finding will be explored. When 
the probability of a clinically significant associated finding for a single participant is 0.1%, 1%, 
5%, and 10%, then with a sample size of 40 participants, the probability of detecting at least 


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1 clinically significant associated finding across all participants is 3.9%, 33.1%, 87.1%, and 
98.5%, respectively. 
Part 2 (Optional OLE) 
It is estimated that up to 40 participants from Part 1 of the study will be eligible to continue with 
Part 2 of the study. Part 2 is optional for participants, and at the discretion of the investigator. 
2.2.   Randomization and Blinding 
This is an open label study where all participants will receive AL001, and doses are not 
concealed; randomization and blinding, therefore, are not required. 
2.3.  Analysis Populations 
The following analysis sets will be used in the statistical analyses: 
2.3.1. Enrolled Population 
The enrolled population will consist of all participants who signed the ICF. 
2.3.2. Safety Analysis Population 
The safety analysis population will consist of all participants who received at least 1 dose of 
AL001. The safety analysis population will be used for all safety and COA summaries. 
2.3.3. PK Analysis Population 
The PK analysis population will include all participants in the safety population who had 
adequate assessments for determination of at least 1 PK parameter. The PK analysis population 
will be used for PK parameter summaries. 
2.3.4. Full Analysis Population 
The Full analysis population will include all participants in the safety population who had both a 
baseline and at least 1 postdose PD assessment. The Full analysis population will be used for 
summaries of all PD and PD biomarker summaries. 
3. Participant Disposition and Protocol Deviations 
3.1.   Disposition 
Participant disposition will be summarized. The number of participants and reasons for study 
discontinuation, reasons for study drug discontinuation, and the number of participants in each 
analysis population will be presented.  
Participant disposition data and membership in analysis populations for participants in the 
Enrolled population will be presented in data listings. 


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Data collected for participants who failed screening will not be presented in any summaries or 
data listings. 
3.2.   Protocol Deviations 
A protocol deviation occurs when the participant, investigator, or Alector (or designee) fails to 
adhere to protocol requirements. Major protocol deviations are the ones that affect the 
participants' safety or the primary endpoint (safety). Major protocol deviations for this study 
include, but are not limited to, the following: 
 Failure to meet inclusion/exclusion criteria 
 Failure to comply with GCP guidelines will also result in a major protocol deviation; 
Alector will determine if a major protocol deviation will result in withdrawal of a 
participant. 
Major protocol deviations will be summarized for the Safety population, and all protocol 
deviations will be presented in a data listing, including the categorization of the deviation as 
major or minor. 
4. Demographics and Baseline Characteristics 
Qualitative data (eg, genotyping data, diagnostic characterization) will be summarized in 
contingency tables, and quantitative data (eg, age) will be summarized using quantitative 
descriptive statistics. 
4.1.   Demographics 
Demographic information (year of birth, age, sex, race) will be recorded at screening, unless 
disallowed by local regulatory agencies. Demographics (including but not limited to age, age 
group (19-64, >=65), sex, and race, if allowable per local regulatory authorities) and baseline 
characteristics will be presented in summary tables.  
For US, UK, and Canadian participants who will be performing the optional WLA, additional 
demographic information will be collected. The optional WLA data will be analyzed and 
reported outside of this SAP. 
Demographic information collected at Screening will be summarized by group and overall for all 
participants in the safety population and listed. Descriptive statistics will be calculated for the 
following continuous demographic characteristics: age (years), screening and Day 1 pre-dose 
weight (kg), screening height (cm), and screening body mass index (BMI) (kg/m2). Frequency 
counts will be tabulated for the categorical variables sex, race, and ethnicity. 
 
 


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4.2.   Diagnostics Characterization 
A diagnostic characterization form will be completed in the electronic case report form (eCRF) 
only at screening, week 97 and week 197 (if applicable for symptomatic participants in the 
optional Part 2 OLE). It will also be completed for any asymptomatic participant who becomes 
symptomatic during the course of the study; for these participants, the diagnostic characterization 
form will be completed only at the first visit in which they exhibit clinical symptomatology. 
Diagnostic characterization data will be summarized for the Safety population and will be 
presented in a data listing. 
4.3.   Medical History 
 All relevant medical history and information regarding underlying diseases will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA), version to be delineated in the 
CSR. 
Medical history data will be summarized by system organ class (SOC), preferred term (PT) for 
the Safety population. Medical history data will be presented in a data listing. 
4.4.   Admission Criteria Deviation 
Admission criteria deviation data (violations of the inclusion/exclusion criteria) will be presented 
in a data listing.  
4.5.   Pharmacogenomic Measurements 
A blood sample will be collected during Part 1 at screening for DNA extraction to enable 
analysis via whole genome sequencing (WGS) to identify common and rare genetic variants that 
are predictive of response to study drug, are associated with progression to a more severe disease 
state, are associated with susceptibility to developing AEs, or can increase the knowledge and 
understanding of disease biology. 
Pharmacogenomic data will not be analyzed or reported in the CSR. 
5. Treatments and Medications 
5.1.   Prior and Concomitant Medications 
All concomitant medications used by a participant from informed consent through Study 
Completion or ET visit, whichever is later, will be recorded in the participant’s eCRF and coded 
using the World Health Organization Drug Dictionary (WHO-DD), version to be delineated in 
the CSR. The minimum requirement is that drug name, total daily dose, route, frequency of 
dosing, indicated use, and the dates of administration are to be recorded. This will include all 
prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and 
over-the-counter medications. Any changes in concomitant medications also will be recorded in 
the participant’s eCRF. 


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Any restricted medication must have been stopped as required by the study inclusion and 
exclusion criterion (Protocol Sections 4.2.1 and 4.2.2 respectively); participants who start these 
medications during the study may be withdrawn from study treatment at the discretion of the 
sponsor’s medical monitor.  
A medication will be considered as concomitant if the end date and time of administration is 
after start of administration of study drug. If the date and time of administration contains partial 
information such that the attribution of concomitant administration cannot be ruled out then it 
will be considered as concomitant. A medication will be considered as prior if the start and stop 
date and time of administration is prior to the start of administration of study drug. A medication 
started prior to study drug and continuing during the study will be considered as concomitant.   
The number and percentage of participants taking prior and concomitant medications will be 
summarized for each level of ATC (Anatomical-Therapeutic-Chemical) and preferred drug 
name, and alphabetically sorted for participants in the Safety population.  
Prior and concomitant medications will be presented in a data listing. 
5.2.   Medical and Surgical Treatment Procedures 
Medical and surgical treatment procedure data will be presented in a data listing. 
5.3.   Study Drug Administration 
Study drug administration data will be summarized for the Safety population. The summary will 
include duration of exposure to study drug (in days), the number of doses received, treatment 
compliance, number of doses interrupted, discontinued, and total dose (mg) received.  
Duration of exposure to study drug (days) is defined as the total number of days a participant is 
exposed to AL001 and will be calculated as the total number of days from the first dose date 
(Study Day 1) to the last dose date + 28 days, regardless of any temporary interruptions in study 
drug administration. 28 days is the study treatment administration (IV) interval. 
Treatment compliance will be defined as the total cumulative received dose (mg/kg) divided by 
the total cumulative expected dose (mg/kg) up to the last dose, and then multiplied by 100. The 
total cumulative expected dose will be the sum of the expected doses while they are on study 
treatment across all planned study days, up to the date of withdrawal, if participant discontinued 
study drug early.  
The function is as follow: 
Treatment Compliance=100×(total cumulative received dose (mg/kg))/(total cumulative 
expected dose (mg/kg)) 
Study drug administration data will be presented in a listing. Any drug administration 
interruption and reasons will be listed. 


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6. Safety Analysis 
All analyses of safety data will be conducted using the Safety population. All safety data will be 
listed. 
6.1.   Adverse Events 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to study drug. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study 
drug, or any event already present that worsens in either intensity or frequency after exposure. 
An imputation will be performed for AEs with incomplete (partial) dates to determine whether 
an AE is treatment emergent.  
For AEs with a partial start date:  
 If the year is unknown, then the AE start date will be the date of first dose.  
 If the month is unknown, then:  
o If the year matches the year of the first dose date, then the month and day of the 
first dose date will be imputed.  
o Otherwise, ‘January’ will be assigned.  
 If the day is unknown, then:  
o If the month and year match the month and year of the first dose date, then the 
day of the first dose date will be imputed.  
o Otherwise, ‘01’ will be assigned.  
For AEs with a partial end date:  
 If the year is unknown, then the date assigned will be the last visit date.  
 If the month is unknown, then the month from the last visit date will be assigned.  
 If the day is unknown, then the last day of the month will be assigned.  
If the imputation approach results in a start date that is after a known end date, then the start date 
will be set to the day before the end date. If the imputation approach results in an end date that is 
before a known start date, then the end date will be set to the day after the start date. 
An AE with completely missing onset and end dates, or with the start date missing and an end 
date later than the first dose date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the start date missing and incomplete end date with the same or later month 
and year (or year alone if month is not recorded) as the first dose date of study drug will be 
considered treatment emergent.  
The relationship of AE to study drug will be classified as Not Related or Related by the 
Investigator. If the relationship information is missing, the AE will be considered Related in the 
summary but will be presented as missing in the listings.  


