A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo, and in Non-Randomized, Placebo-Treated Non-Carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Crenezumab in the Treatment of Autosomal-Dominant Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer's Disease
Sponsor: Genentech, Inc.

 
Official Title: A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical 
PSEN1 E280A Mutation Carriers Randomized to Crenezumab or 
Placebo, and in Non-Randomized, Placebo-Treated Non-Carriers 
From the Same Kindred, to Evaluate the Efficacy and Safety of 
Crenezumab in the Treatment of Autosomal-Dominant Alzheimer’s 
Disease 
NCT Number: NCT01998841   
Document Date: Protocol Version 11: 10-May-2022 
 
 
 

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland.  
However, it may be implemented in individual countries by Roche’s local affiliates, including 
Genentech, Inc. in the United States.  The information contained in this document, especially any 
unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and; therefore, is 
provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, 
your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that this 
information will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Crenezumab—F. Hoffmann-La Roche Ltd 
Protocol GN28352, Version 11 
PROTOCOL 
TITLE: 
A DOUBLE-BLIND, PLACEBO-CONTROLLED 
PARALLEL-GROUP STUDY IN PRECLINICAL 
PSEN1 E280A MUTATION CARRIERS 
RANDOMIZED TO CRENEZUMAB OR PLACEBO, 
AND IN NON-RANDOMIZED, PLACEBO-TREATED 
NON-CARRIERS FROM THE SAME KINDRED, TO 
EVALUATE THE EFFICACY AND SAFETY OF 
CRENEZUMAB IN THE TREATMENT OF 
AUTOSOMAL-DOMINANT ALZHEIMER’S 
DISEASE 
PROTOCOL NUMBER: GN28352 
VERSION NUMBER: 
11 
STUDY DRUG: 
Crenezumab (MABT5102A) 
NCT NUMBER 
NCT01998841 
MEDICAL MONITOR: 
, M.D., M.A.S. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
CH-4070 Basel, Switzerland 
 
In collaboration with: 
Banner Alzheimer’s Institute 
901 East Willetta St. 
Phoenix, AZ 85006 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
2/Protocol GN28352, Version 11 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
11 
See electronic date stamp on the final page of this document 
10 
23 August 2021 
9 
19 March 2021 
8 
10 September 2020 
7 
18 December 2019 
6 
26 May 2017 
5 
9 March 2016 
4 
19 November 2014 
3 
19 July 2014 
2 
12 April 2013 
1 
20 August 2012 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
3/Protocol GN28352, Version 11 
PROTOCOL AMENDMENT, VERSION 11 
RATIONALE 
Protocol GN28352 has been amended.  Changes to the protocol, along with a rationale 
for each change, are summarized below: 
 
Protocol GN28352 has been amended to extend Study Period B so that participants 
may have the opportunity to continue receiving study drug until the regulatory 
approval of crenezumab (or another mechanism of post-trial access to crenezumab 
is initiated) or development of crenezumab is discontinued during “Study Period B”.  
Text has been modified throughout to reflect this. 
 
The description of the safety analyses has been amended to include the 16-week 
follow-up data from Study Period A in the primary safety analyses.  The protocol 
indicated previously that adverse events reported during the 16-week follow-up 
period of Study Period A would be summarized separately. 
– 
Study participants are considered treatment-exposed during the 16-week 
follow-up period (approximately 5 half-lives); therefore, adverse events 
reported within 16 weeks after the last dose of study drug administered in 
Study Period A will be included in the safety analyses from Study Period A.  
At the end of Study Period B, safety analyses on Study Period A will be 
refreshed and reported in the final Clinical Study Report. 
– 
Adverse events reported within 16 weeks after the last dose of study drug 
administered in Study Period B will be included in the safety analyses for 
Study Period B 
 
The tables for Study Period B in the Schedule of Activities have been modified to 
reflect the extension of Study Period B (Appendix 5 and Appendix 6) 
 
Optional cerebrospinal fluid (CSF) and Tau-positron emission tomography (PET) 
assessments have been added to the schedule of activities for participants who 
participated in the Tau-PET substudy and consented to optional CSF samples 
collection in Study Period A 
 