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The severity of AEs will be classified as Mild, Moderate, Severe, Life-threatening, or Death by 
the Investigator. If the severity information is missing, the AE will be considered Severe in the 
summary but will be presented as missing in the listings. 
Adverse Events will be coded by SOC and PT according to MedDRA, version to be delineated in 
the CSR. 
All summary tables will include counts and frequency of participants and number of events. 
Subject incidence rate of AEs will be summarized by SOC and PT and for PT only. The 
summary will be provided separately by overall descending incidence rate and then by 
alphabetical order. A separate summary will be provided by alphabetical order for SOC and PT. 
A participant with 2 or more occurrences for the same AE, the subject will be counted only once 
in that level using the worst severity (for the severity table) or the most related (for the 
relationship to study drug table). Percentages will be based upon the number of participants in 
the Safety population. 
6.1.1.   Incidence of Adverse Events 
An overall summary of AEs will be presented and will include summaries for the following: 
 Any TEAE 
 Any Treatment-Related TEAE 
 TEAEs by Severity 
 Treatment-Related TEAEs by Severity 
 Any SAE 
 Any Treatment-Emergent SAE 
 Any Treatment-Related TESAE 
 Any TEAE Leading to Study Drug Discontinuation 
 Fatal TESAE 
In addition, all TEAEs will be summarized by SOC and PT.  
6.1.2. Relationship of Adverse Events to Study Drug 
Treatment-emergent AEs will be summarized by SOC, PT, and relationship to study drug. 
Treatment-related AEs will be presented in a data listing. 
6.1.3. Severity of Adverse Event 
The TEAEs will be summarized by SOC, PT, and severity.  
 
 


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6.1.4. Serious Adverse Events 
An SAE is defined as any event that 
 results in death 
 is immediately life threatening 
 requires inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the participant or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Social hospitalization, defined as inadequate family support or care at the participant’s primary 
residence resulting in participant hospitalization, will not be considered an SAE. 
Serious TEAEs will be summarized by SOC and PT. 
All SAEs will be presented in a data listing. 
6.1.5. Adverse Events Leading to Study Drug Discontinuation 
Treatment-emergent AEs leading to study drug discontinuation will be summarized by SOC and 
PT and will be presented in a data listing. 
6.2.   Clinical Laboratory Evaluations 
Blood and urine samples that will be collected for clinical safety laboratory tests (chemistry, 
coagulation, hematology, urinalysis, serology, and pregnancy testing) are indicated in Table 8-1. 
Laboratory assessment analysis will be performed at a central laboratory, with the exception of 
urine pregnancy testing which will be done at local laboratories. 
Hematology, coagulation, serum chemistry, and urinalysis will be performed at the timepoints 
identified in Appendix 14.1, Appendix 14.2, Appendix 14.4 and Appendix 14.5. Additionally, 
unscheduled testing may be done during the study if medically indicated.  
Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference ranges for each laboratory parameter. The investigator will 
determine whether any of the abnormally high or low results are clinically significant or not 
clinically significant. Any clinically significant results will be entered into the eCRF as AEs, 
however the attribution of clinical significance will not be available in the data. 


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Actual results and change from baseline values for hematology, coagulation, serum chemistry, 
and urinalysis tests will be summarized by visit using descriptive statistics. 
Shift from baseline in hematology, coagulation, serum chemistry, and urinalysis tests results 
relative to the reference range will be summarized by visit using the frequency count and 
percentage of participants in each category.  
Refer to Section 4 for the definition of baseline. 
All laboratory test results will be presented in data listings. 
Table 8-1 
Laboratory Assessments 
Chemistry 
Coagulation 
Hematology 
Serology 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
gammaGT 
AST 
ALT 
LDH 
Creatine kinase 
Creatinine a 
Urea 
Uric acid 
Cholesterol 
HDL 
LDL 
Triglycerides 
Total protein 
Albumin 
Glucose 
Bicarbonate 
Inorganic phosphate 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Lipase 
Apolipoprotein B100 
PT 
INR 
aPTT 
HbA1c  
Leukocytes 
Erythrocytes 
Hemoglobin 
Hematocrit 
Thrombocytes (platelets) 
MCV 
MCH 
MCHC 
 
Partial automated 
differentiation: 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Neutrophils b 
ANC b 
anti-HCV 
anti-HIV  
HIV antigen 
HBsAg 
Total hepatitis B core 
antibody 
Urinalysis 
Pregnancy Test 
Hemoglobin (blood urine) 
Ketones 
Glucose 
Protein 
Leukocyte esterase 
Nitrite 
pH 
Specific gravity 
Microscopic analysis d (sediment, erythrocytes, 
leukocytes, casts, crystals, epithelial cells, and bacteria) 
Serum β-hCG or urine 
pregnancy test c 
Abbreviations: ALT, alanine aminotransferase; ANC: absolute neutrophils count; aPTT, activated partial 
thromboplastin time; AST, aspartate aminotransferase; β-hCG, β-human chorionic gonadotropin; gammaGT, 
gamma glutamyl transferase; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDL, high-density 
lipoprotein-cholesterol; HIV, human immunodeficiency virus; INR, international normalized ratio; LDH, lactate 
dehydrogenase; LDL, low-density lipoprotein-cholesterol; MCH, mean corpuscular haemoglobin; MCHC, mean 
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PT, prothrombin time. 
a Creatinine (and calculation of glomerular filtration rate). 
b ANC will be calculated at Screening only. Neutrophils will be assessed at all other time points. 


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c  All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be 
performed at specified subsequent visits prior to study drug administration. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.  
d Microscopic examination of the sediment if blood, protein, leukocytes esterase, or nitrite are positive on the 
dipstick.  
6.3.   Vital Signs and Weights Measurements 
Vital sign measurements including systolic and diastolic BP, pulse rate, body temperature, 
respiratory rate, height, and weight will be collected at the timepoints identified in Appendix 
14.1, Appendix 14.2, Appendix 14.4 and Appendix 14.5. Additional, unscheduled testing may be 
done during the study if medically indicated. 
Supine systolic and diastolic BP, pulse, body temperature, and respiratory rate will be recorded 
after the participant has been resting for ≥5 minutes in the supine position.  
Actual results and change from baseline values for vital signs will be summarized by visit and 
timepoint using descriptive statistics. Since the infusion is scheduled to last for approximately 60 
minutes and Protocol section 5.5.4 allows for interruptions and rate reductions that would extend 
the infusion duration beyond 60 minutes, therefore; for summarization purposes all vital sign 
measurements collected during the infusion up to and including 60 minutes after the start of the 
infusion will be included. Vital sign measurements collected beyond 60 minutes after the start of 
the infusion and before the end of the infusion, in case that the infusion duration is beyond 60 
minutes, will not be summarized. All vital sign measurements collected after the end of the 
infusion will be summarized. All vital signs data will be presented in a data listing. 
Refer to Section 4 for the definition of baseline. 
6.4.   Triplicate 12-Lead Electrocardiograms 
Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for 
≥5 minutes. ECG measurements will be collected at the timepoints identified in Appendix 14.1, 
Appendix 14.2, Appendix 14.4 and Appendix 14.5. 
All ECGs will be analyzed from a clinical safety basis (without intensive QT analysis). The 
clinical significance of ECG changes will be determined by the investigator after review of the 
ECG report in relation to the participant’s medical history, PE, and concomitant medications and 
documented on the eCRF. 
For summaries of quantitative triplicate 12-lead ECG parameters, the average of the triplicate 
12-lead ECG measurements will be used for the determination of baseline and calculation of 
summary statistics.   
For interpretation of triplicate 12-lead ECGs, baseline will be defined as the best case of the last 
non-missing triplicate measurements (including repeated and unscheduled measurements) before 
the start of first study drug administration. For calculation of post-dose summary statistics, the 
worst case of the non-missing triplicate measurements will be used. The order of interpretation 


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for 12-lead ECGs (best to worst case): Normal; Abnormal, Not Clinically Significant; Abnormal, 
Clinically Significant. Interpretations of Indeterminate, Not Evaluable, or Unknown will not be 
considered when determining the worst or best case. 
Actual values and changes from baseline for quantitative ECG results will be summarized at 
each time point using descriptive statistics.  
Shift from baseline in ECG interpretation and clinical significance will be summarized by visit 
using the frequency count and percentage of participants in each category.  
In addition, the number (percentage) of subjects with at least 1 post-baseline abnormal ECG 
result in corrected QT interval calculated using Fridericia’s formula (QTcF) interval, PR, QRS or 
HR will be summarized. Clinically abnormal ECG results will be categorized as follows: 
Absolute QTcF interval prolongation: 
• QTcF interval >450 msec 
• QTcF interval >480 msec 
• QTcF interval >500 msec 
Change from baseline in QTcF interval: 
• QTcF interval increases from baseline >30 msec 
• QTcF interval increases from baseline >60 msec 
• PR < 120 msec 
• PR > 200 msec 
• QRS < 60 msec 
• QRS > 100 msec 
• HR < 60 bpm 
• HR > 100 bpm 
All 12-lead ECG data will be presented in a data listing, 12-Lead Electrocardiogram data for 
participants with abnormal post-baseline result in QTcF interval will also be listed. 
6.5.   Physical and Neurological Examinations 
A complete PE includes evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, and gastrointestinal systems. 
Breast, genital, and rectal examinations are not required, unless warranted in opinion of the 


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health care provider. The examination will be performed by a physician, or a nurse practitioner 
or physician’s assistant under the supervision of a physician.   
A limited, symptom-directed examination will be performed at all other specified time points, 
prior to study drug administration (if applicable) or as clinically indicated. 
Abnormalities observed at screening will be recorded on the General Medical History and 
Baseline Conditions page of the eCRF. At subsequent visits, new or worsened clinically 
significant abnormalities will be recorded on the AE eCRF. 
A complete neurologic examination will include the evaluation of consciousness, orientation, 
cranial nerves, motor and sensory system, coordination and gait, and reflexes. Changes from 
baseline abnormalities and changes from previous neurological examinations should be recorded 
at each subsequent neurologic examination. New or worsened abnormalities should be recorded 
as AEs on the AE eCRF if considered clinically significant. 
Physical and neurologic examinations will be collected at the timepoints identified in Appendix 
14.1, Appendix 14.2, Appendix 14.4 and Appendix 14.5. 
Physical and neurological examinations will not be summarized or listed since exam results are 
only entered on the General Medical History and Baseline Conditions or AE pages of the eCRF 
6.6.   Sheehan Suicidality Tracking Scale (S-STS) 
The S-STS will be performed at the timepoints identified in Appendix 14.1, Appendix 14.2, 
Appendix 14.4 and Appendix 14.5. 
The S-STS is a brief scale designed to assess and monitor over time the core phenomena of 
suicidality. The Sheehan-STS is a 16-item scale that will be administered either by a clinician or 
participant through self-report. Each item in the Sheehan-STS is scored on a 5-point Likert scale 
(0=not at all, 1=a little, 2=moderately, 3=very, and 4=extremely). Any change in the 
Sheehan-STS score indicating the presence of suicidality should be immediately evaluated by the 
investigator and reported to the medical monitor. An AE should only be recorded if the 
investigator makes an evaluation and deems there to be suicidal ideation or behavior. 
Actual results and change from baseline values for the S-STS Total Score will be summarized by 
visit using descriptive statistics.  
All S-STS data will be presented in a data listing. 
 
 


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6.7.   Immunogenicity 
Immunogenicity sample collection for ADA will be collected at the timepoints indicated in 
Appendix 14.1, Appendix 14.2, Appendix 14.3, Appendix 14.4 and Appendix 14.5. Additional 
unscheduled assessments for participants with signs and symptoms of infusion-related reactions 
may be collected. 
Antidrug antibody results will be summarized by visit using the frequency count and percentage 
of participants in each result category, as well as descriptive statistics of ADA titer by visit. The 
summary of ADA results will not include unscheduled assessments for participants with signs 
and symptoms of infusion-related reactions. Instead, data at baseline and the following visits for 
subjects with signs and symptoms will be listed separately. All immunogenicity data will be 
presented in a data listing. 
6.8.   Magnetic Resonance Imaging 
Magnetic resonance imaging assessments will be performed at the timepoints indicated in 
Appendix 14.1, Appendix 14.2, Appendix 14.4 and Appendix 14.5. 
MRI scans of the brain will be performed and centrally reviewed for assessment of safety 
(structural images). The safety assessment on MRI scans will be presented in a data listing. 
7. Pharmacokinetics 
7.1.  Serum Pharmacokinetics Samples 
Blood samples will be collected for assessment of serum concentrations of AL001. All serum PK 
samples should be drawn from the arm that is not used for the infusion on day of study drug 
administration. Specific information on PK sample collection, processing, storage, and shipment 
will be provided in a separate manual. Serum PK samples for AL001 will be collected at predose 
and at the end of infusion (within 15 minutes after the end of infusion) on weeks 1, 2, 5, 9, 13, 
17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 61 (3h post EOI and 24h also), 73, 85, 97, and 105 or study 
completion/ET for all participants.   
Serum concentration and time deviation data at each study visit/timepoint will be presented in 
data listings by cohort (aFTD-GRN, FTD-GRN, FTD-C9orf72) at baseline in the Safety 
population. Serum concentration data will be summarized by study visit/timepoint and cohort at 
baseline for the PK analysis population using descriptive statistics: number of participants with 
non-missing data (n), mean, SD, CV, median, minimum, maximum, geometric mean, and 
geometric CV. All serum concentration values below the limit of quantification (BLQ) will be 
set to zero when calculating summary statistics. 
Mean serum concentration versus nominal time profiles will be plotted on both linear and 
semilogarithmic scales for the PK analysis population by cohort at baseline. Individual serum 
concentration versus actual time profiles will be plotted on both linear and semilogarithmic 
scales for the Safety population. 
 


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7.2.   CSF Pharmacokinetic Samples 
Cerebrospinal fluid (CSF) samples will be collected via lumbar puncture prior to study drug 
administration (if applicable) at Screening, Week 25, Week 49, and Week 97 (or the EOT/EOS 
Visit) to evaluate CSF PK  in Part 1 only. The Week 25 lumbar puncture may be adjusted as 
determined by Alector’s review of exploratory PD biomarkers. 
CSF concentration and time deviation data will be presented in data listings by study visit and 
cohort in the Safety population. CSF concentration data will be summarized by study visit and 
cohort for the PK population using descriptive statistics: number of participants with non-
missing data (n), mean, SD, CV, median, minimum, maximum, geometric mean, and geometric 
CV. All CSF concentration values that are BLQ will be set to zero when calculating summary 
statistics.  
Mean CSF concentration versus nominal time profiles will be plotted on linear scale and 
semilogarithmic scales for the PK population by cohort at baseline. Individual CSF concentration 
versus actual time profiles will be plotted on linear scale and semilogarithmic scales for the 
Safety population. 
7.3. Serum Pharmacokinetic Parameters 
The individual serum concentration versus actual time data for AL001 will be used to derive the 
following PK parameters if data permit, by standard noncompartmental methods using Phoenix® 
WinNonlin® Version 8.3 or higher (Certara USA, Inc., Princeton, NJ, USA). 
Parameter 
Description 
Cmax  
Observed maximum serum concentration 
Ctrough 
Trough serum concentration following each dose (equivalent to the trough 
concentration prior to each dose)
ARCtrough 
 Accumulation ratio using Ctrough: calculated as Ctrough for Week 
61/Day 1
For the calculation of PK parameters, all serum concentrations that are BLQ prior to the first 
measurable concentration will be set to zero and treated as missing thereafter. 
PK parameters will be summarized for the PK population by cohort in tables using the following 
descriptive statistics: n, arithmetic mean, SD, CV), geometric mean, geometric mean CV, 90% 
CI, minimum, median, and maximum. Individual PK parameters will be presented in data 
listings for the PK population.  
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8.  Pharmacodynamic Biomarkers 
PD endpoints will be described and summarized by cohort at baseline and each timepoint, as will 
the percent change from baseline for each PD endpoint. PGRN will be evaluated in plasma and 
CSF samples.  
8.1. Progranulin Plasma Samples 
Blood samples will be collected for evaluation of levels of PGRN in plasma. 
PGRN plasma samples will be collected prior to study drug administration on weeks 1, 2, 5, 9, 
13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 61 (24 h also), 73, 85, 97, and 105 or study 
completion/ET for all participants. 
The absolute value, absolute change, and percent change from baseline of plasma PGRN will be 
presented in data listings by cohort and timepoint for the Full Analysis population. Plasma 
PGRN concentration data will be summarized by cohort and timepoint for the Full Analysis 
population using descriptive statistics: number of participants with non-missing data (n), mean, 
SD, CV, median, minimum, maximum, geometric mean and geometric CV. All plasma PGRN 
concentration values that are BLQ will be set to ½ the lower limit of quantification (LLOQ) 
when calculating summary statistics. 
Mean (±SD) absolute value, absolute change and percent change from baseline in plasma PGRN 
concentration versus nominal time profiles will be plotted on linear and semilogarithmic scales 
by cohort for the Full Analysis population. In addition, the absolute value, absolute change and 
percent change from baseline in plasma PGRN concentration at the individual level versus actual 
time profiles will be plotted on linear and semilogarithmic scales by cohort for the Full Analysis 
population. 
8.2. Progranulin Cerebrospinal Fluid Samples 
CSF samples will be evaluated for levels of PGRN. Cerebrospinal fluid samples will be collected 
in Part 1 only via lumbar puncture prior to study drug administration (if applicable) at Screening, 
Week 25, Week 49, and Week 97 (or the Part 1 EOT/EOS Visit) to evaluate PGRN. 
The absolute value, absolute change, and percent change from baseline in CSF PGRN will be 
presented in data listings by cohort and timepoint for the Full Analysis population. CSF PGRN 
concentration data will be summarized by cohort and timepoint for the Full Analysis population 
using descriptive statistics: number of participants with non-missing data (n), mean, SD, CV, 
median, minimum, maximum, geometric mean and geometric CV. All CSF PGRN concentration 
values that are BLQ will be set to ½ the lower limit of quantification when calculating summary 
statistics. 
Mean (±SD) absolute value, absolute change and percent change from baseline in CSF PGRN 
concentration versus nominal time profiles will be plotted on linear and semilogarithmic scales 
by cohort for the Full Analysis population. In addition, the absolute value, absolute change and 


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percent change from baseline in CSF PGRN concentration at the individual level versus actual 
time profiles will be plotted on linear and semilogarithmic scales by cohort for the Full Analysis 
population. 
9. Exploratory Clinical outcome Assessments 
All COAs will be collected at the timepoints identified in Appendix 14.1, Appendix 14.2, 
Appendix 14.4 and Appendix 14.5. The details of the COA are provided in Protocol Appendix 2. 
Summaries of COA data will be provided using the Safety population. All COA data will be 
listed using the Enrolled population.  
All COAs, except where indicated, will be assessed using MMRM methodology. The dependent 
variable will be the change from baseline to each postbaseline visit assessment. The fixed effect 
will include cohort, and time point will be the repeated measure. An interaction term for 
timepoint with cohort will be included. Covariates will not be explored due to small sample size. 
The MMRM will be constructed using unstructured covariance structure, however if the model 
will not converge AR(1) could be assessed . Estimates of the Least-squares mean, standard error, 
and 95% CI will be presented for each cohort and timepoint.  The least-square means and 95% 
CI will be plotted by cohort and timepoint. 
9.1. Analysis visit windows 
The following analysis visit windows will be used for all COAs analyses: 
Study day 
Analysis Visit 
Less or equal to 1
Baseline
Between 2 and 127
Week 13
Between 128 and 211
Week 25
Between 212 and 295
Week 37
Between 296 and 379
Week 49
Between 380 and 463
Week 61
Between 464 and 547
Week 73
Between 548 and 631
Week 85
Between 632 and 757
Week 97
Between 758 and 925
Week 121
Between 926 and 1093
Week 145
Between 1094 and 1275
Week 169
Greater than or equal to 1276
Week 197
 
 


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9.2. Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer’s 
Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and 
Language Domains (CDR® plus NACC FTLD) 
The CDR® plus NACC FTLD results will be summarized by visit and domain. The Global 
Scores and individual domains will be summarized using the frequency count and percentage of 
participants in each result and the actual values and changes from baseline using descriptive 
statistics. The Sum of Boxes and Global Scores will be summarized for actual values and 
changes from baseline using descriptive statistics. Mean change from baseline, plus or minus the 
SD, will also be presented in a plot. Subject level data will be presented in a plot, grouped by 
cohort.  
The Sum of Boxes will be assessed using the MMRM methodology described in Section 9.  
9.3. Frontotemporal Dementia Rating Scale (FRS) 
The FRS results will be summarized by visit and question. The question results will be 
summarized using the frequency count and percentage of participants in each response. The FRS 
Score, FRS Percentage Score, FRS Logit Score, and FRS Severity Category Score will be 
summarized for actual values and changes from baseline using descriptive statistics. Mean 
change from baseline, plus or minus the SD, will also be presented in a plot. Subject level data 
will be presented in a plot, grouped by cohort.  
The FRS Score and FRS Percentage Score endpoints will be assessed using MMRM 
methodology described in Section 9. 
9.4. Clinical Global Impression of Severity (CGI-S) and of Improvement (CGI-I) 
The CGI-S and CGI-I results will be summarized by visit and question.  
The question results will be summarized using the frequency count and percentage of 
participants in each response. In addition, the numeric score for each result will be summarized 
for actual values (both CGI-S and CGI-I) and changes from baseline (CGI-S only) using 
descriptive statistics. Mean (CGI-I), plus or minus the SD, will also be presented in a plot. 
Subject level data will be presented in a plot, grouped by cohort.  
For the purposes of summarization using descriptive statistics and plots, the CGI-S Likert scores 
will equal character responses as follows: 1=Normal, not at all; 2=Borderline ill; 3=Mildly ill; 
4=Moderately ill; 5=Markedly ill; 6=Severely ill; and 7=Among the most extremely ill.  
For the purposes of summarization using descriptive statistics, and plots, the CGI-I Likert scores 
will be anchored to 0 as follows: -3=Very much worse; -2=Much Worse; -1=Minimally worse; 
0=No change; 1=Minimally improved; 2=Much improved; 3=Very much improved. 
 
 


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9.5. Color Trails Test (CTT) 
The CTT results will be summarized by visit and test. The question results will be summarized 
using the frequency count and percentage of participants in each response. The duration of the 
pretest and test will be summarized for actual values and changes from baseline using descriptive 
statistics. Mean change from baseline, plus or minus the SD, will also be presented in a plot. 
Subject level data will be presented in a plot, grouped by cohort.  
In addition, CTT2 total time - CTT1 total time and CTT2 total time/CTT1 total time will be 
calculated and summarized.  
The duration of test endpoint will be assessed using MMRM methodology described in Section 
9.  
9.6. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
The RBANS results will be summarized by visit, domain, domain index score, and overall index 
score. The domain and overall index scores will be summarized for actual values and changes 
from baseline using descriptive statistics. Mean change from baseline, plus or minus the SD, will 
also be presented in a plot. Subject level data will be presented in a plot, grouped by cohort.  
The index score endpoints will be assessed using MMRM methodology described in Section 9.  
9.7. Neuropsychiatric Inventory (NPI), 
 
(
; Part III), Delis-Kaplan Executive Function System (D-KEFS), and 
Interpersonal Reactivity Index (IRI) 
The NPI, UPDRS, D-KEFS, and IRI were administered on participants enrolled under the 
original protocol dated 09 Apr 2019. The protocol amendment 1 dated 26 Sep 2019 did not 
include these assessments. Due to the limited availability of data from this change, the data from 
these assessments will not be summarized. 
9.8. Optional Winterlight Labs Speech Assessments 
The optional WLA will be analyzed and reported outside of this SAP. 
10. Exploratory Pharmacodynamic Biomarkers  
All analyses of exploratory PD biomarker data will be conducted using the Full analysis 
population. 
 
 


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10.1. Analysis visit windows 
The following analysis visit windows will be used for all PD biomarker analyses: 
Study day 
Analysis Visit 
Less or equal to 1
Baseline
Between 2 and 20
Week 2
Between 21 and 43
Week 5
Between 44 and 71
Week 9
Between 72 and 99
Week 13
Between 100 and 127
Week 17
Between 128 and 155
Week 21
Between 156 and 183
Week 25
Between 184 and 211
Week 29
Between 212 and 239
Week 33
Between 240 and 267
Week 37
Between 268 and 295
Week 41
Between 296 and 323
Week 45
Between 324 and 351
Week 49
Between 352 and 393
Week 53
Between 394 and 463
Week 61
Between 464 and 547
Week 73
Between 548 and 631
Week 85
Between 632 and 757
Week 97
Between 758 and 925
Week 121
Between 926 and 1093
Week 145
Between 1094 and 1275
Week 169
Greater than or equal to 1276
Week 197
All PD biomarker analyses will be conducted with one data point per time point and subject. If 
the measurement is available for the nominal time, its value will be used in the analyses. If the 
measurement for a nominal time point is missing and measurements for unscheduled visits that 
fall in the corresponding analysis window are available, the value from the sample collected 
closest to the nominal time point will be used.  
10.2. Exploratory Pharmacodynamic Biomarkers of Neurodegeneration, lysosomal 
function, and glial activity 
Exploratory plasma and CSF PD biomarker samples are collected for evaluation for 
neurodegeneration (e.g., neurofilament-light chain [NfL]), lysosomal function (e.g., cathepsins), 
and glial activity (e.g., YKL 40, GFAP), and to potentially evaluate levels of other analytes 
relevant to disease biology and response to AL001. CSF PD biomarker samples are collected in 
Part 1 only. The timepoint at which the exploratory PD biomarkers of neurodegeneration are 
identified in Appendix 14.1, Appendix 14.2, Appendix 14.4 and Appendix 14.5. 


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For all biomarkers listed in the following table, the absolute value, absolute change, percent 
change from baseline, and ratio to baseline values for exploratory biomarker parameters will be 
summarized by visit and cohort using descriptive statistics, including the number of participants, 
mean, SD, median, min and max. Additionally, for absolute value and ratio to baseline, 
geometric mean (calculated as exp (mean(log(absolute value or ratio to baseline)))) and 
geometric SD will be summarized. For NfL and GFAP, mean absolute value, mean percent 
change from baseline values, and geometric mean ratio to baseline plus or minus the SD, will 
also be plotted versus nominal time points up to Week 49. All biomarker concentration values 
that are BLQ will be set to ½ of LLOQ when calculating summary statistics. In the case of 
Vendor not providing LLOQ, such as Cell Carta, data points with results being 0 will be 
excluded from the analysis.  
Exploratory Pharmacodynamic Biomarkers 
C1Qb 
 
C1Qc 
 
 
 
 
 
YKL40 
CTSD 
LAMP1 
 
 
MIF 
 
 
 
 
GFAP 
 
 
 For the GFAP analysis, only GFAP data from Quanterix will be used.  Data on CSF GFAP 
initially obtained on the Roche NTK platform will be excluded from the data analysis, as 
those samples were subsequently re-analyzed on the Quanterix SIMOA platform. At the time 
of analysis, Roche did not have the capability to analyze plasma samples for GFAP. Since 
plasma GFAP was analyzed on the Quanterix platform, all GFAP (plasma and CSF) analyses 
were ultimately conducted on the Quanterix platform in order to maintain consistency 
between matrices. 
 
 


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 For the biomarker data obtained from Cell Carta, each biomarker was assayed with 7 
different peptides. The analysis will only include data from the peptide recommended by the 
Vendor for each biomarker for analysis. The list of recommended peptides is shown in the 
following table: 
Protein 
 
C1qB 
C1QB_HUMAN_IAFSATR_y4+ 
C1qC 
C1QC_HUMAN_FQSVFTVTR_b2+ 
 
CTSD 
CATD_HUMAN_VSTLPAITLK_y7+ 
 
 
 
G
 
 
LAMP1 
LAMP1_HUMAN_AFSVNIFK_y6+ 
 
 
 
 Participants who have completed Study AL001-1 and who enrolled in this study may not 
have had a CSF collection at screening in this study if the baseline LP was performed in the 
AL001-1 study within 3 months prior to screening into AL001-2. For those participants, the 
baseline values for certain CSF biomarkers will be obtained from the data in the AL001-1 
study. 
10.3. Brain Imaging 
Brain imaging including structural MRI and DTI assessments will be performed at the timepoints 
indicated in Appendix 14.1, Appendix 14.2, Appendix 14.4 and Appendix 14.5. 
Brain imaging measurements include: 
 Regional brain volumes as measured by MRI  
 Diffusion fractional anisotropy (FA) in Corpus Callosum only as measured by DTI 
Actual results and percent change from baseline values for quantitative MRI (frontotemporal, 
parietal, and subcortical regions only) and FA parameters will be summarized by visit using 
descriptive statistics. Mean and median percent change from baseline values, the standard 
deviation, minimum and maximum will also be presented in a plot. 


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All MRI and DTI data will be presented in data listings. 
10.4. Exploratory Correlation Analyses 
Exploratory correlation analysis will be conducted between selected biomarkers (PGRN, NfL 
and GFAP) and CDR® plus NACC FTLD Sum of Boxes (FTLD-CDR-SB), for samples 
collected from both plasma and CSF with baseline and at least one post-baseline measurement in 
the full analysis population. Summary tables will be provided to show the relationship between 
each fluid PD biomarker and FTLD-CDR-SB by cohort. The summary tables will include the 
total number of data points, as well as the Pearson and Spearman correlation coefficients. Scatter 
plots of actual values for fluid PD biomarkers as the X-axis variable and FTLD-CDR-SB scores 
as the Y-axis variable will be plotted and will include the Pearson and Spearman correlation 
coefficients from the summary tables.  
A similar but separate analysis to assess the correlations among selected fluid PD biomarker 
(NfL and GFAP only) levels and quantitative brain imaging parameters MRI (frontotemporal, 
parietal, and subcortical regions only) will be performed. 
Additionally, for the selected fluid biomarkers, the absolute change from baseline to week 49 and 
percent change over the same interval will be correlated against the absolute change in FTLD-
CDR-SB. For selected regional volumetrics (i.e., frontotemporal, parietal, and subcortical 
regions), the percent change from baseline to week 49 will be correlated with FTLD-CDR-SB 
scores. The results will be presented in summary tables and scatter plots as described above. 
Only subjects with both baseline and week-49 biomarker and FTLD-CDR-SB data in the full 
analysis population will be included. 
11. Interim Analysis 
No interim analyses are planned for this study.  
An iDMC will review safety data during the course of the study to provide recommendations to 
Alector on study conduct. The details of the iDMC are provided in a separate charter. 
12. Changes in the Planned Analysis 
Physical and neurological examinations will not be summarized or listed since exam results are 
only entered on the General Medical History and Baseline Conditions or AE pages of the eCRF.  
Due to the high rate of participant attrition over the study duration and small FTD cohort sizes, 
time points beyond Week 49 will not be included in the cohort level summary of the figures.  
Apolipoprotein-B100 samples will not be analyzed (or summarized/listed) due to vendor 
discontinuation of the assay. Standard lipid analytes are evaluated for safety (Cholesterol, HDL, 
LDL, Triglycerides) and will be reported as summarized in Section 8.2. 


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WBC samples for analysis for Sortilin expression were collected to serve as a pharmacodynamic 
biomarker of target engagement. Development of this assay found that stability of these samples 
was not reliable for accurate measurement. Expression of PGRN levels in the plasma and CSF 
will be used as a biomarker of target engagement, and will be reported as summarized in Section 
10. 
The following exploratory MRI analyses listed in the protocol will not be performed due to 
evidence from the literature that these are unlikely to change over the duration of participation in 
this trial: global brain volume; white matter hyperintensities; brain perfusion as measured by 
arterial spin labeling; and mean, axial and radial diffusivity as measured by diffusion tensor 
imaging. Other MRI analyses (including safety assessments) will be reported as summarized in 
Sections 8.8 and 12.2. 
 
 


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carriers against frontotemporal dementia. Acta Neuropathol. 2014;127(3):397-406. 
Zhang Y, Xu Y, Dickey CA, et al. Progranulin mediates caspase-dependent cleavage of TAR 
DNA binding protein-43. J Neurosci. 2007;27(39):10530-4. 
Zhang Y, Xu Y, Cook C, et al. Aberrant cleavage of TDP-43 enhances aggregation and cellular 
toxicity. Proc Natl Acad Sci USA. 2009;106(18):7607-12. 
 
 


Alector Inc. 
 
Final Statistical Analysis Plan, Version 3.0  
AL001-2 
 
Date Issued: 19MAR2024 
 
  
 
 
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14. Appendices 
14.1. Schedule of Assessments for Part 1, Treatment Period (Through Week 53) 
Proceduresm 
Screening 
Treatment Period 
 
Visits 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13
V14 
V15 
Study week 
-6 
1 
2 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Study day 
 
1 
10 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Visit window (days) 
42 
Total
0 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Informed consent 
x 
 
Demographicsa 
x 
 
Medical history review
x 
x 
 
Physical examinationb 
xb 
x 
x
x
x
x
x
x 
xb
x
x
x
x 
x 
xb
X
Neurological 
examinationc
xc 
x 
 
x 
x 
x 
x 
x 
xc 
x 
x 
x 
x 
x 
xc 
x 
Vital signs and weightd,f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECGe,f
x 
x 
 
x
x 
Clinical chemistry, 
hematologyg
x 
x 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
Coagulationg,h 
x 
 
x 
x 
Urinalysisg
x 
x 
x
x
x
x 
Serologyg,i
x 
 
Pregnancy testg,j
x 
x 
x
x
x
x
x 
x
x
x
x
x 
x 
x 
x
Serum PK samplesf,g,k
x 
x
x
x
x
x
x 
x
x
x
x
x 
x 
x 
x
PGRN Plasma samplesf,g
x 
x
x
x
x
x
x 
x
x
x
x
x 
x 
x 
x
Whole blood for WBCf,g
x 
x
x
x
x
x
x 
x
x
x
x
x 
x 
x 
x
Whole blood for WGS
x 
 
Serum ADA samplesf,g,k
x 
x
x
x
x
x
x 
x
x
x
x
x 
x 
x 
x
Exploratory plasma PD 
biomarker samples f,g
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Alector Inc. 
 
Final Statistical Analysis Plan, Version 3.0  
AL001-2 
 
Date Issued: 19MAR2024 
 
  
 
 
 33
Proceduresm 
Screening 
Treatment Period 
 
Visits 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13
V14 
V15 
Study week 
-6 
1 
2 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
Study day 
 
1 
10 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
Visit window (days) 
42 
Total
0 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Exploratory whole blood 
PD biomarker samples f,g 
 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Lumbar puncture/CSFl 
x 
 
x
x 
Brain MRIn 
x 
 
x
x 
Diagnostic 
characterizationo
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COAsp
x 
x
x
x
x 
Winterlight-A Lab 
Speech Assessment 
(Optional)q
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
Winterlight-B Lab 
Speech Assessment 
(Optional)q
 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
Review of AEs and 
concomitant medicationsr
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sheehan-STS
x 
x 
x
x
x
x
x
x 
x
x
x
x
x 
x 
x 
x
Study drug administration
x 
x
x
x
x
x 
x
x
x
x
x 
x 
x 
x


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 34
Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; 
CSF, cerebrospinal fluid; ECG, electrocardiogram; eCRF, electronic case report form; IL-6, Interleukin 6; MRI, magnetic resonance imaging; PD, 
pharmacodynamic; PE, physical examination; PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, Sheehan Suicidality Tracking Scale; V, visit; 
WBC, white blood cell; WGS, whole genome sequencing. 
a Demographic information (year of birth, age, sex, race, ethnicity) will be recorded at screening, unless disallowed by local regulatory agencies. 
b A complete PE will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, and includes evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, 
genital, and rectal examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a 
physician, or a nurse practitioner or physician’s assistant under the supervision of a physician. Limited or symptom-directed examinations is required 
at all other specified time points, prior to study drug administration (if applicable). A limited examination or symptom-directed examination should 
focus on the affected organ system or body area. Record abnormalities observed at screening on the General Medical History and Baseline Conditions 
page of the eCRF. At subsequent visits, record new or worsened clinically significant abnormalities on the AE eCRF. Height (cm) will be measured at 
screening. 
c A complete neurological examination will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, 
and includes the evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. Limited or 
symptom directed examinations are required at all other specified time points, prior to study drug administration (if applicable). A limited examination 
or symptom directed examination should focus on the organ system or affected body area. Record abnormalities observed at screening on the General 
Medical History and Baseline Conditions page of the eCRF. At subsequent visits, record new or worsened clinically significant abnormalities as AEs 
on the AE eCRF. 
d Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be 
recorded prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight 
(kg) will be collected at the same visits that vital signs are taken. 
e Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days ECG will be 
obtained prior to study drug administration and within 60 minutes after the end of infusion, and once at all other specified time points as indicated. 
Additional ECG monitoring must be performed during the treatment period if clinically indicated. 
f Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, exploratory plasma PD 
biomarker samples, whole blood samples for WBC analysis, and exploratory whole blood PD biomarker samples are provided in protocol Table 6. 
g Samples will be collected prior to study drug administration (if applicable). 
h If the lumbar puncture is moved to a different visit, the coagulation panel will be moved to the visit immediately preceding the new lumbar puncture 
visit. 
i Serology testing will include anti-HCV, anti-HIV, HIV antigen, HBsAg, and total hepatitis B core antibody. 
j All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at specified subsequent 
visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
k Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should 
be collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA 
assessment of AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 
l Cerebrospinal fluid samples will be collected via lumbar puncture prior to study drug administration (if applicable). The timing of lumbar punctures 
may be adjusted as determined by Alector’s review of exploratory PD biomarkers. GRN mutation carriers previously treated in Study AL001-1 may 
not be required to repeat the CSF assessment if it has been performed within 3 months prior to screening. 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 35
m If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-
site visit with approval from the medical monitor. Refer to protocol Appendix 3 for additional details on trial adaptations due to COVID-19. 
n During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. GRN mutation carriers previously 
treated in Study AL001-1 may not be required to repeat the imaging screening assessment if it has been performed within 3 months prior to screening. 
o A diagnostic characterization form will be completed in an electronic data capture system at screening, week 97, and EOT/EOS for symptomatic 
participants only. It will also be completed for any asymptomatic participant who becomes symptomatic during the course of the study; for these 
participants, the diagnostic characterization form will be completed only at the first visit in which they exhibit clinical symptomatology. 
p The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating 
Center Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical 
Global Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. The Clinical 
Global Impression of Improvement is not administered at baseline. Neurocognitive and functional tests will be performed prior to study drug 
administration (if applicable) and prior to any stressful procedures (e.g., blood collections, imaging). 
q Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) 
will be conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only 
(WLA-B) or both (WLA-A and WLA-B). Assessments are conducted at home within ±7 days of the visit and will be supervised by the study partner. 
The study partner will be asked to complete a questionnaire online within ±7 days of the EOS visit. 
r All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and 
through the Part1/Part 2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory 
clinical resolution. Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator 
regardless of the AE/SAE collection window. At every study visit, participants will be asked a standard nonleading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed 
concomitant medication regimens (prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter 
medications). Review of AEs and concomitant medications will be performed before and after study drug administration (when applicable). 
 
 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 36
14.2. Appendices Schedule of Assessments for Part 1, Treatment Period (Through Week 97) 
Proceduresm 
Treatment Period (continued) 
 
Part 1 
EOT/EOSs,t 
Safety 
Follow-upb,s 
Visits 
V16 V17
V17Aa 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26s 
 
 
Study week 
57 
61 
61 
65 
69 
73 
77 
81 
85 
89 
93 
97b 
 
 
Study day 
393 
421 
422 
449 
477 
505 
533 
561 
589 
617 
645 
673 
 
 
Visit window (days) 
±7 
±7 
±7a
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
±7 
Physical examinationc 
x 
x
x 
x
xc 
x
x
x
x
x
xc
xc
xc
Neurological examinationd
x 
x
x 
x
xd 
x
x
x
x
x
xd
xd
xd 
Vital signs and weighte,g 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECGf,g
x 
x
x
x
Clinical chemistry, hematologyh
x
x 
x
x
x
x
Coagulationh,i 
x 
x
Urinalysish
x
x 
x
x
x
x
Pregnancy testh,j 
x 
x
x 
x
x 
x
x
x
x
x
x
x
x
Serum PK samplesg,h,k
x
x
x 
x
x
x
x
PGRN Plasma samplesg,h
x
x
x 
x
x
x
x
Whole blood for WBCg,h
x
x 
x
x
x
Serum ADA samplesg,h,k
x
x 
x
x
x
x
Exploratory plasma PD biomarker samples g,h 
x
x 
x
x
x
Exploratory whole blood PD biomarker 
samples g,h 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Lumbar puncture/CSFl 
x
x
Brain MRIn 
x 
x
x
Diagnostic characterizationo 
x
x
COAsp
x
x 
x
x
x
Winterlight-A Lab Speech Assessment 
(Optional)q
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
Winterlight-B Lab Speech Assessment 
(Optional)q
x 
 
 
x 
x 
 
x 
x 
 
x 
x 
 
 
 
Review of AEs and concomitant medicationsr 
x 
x
x 
x
x 
x
x
x
x
x
x
x
x
Sheehan-STS
x 
x
x 
x
x 
x
x
x
x
x
x
x
x
Study drug administration
x 
x
x 
x
x 
x
x
x
x
x
x
 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 37
Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; 
CSF, cerebrospinal fluid; ECG, electrocardiogram; eCRF, electronic case report form; EOS, End of Study; EOT, End of Treatment; IL-6, Interleukin 
6; MRI, magnetic resonance imaging; PD, pharmacodynamic; PE, physical examination; PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, 
Sheehan Suicidality Tracking Scale; V, visit; WBC, white blood cell; WGS, whole genome sequencing. 
a Visit 17A should occur the following day after Visit 17. 
b A Safety Follow-up visit will be performed 10 weeks following the last dose of AL001. The Safety Follow-up visit may be substituted by a 
scheduled visit if it occurs within the same window. 
c A complete PE will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, and includes evaluation 
of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, 
genital, and rectal examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a 
physician, or a nurse practitioner or physician’s assistant under the supervision of a physician. Limited or symptom-directed examination are required 
at all other specified time points, prior to study drug administration (if applicable). A limited examination or symptom-directed examination should 
focus on the organ system or affected body area. Record abnormalities observed at screening on the General Medical History and Baseline Conditions 
page of the eCRF. Height (cm) will be measured at screening. At subsequent visits, record new or worsened clinically significant abnormalities on the 
AE eCRF. 
d A complete neurological examination will be performed at screening, Week 25, Week 49, Week 73, Week 97 and at EOT/EOS/Safety Follow-up, 
and includes the evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. Limited or 
symptomdirected examinations are required at all other specified time points, prior to study drug administration (if applicable). A limited examination 
or symptomdirected examination should focus on the affected organ system or body area. Record abnormalities observed at screening on the General 
Medical History and Baseline Conditions page of the eCRF. At subsequent visits, record new or worsened clinically significant abnormalities as AEs 
on the AE eCRF. 
e Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be 
recorded prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight 
(kg) will be collected at the same visits that vital signs are taken. 
f Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days ECG will be 
obtained prior to study drug administration and within 60 minutes after the end of infusion, and once at all other specified time points as indicated. 
Additional ECG monitoring must be performed during the treatment period if clinically indicated. 
g Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, exploratory plasma PD 
biomarker samples, whole blood samples for WBC analysis, and exploratory whole blood PD biomarker samples are provided in protocol Table 6. 
H Samples will be collected prior to study drug administration (if applicable). 
I If the lumbar puncture is moved to a different visit, the coagulation panel will be moved to the visit immediately preceding the new lumbar puncture 
visit. 
J All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at specified subsequent 
visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
K Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should 
be collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA 
assessment of AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 
L Cerebrospinal fluid samples will be collected via lumbar puncture prior to study drug administration (if applicable). The timing of lumbar puncture 
may be adjusted as determined by Alector’s review of exploratory PD biomarkers. GRN mutation carriers previously treated in Study AL001-1 may 
not be required to repeat the CSF assessment if it has been performed within 3 months prior to screening. 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 38
M If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-
site visit with approval from the medical monitor. Refer to protocol Appendix 3 for additional details on trial adaptations due to COVID-19. 
n During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. GRN mutation carriers previously 
treated in Study AL001-1 may not be required to repeat the imaging screening assessment if it has been performed within 3 months prior to screening. 
o A diagnostic characterization form will be completed in an electronic data capture system at screening, week 97, and EOT/EOS for symptomatic 
participants only. It will also be completed for any asymptomatic participant who becomes symptomatic during the course of the study; for these 
participants, the diagnostic characterization form will be completed only at the first visit in which they exhibit clinical symptomatology. 
p The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating 
Center Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical 
Global Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. The Clinical 
Global Impression of Improvement is not administered at baseline. Neurocognitive and functional tests will be performed prior to study drug 
administration (if applicable) and prior to any stressful procedures (e.g., blood collections, imaging). 
q Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) 
will be conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only 
(WLA-B) or both (WLA-A and WLA-B). Assessments are conducted at home within +/- 7 days of the visit and will be supervised by the study 
partner. The study partner will be asked to complete a questionnaire online within +/- 7 days of the Study Completion visit. 
r All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and 
through the Part 1/Part 2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory 
clinical resolution. Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator 
regardless of the AE/SAE collection window. At every study visit, participants will be asked a standard nonleading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed 
concomitant medication regimens (prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter 
medications). Review of AEs and concomitant medications will be performed before and after study drug administration (when applicable). 
s Participants who complete the Part 1 96-week treatment period (Week 97), who provide informed consent to participate in Part 2 (optional OLE) and 
meet all the eligibility criteria for the Part 2 OLE (prior to Week 101 study drug administration), will complete the Week 97 visit and continue to Part 
2 (Week 101) to receive their next regularly scheduled dose of AL001 according to the OLE administration schedule (continuation from Week 97 to 
Week 101). All other participants who complete the Part 1 96-week treatment period and who do not continue in Part 2 will complete a Part 1 EOS 
visit at the scheduled Week 97 timepoint. A Safety Follow-up visit will be performed 10-weeks after their last study drug administration (Week 107, 
+/- 7 days). 
t A Part 1 EOT visit will be completed by participants who discontinue study drug but remain in the study and continue to perform assessments. Part 1 
EOT assessments should be completed as soon as possible after the decision is made. A Part 1 EOS visit will be completed by participants who 
discontinue study drug and all assessments. Part 1 EOS assessments should be completed as soon as possible after the decision is made. 
 
 
 
 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 39
14.3. Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker Sample and Imaging 
Assessments – Part 1, Treatment Period  
Timepoint 
Vital 
Signs 
Serum PK 
sample a 
Triplicate 
ECG 
Serum ADA 
sample 
Progranulin 
plasma 
sample 
Exploratory 
plasma PD 
biomarker 
samples b 
Whole 
blood for 
WBC 
Exploratory 
whole blood 
PD biomarker 
samples c 
Screening
x
x
V1 (Week 1): Predose
x
x
x
x 
x 
x
x
x
V1 (Week 1): End of infusion 
x
x
x
V2 (Week 2)
x
x
x 
x 
x
x
x
V3 (Week 5): Predose 
x
x
 
x 
x 
x
V3 (Week 5): End of infusion 
x
x
 
 
V4 (Week 9): Predose 
x
x
x 
x
x
V4 (Week 9): End of infusion 
x
x
V5 (Week 13): Predose  
x
x
x 
x 
x
x
x
V5 (Week 13): End of infusion 
x
x
V6 (Week 17): Predose  
x
x
x 
x
x
V6 (Week 17): End of infusion 
x
x
V7 (Week 21): Predose  
x
x
x 
x
x
V7 (Week 21): End of infusion 
x
x
V8 (Week 25): Predose  
x
x
x
x 
x 
x
x
x
V8 (Week 25): End of infusion 
x
x
x
V9 (Week 29): Predose  
x
x
x 
x
x
V9 (Week 29): End of infusion 
x
x
V10 (Week 33): Predose 
x
x
x 
x
x
V10 (Week 33): End of infusion 
x
x
V11 (Week 37): Predose 
x
x
x 
x 
x
x
x
V11 (Week 37): End of infusion 
x
x
V12 (Week 41): Predose 
x
x
x 
x
x
V12 (Week 41): End of infusion 
x
x
V13 (Week 45): Predose 
x
x
x 
x
x
V13 (Week 45): End of infusion 
x
x
V14 (Week 49): Predose
x
x
x
x 
x 
x
x
x
V14 (Week 49): End of infusion
x
x
x
V15 (Week 53): Predose
x
x
x 
x 
x
x
V15 (Week 53): End of infusion
x
x
V16 (Week 57): Predose
x


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 40
Timepoint 
Vital 
Signs 
Serum PK 
sample a 
Triplicate 
ECG 
Serum ADA 
sample 
Progranulin 
plasma 
sample 
Exploratory 
plasma PD 
biomarker 
samples b 
Whole 
blood for 
WBC 
Exploratory 
whole blood 
PD biomarker 
samples c 
V16 (Week 57): End of infusion
x
V17 (Week 61): Predose
x
x
V17 (Week 61): End of infusion
x
x
x
x
x
x
x
V17 (Week 61): 3 hr ± 90 minutes post end of 
infusion
 
x 
 
 
 
 
 
 
V17A (Week 61): The next day after V17
x
x
V18 (Week 65): Predose
x
V18 (Week 65): End of infusion
x
V19 (Week 69): Predose
x
V19 (Week 69): End of infusion
x
V20 (Week 73): Predose
x
x
x
x
x
x
x
x
V20 (Week 73): End of infusion
x
x
x
V21 (Week 77): Predose
x
V21 (Week 77): End of infusion
x
V22 (Week 81): Predose
x
V22 (Week 81): End of infusion
x
V23 (Week 85): Predose
x
x
x
x
x
x
x
V23 (Week 85): End of infusion
x
x
V24 (Week 89): Predose
x
V24 (Week 89): End of infusion
x
V25 (Week 93): Predose
x
V25 (Week 93): End of infusion
x
V26 (Week 97): Predose
x
x
x
x
x
x
x
x
V26 (Week 97): End of infusion
x
x
x
Safety Follow-up 
x 
x 
x 
x 
x 
 
 
 
Part 1 EOT/EOS
x
x
x
x
x
x
x
x
Abbreviations: ADA, anti-drug antibody; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; hr, hour; PD, pharmacodynamic; 
PK,:pharmacokinetic; V, visit; WBC, white blood cell. 
a The window for serum PK samples is within 15 minutes after the end of the infusion. 
b Exploratory PD biomarkers include Neurofilament Light chain, 
u in plasma and other analytes. 
c Exploratory whole blood biomarkers include mRNA and other analytes. 
 
 
 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
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          Date Issued: 19MAR2024 
 
  
 
 
 41
14.4. Schedule of Assessments for Part 2 (Optional OLE) (Through Week 161)  
Proceduresj  
OLE Part 2 Treatment Period  
Visits  
V27a V28 V29 V30 V31 V32 V33 V34 V35 V36 V37 V38 V39 V40 V41 V42 
Study week  
101  105 109 113  117 121  125 129 133 137 141 145 
149 
153 
157  161 
Study day  
701  729 757 785  813 841  869 897 925 953 981 1009 1037 1065 1093 1121
Visit window (days)  
±7  
±7 
±7 
±7 
±7 
±7 
±7  
±7 
±7 
±7 
±7 
±7  
±7  
±7  
±7  
±7  
Informed Consenta  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb  
 
 
 
 
 
xb 
 
 
 
 
 
xb 
 
 
 
 
Neurological examinationc  
 
 
 
 
 
xc 
 
 
 
 
 
xc 
 
 
 
 
Vital signs and weightd,f  
x  
x  
x  
x   
x  
x   
x  
x  
x  
x  
x  
x   
x  
x  
x  
x   
ECGe,f  
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
Clinical chemistry, hematologyg  
 
 
x  
 
 
x 
 
 
x  
 
 
x 
 
 
x  
 
Urinalysisg  
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
Pregnancy testg,h  
x  
x  
x  
x   
x  
x   
x  
x  
x  
x  
x  
x   
x  
x  
x  
x   
Serum PK samplesf,g,i  
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
PGRN Plasma samplesf,g  
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
Serum ADA samplesf,g,i  
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
Exploratory plasma PD biomarker samples f,g  
 
 
 
 
 
x   
 
 
 
 
 
x 
 
 
 
 
Brain MRIk  
 
 
 
 
 
 
 
 
 
 
 
x  
 
 
 
 
Diagnostic characterizationl  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COAsm  
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
Winterlight-A Labs Speech Assessment 
(Optional)n  
 
 
x  
 
 
x   
 
 
x  
 
 
x  
 
 
x  
 
Winterlight-B Labs Speech Assessment 
(Optional)n  
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 42
Review of AEs and concomitant medicationso  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Sheehan-STS  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Study drug administration  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; 
ECG, electrocardiogram; eCRF, electronic case report form; IL-6, Interleukin 6; MRI, magnetic resonance imaging; PD, pharmacodynamic; PE, 
physical examination; PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, Sheehan Suicidality Tracking Scale; V, visit. 
a There is no Screening period for participants that opt-in to continue receiving AL001 in Part 2 (Optional OLE) of the study. Participants who 
complete the Part 1 96-week treatment period (Week 97), who provide informed consent to participate in Part 2 (optional OLE) and meet all the 
eligibility criteria for the Part 2 OLE (prior to Week 101 study drug administration), will complete the Week 97 visit and continue to Part 2 (Week 
101) to receive their next regularly scheduled dose of AL001 according to the OLE administration schedule (continuation from Week 97 to Week 
101). Visit 27/Week 101 of Part 2 (Optional OLE) will be conducted 4 weeks after Visit 26/Week 97 of the Part 1 Treatment Period for those 
participants who are eligible to participate. 
b A complete PE will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes evaluation of the head, 
eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, genital, and 
rectal examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a physician, or a 
nurse practitioner or physician’s assistant under the supervision of a physician. If applicable, limited or symptom-directed examinations will be 
performed at all other specified time points, prior to study drug administration. A limited examination or symptom-directed examination should focus 
on the affected organ system or body area. Record new or worsened clinically significant abnormalities on the AE eCRF. Height (cm) does not need to 
be collected in Part 2 OLE. 
c A complete neurological examination will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes 
the evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. If applicable, limited or 
symptomdirected examinations will be performed at all other specified time points, prior to study drug administration. A limited examination or 
symptom-directed examination should focus on the organ system or affected body area. Record new or worsened clinically significant abnormalities 
as AEs on the AE eCRF. 
d Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be 
recorded prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight 
(kg) will be collected at the same visits that vital signs are taken. 
e Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days, ECG will be 
obtained prior to study drug administration and within 60 minutes after the end of the infusion, and once at all other specified time points as indicated. 
Additional ECG monitoring must be performed during treatment period if clinically indicated. 
f Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, and exploratory plasma PD 
biomarker samples, are provided in protocol Table 9. 
g Samples will be collected prior to study drug administration (if applicable). 
h All women of childbearing potential will have urine pregnancy tests at specified visits. If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test. 
i Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should 
be collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA 
assessment of AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
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          Date Issued: 19MAR2024 
 
  
 
 
 43
j If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-
site visit with approval from the medical monitor. Refer to protocol Appendix 3 for additional details on trial adaptations due to COVID-19. 
k During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. 
l A diagnostic characterization form will be completed for symptomatic patients at Week 197/Part 2 EOS. It will also be completed for any 
asymptomatic participant who becomes symptomatic during the course of the study; for these participants, the diagnostic characterization form will be 
completed only at the first visit in which they exhibit clinical symptomatology. 
m The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating 
Center Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical 
Global Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. Neurocognitive 
and functional tests will be performed prior to study drug administration (if applicable) and prior to any stressful procedures (e.g., blood collections, 
imaging).  
n Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) 
will be conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only 
(WLA-B) or both (WLA-A and WLA-B). Assessments are conducted at home within ±7 days of the visit and will be supervised by the study partner. 
The study partner will be asked to complete a questionnaire online within ±7 days of the EOS visit. 
o All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and 
through the Part1/Part2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory 
clinical resolution. Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator 
regardless of the AE/SAE collection window. At every study visit, participants will be asked a standard non-leading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed 
concomitant medication regimens (prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter 
medications). Review of AEs and concomitant medications will be performed before and after study drug administration (when applicable). 
 
 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 44
14.5. Schedule of Assessments for Part 2 (Optional OLE) (Through Week 197)  
Proceduresi  
OLE Part 2 Treatment Period (continued)  
 
Part 2  
EOSo,p  
Safety 
Follow-upq  
Visits  
V43  
V44  
V45  
V46  
V47  
V48  
V49  
V50  
V51o  
  
  
Study week  
165  
169  
173  
177  
181  
185  
189  
193  
197  
  
  
Study day  
1149  
1177  
1205  
1233  
1261  
1289  
1317  
1345  
1373  
  
  
Visit window (days)  
±7  
±7  
±7  
±7  
±7  
±7  
±7  
±7  
±7  
  
±7  
Physical examinationa  
  
xa  
  
  
  
  
  
  
xa  
xa  
xa  
Neurological examinationb  
  
xb  
  
  
  
  
  
  
xb  
xb  
xb  
Vital signs and weightc,e  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
x  
ECGd,e  
  
x  
  
  
  
  
  
  
x  
x 
x  
Clinical chemistry, hematologyf  
  
x  
  
  
x  
  
  
  
x  
x 
x  
Urinalysisf  
  
x  
  
  
  
  
  
  
x  
x 
x  
Pregnancy testf,g  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
x  
Serum PK samplese,f,h  
  
x  
  
  
  
  
  
  
x  
x 
x  
PGRN Plasma samplese,f  
  
x  
  
  
  
  
  
  
x  
x 
x  
Serum ADA samplese,f,h  
  
x  
  
  
  
  
  
  
x  
x 
x  
Exploratory plasma PD biomarker 
samplese,f  
  
x  
  
  
  
  
  
  
x  
x 
  
Brain MRIj  
  
  
  
  
  
  
  
  
x  
x 
  
Diagnostic characterizationk  
  
  
  
  
  
  
  
  
x  
x 
  
COAsl  
  
x  
  
  
  
  
  
  
x  
x 
  
Winterlight-A Labs Speech  
Assessment (Optional)m  
  
x  
  
  
x  
  
  
  
x  
x 
  
Winterlight-B Labs Speech  
Assessment (Optional)m  
x  
  
x  
x  
  
x  
x  
x  
  
  
  
Review of AEs and concomitant 
medicationsn  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x 
x  
Sheehan-STS  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
x  
Study drug administration  
x  
x  
x  
x  
x  
x  
x  
x  
x  
  
  


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 45
Abbreviations: ADA, anti-drug antibody; AE, adverse event; CGI-I, Clinical Global Impression of Improvement; COA, clinical outcome assessment; 
ECG, electrocardiogram; eCRF, electronic case report form; IL-6, Interleukin 6; MRI, magnetic resonance imaging; PD, pharmacodynamic; PE, 
physical examination; PGRN, progranulin; PK, pharmacokinetic; Sheehan-STS, Sheehan Suicidality Tracking Scale; V, visit. 
a A complete PE will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes evaluation of the head, 
eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory and gastrointestinal systems. Breast, genital, and 
rectal examinations are not required, unless warranted in opinion of the health care provider. The examination will be performed by a physician, or a 
nurse practitioner or physician’s assistant under the supervision of a physician. If applicable, limited or symptom-directed examinations will be 
performed at all other specified time points, prior to study drug administration. A limited examination or symptom-directed examination should focus 
on the affected organ system or body area. Record new or worsened clinically significant abnormalities on the AE eCRF. Height (cm) does not need to 
be collected in Part 2 OLE. 
b A complete neurological examination will be performed at Week 121, Week 145, Week 169, Week 197 and at EOS/Safety Follow-up, and includes 
the evaluation of consciousness, orientation, cranial nerves, motor and sensory system, coordination and gait, and reflexes. If applicable, limited or 
symptom directed examinations will be performed at all other specified time points, prior to study drug administration. A limited examination or 
symptom-directed examination should focus on the organ system or affected body area. Record new or worsened clinically significant abnormalities 
as AEs on the AE eCRF. 
c Vital signs will be recorded after the participant has been resting for at least 5 minutes in the supine position. On dosing days, vital signs will be 
recorded prior to infusion (pre-dose) and within 15 minutes after the end of infusion, and once at all other specified time points as indicated. Weight 
(kg) will be collected at the same visits that vital signs are taken. 
d Triplicate 12-lead ECGs will be obtained after the participant has been in the supine position for ≥5 minutes. On specified dosing days, ECG will 
be obtained prior to study drug administration and within 60 minutes after the end of the infusion, and once at all other specified time points as 
indicated. Additional ECG monitoring must be performed during treatment period if clinically indicated. 
e Details on timing of vital signs, serum PK samples, triplicate ECGs, serum ADA samples, progranulin plasma samples, and exploratory plasma PD 
biomarker samples, are provided in protocol Table 9. 
f Samples will be collected prior to study drug administration (if applicable). 
g All women of childbearing potential will have urine pregnancy tests at specified visits. If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test. 
h Blood serum samples will be collected for determination of ADA prior to study drug administration (if applicable). Additional ADA samples should 
be collected in participants with signs and symptoms of infusion-related reactions. A sample of blood should be obtained for PK serum and ADA 
assessment of AL001, and testing should be performed for C-reactive protein, tryptase, and Interleukin 6 (IL-6). 
i If the assessment is unable to be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed at a future on-
site visit with approval from the medical monitor. Refer to protocol Appendix 3 for additional details on trial adaptations due to COVID-19. 
j During study drug treatment, magnetic resonance imaging to be performed within ±7 days of a treatment visit. 
k A diagnostic characterization form will be completed for symptomatic patients at Week 197/Part 2 EOS. It will also be completed for any 
asymptomatic participant who becomes symptomatic during the course of the study; for these participants, the diagnostic characterization form will be 
completed only at the first visit in which they exhibit clinical symptomatology. 
l The COAs consist of the Clinical Dementia Rating Scale plus behavior and language domains from the National Alzheimer’s Disease Coordinating 
Center Frontotemporal Lobar Degeneration module, Frontotemporal Dementia Rating Scale, Clinical Global Impression of Improvement, Clinical 
Global Impression of Severity, Color Trails Test Part 2, and the Repeatable Battery for the Assessment of Neuropsychological Status. Neurocognitive 
and functional tests will be performed prior to study drug administration (if applicable) and prior to any stressful procedures (e.g., blood collections, 
imaging). 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 46
m Winterlight Labs Speech Assessments (WLA) (for US, UK, and Canadian participants who agree to participate in the optional assessments only) 
will be conducted at home. Participants will have the option to complete the WLA after assessment visits only (WLA-A), after treatment visits only 
(WLA-B) or both (WLA-A and WLA-B). Assessments are conducted at home within ±7 days of the visit and will be supervised by the study partner. 
The study partner will be asked to complete a questionnaire online within ±7 days of the EOS visit. 
n All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur after the participant signs informed consent and 
through the Part1/Part2 EOS or Safety Follow-up visit, whichever is later. Any unresolved AEs and SAEs will be followed up through satisfactory 
clinical resolution. Additionally, SAEs considered related to study drug which occur at any time during the study will be reported by the investigator 
regardless of the AE/SAE collection window. At every study visit, participants will be asked a standard non-leading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had any accidents, used any new medications, or changed 
concomitant medication regimens (prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, and over-the-counter 
medications). Review of AEs and concomitant medications will be performed before and after study drug administration (when applicable). 
o At Week 197, participants who complete the Part 2 96-week OLE period will complete a Part 2 EOS visit at the scheduled Week 197 timepoint. 
Participants who complete Visit 51/Week 197 will return for a Safety Follow-up visit 10 weeks after their last AL001 administration (Week 207, +/- 7 
days). 
p Participants who discontinue study drug and/or all assessments prior to completing the 96-week Part 2 treatment period will complete a Part 2 EOS 
visit as soon as possible after the decision is made. 
q A Safety Follow-up visit will be performed 10 weeks following the last dose of AL001. The Safety Follow-up visit may be substituted by a 
scheduled visit if it occurs within the same window. 
 
 


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 47
14.6. Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker Sample and Imaging 
Assessments – Part 2 (Optional OLE)  
Timepoint  
Vital Signs 
Serum PK  
sample a  
Triplicate  
ECG  
Serum  
ADA  
sample  
Progranulin 
plasma sample 
Exploratory plasma PD 
biomarker samples b 
V27 (Week 101): Pre-dose  
x  
  
  
  
  
  
V27 (Week 101): End of infusion   
x  
  
  
  
  
  
V28 (Week 105): Pre-dose  
x  
  
  
  
  
  
V28 (Week 105): End of infusion  
x  
  
  
  
  
  
V29 (Week 109): Pre-dose  
x  
  
  
  
  
  
V29 (Week 109): End of infusion  
x  
  
  
  
  
  
V30 (Week 113): Pre-dose  
x  
  
  
  
  
  
V30 (Week 113): End of infusion  
x  
  
  
  
  
  
V31 (Week 117): Pre-dose  
x  
  
  
  
  
  
V31 (Week 117): End of infusion  
x  
  
  
  
  
  
V32 (Week 121): Pre-dose  
x  
x  
x  
x  
x  
x  
V32 (Week 121): End of infusion   
x  
x  
x  
x  
x  
x  
V33 (Week 125): Pre-dose  
x  
  
  
  
  
  
V33 (Week 125): End of infusion  
x  
  
  
  
  
  
V34 (Week 129): Pre-dose  
x  
  
  
  
  
  
V34 (Week 129): End of infusion  
x  
  
  
  
  
  
V35 (Week 133): Pre-dose  
x  
  
  
  
  
  
V35 (Week 133): End of infusion  
x  
  
  
  
  
  
V36 (Week 137): Pre-dose  
x  
  
  
  
  
  
V36 (Week 137): End of infusion  
x  
  
  
  
  
  
V37 (Week 141): Pre-dose  
x  
  
  
  
  
  
V37 (Week 141): End of infusion  
x  
  
  
  
  
  
V38 (Week 145): Pre-dose   
x  
x  
x  
x  
x  
x  


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 48
Timepoint  
Vital Signs 
Serum PK  
sample a  
Triplicate  
ECG  
Serum  
ADA  
sample  
Progranulin 
plasma sample 
Exploratory plasma PD 
biomarker samples b 
V38 (Week 145): End of infusion   
x  
x  
x  
x  
x  
x  
V39 (Week 149): Pre-dose  
x  
  
  
  
  
  
V39 (Week 149): End of infusion  
x  
  
  
  
  
  
V40 (Week 153): Pre-dose  
x  
  
  
  
  
  
V40 (Week 153): End of infusion  
x  
  
  
  
  
  
V41 (Week 157): Pre-dose  
x  
  
  
  
  
  
V41 (Week 157): End of infusion  
x  
  
  
  
  
  
V42 (Week 161): Pre-dose  
x  
  
  
  
  
  
V42 (Week 161): End of infusion  
x  
  
  
  
  
  
V43 (Week 165): Pre-dose  
x  
  
  
  
  
  
V43 (Week 165): End of infusion  
x  
  
  
  
  
  
V44 (Week 169): Pre-dose   
x  
x  
x  
x  
x  
x  
V44 (Week 169): End of infusion   
x  
x  
x  
x  
x  
x  
V45 (Week 173): Pre-dose  
x  
  
  
  
  
  
V45 (Week 173): End of infusion  
x  
  
  
  
  
  
V46 (Week 177): Pre-dose  
x  
  
  
  
  
  
V46 (Week 177): End of infusion  
x  
  
  
  
  
  
V47 (Week 181): Pre-dose  
x  
  
  
  
  
  
V47 (Week 181): End of infusion  
x  
  
  
  
  
  
V48 (Week 185): Pre-dose  
x  
  
  
  
  
  
V48 (Week 185): End of infusion  
x  
  
  
  
  
  
V49 (Week 189): Pre-dose  
x  
  
  
  
  
  
V49 (Week 189): End of infusion  
x  
  
  
  
  
  
V50 (Week 193): Pre-dose  
x  
  
  
  
  
  
V50 (Week 193): End of infusion  
x  
  
  
  
  
  
V51 (Week 197): Pre-dose   
x  
x  
x  
x  
x  
x  


Alector Inc. 
 
 
Final Statistical Analysis Plan, Version 3.0 
AL001-2 
 
 
          Date Issued: 19MAR2024 
 
  
 
 
 49
V51 (Week 197): End of infusion   
x  
x  
x  
x  
x  
x  
Safety Follow-up   
x  
x  
x  
x  
x  
  
Part 2: EOS  
x  
x  
x  
x  
x  
x  
Abbreviations: ADA, anti-drug antibody; ECG, electrocardiogram; EOS, End of Study; EOT, End of Treatment; hr, hour; PD, pharmacodynamic; PK, 
pharmacokinetic; V, visit; 
a The window for serum PK samples is within 15 minutes after the end of the infusion. 
b Exploratory PD biomarkers include Neurofilament Light chain, 
u in plasma and other analytes.