Additional minor changes have been made to improve readability, clarity, and 
consistency.  Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol. 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
4/Protocol GN28352, Version 11 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND ............................................................................ 29 
1.1 
Background on Disease ........................................................... 29 
1.2 
Background on Crenezumab ................................................... 30 
1.2.1 
Summary of Nonclinical Studies .............................................. 32 
1.2.2 
Clinical Experience .................................................................. 33 
1.2.2.1 
Safety Experience in Patients with Sporadic AD ...................... 34 
1.2.2.2 
Clinical Pharmacokinetics ........................................................ 36 
1.2.2.3 
Immunogenicity ........................................................................ 37 
1.3 
Rationale for Doing this Study ................................................. 37 
1.3.1 
Rationale for the Alzheimer’s Prevention Initiative ................... 37 
1.3.2 
Rationale for Study .................................................................. 37 
2. 
OBJECTIVES ................................................................................ 39 
2.1 
Efficacy Objectives .................................................................. 40 
2.1.1 
Primary Efficacy Objective ....................................................... 40 
2.1.2 
Secondary Efficacy Objectives ................................................ 40 
2.2 
Safety Objectives ..................................................................... 40 
2.3 
Pharmacokinetic/Pharmacodynamic Objectives ...................... 40 
2.4 
Exploratory Objectives ............................................................. 41 
2.5 
Study Period B Objectives ....................................................... 41 
3. 
STUDY DESIGN ........................................................................... 41 
3.1 
Description of the Study ........................................................... 41 
3.2 
Rationale for Study Design ...................................................... 44 
3.2.1 
Rationale for Study Period B.................................................... 44 
3.2.2 
Rationale for Crenezumab Dosage .......................................... 45 
3.2.3 
Rationale for Participant Population ......................................... 47 
3.3 
Outcome Measures in Study period A .................................... 48 
3.3.1 
Primary Efficacy Outcome Measures ....................................... 48 
3.3.2 
Secondary Efficacy Outcome Measures .................................. 48 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
5/Protocol GN28352, Version 11 
3.3.2.1 
Clinical ..................................................................................... 49 
3.3.2.2 
Biomarkers............................................................................... 49 
3.3.3 
Safety Outcome Measures ...................................................... 49 
3.3.4 
Pharmacokinetic/Pharmacodynamic Outcome Measures ....... 50 
3.3.5 
Exploratory Outcome Measures .............................................. 50 
3.3.5.1 
Clinical ..................................................................................... 50 
3.3.5.2 
Fluid Biomarkers ...................................................................... 50 
3.3.5.3 
Imaging Biomarkers ................................................................. 50 
3.3.5.4 
Other Outcome Measures ....................................................... 51 
3.4 
outcome measures in study period b ........................................ 51 
3.5 
Safety Plan .............................................................................. 51 
3.5.1 
Immunogenicity ........................................................................ 52 
3.5.2 
Amyloid-Related Imaging Abnormalities .................................. 52 
3.5.2.1 
Monitoring for Amyloid-Related Imaging Abnormalities ........... 53 
3.5.2.2 
Management of Amyloid-Related Imaging Abnormalities ........ 54 
3.5.3 
Pneumonia............................................................................... 55 
3.5.3.1 
Monitoring for Pneumonia ........................................................ 56 
3.5.4 
Injection and Infusion Reactions ............................................ 56 
3.5.4.1 
Systemic Injection and Infusion-Related Reactions ................. 56 
3.5.5 
Additional Safety Monitoring .................................................... 57 
3.6 
Study Participants and Analysis Groups .................................. 57 
3.7 
Control Groups ........................................................................ 58 
3.8 
Minimization of Bias ................................................................. 58 
3.9 
Ethical Considerations ............................................................. 59 
3.10 
Administrative Structure ........................................................... 60 
3.11 
Compliance with Laws and Regulations .................................. 60 
4. 
MATERIALS AND METHODS ...................................................... 60 
4.1 
Participants .............................................................................. 60 
4.1.1 
Participant Selection ................................................................ 60 
4.1.2 
Inclusion Criteria ...................................................................... 61 
4.1.3 
Exclusion Criteria ..................................................................... 63 
4.2 
Method of Treatment Assignment and Blinding ....................... 66 
4.3 
Study Treatment ...................................................................... 67 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
6/Protocol GN28352, Version 11 
4.3.1 
Crenezumab and Placebo ....................................................... 67 
4.3.1.1 
Formulation .............................................................................. 67 
4.3.1.2 
Dosage, Administration, and Storage ...................................... 68 
4.3.1.3 
Dosage Modification ................................................................ 69 
4.3.2 
PET Tracers ............................................................................. 70 
4.4 
Concomitant and Excluded Therapies ..................................... 70 
4.4.1 
Concomitant Therapy .............................................................. 70 
4.4.1.1 
Permitted Therapies ................................................................ 70 
4.4.1.2 
Permitted Therapies under Special Circumstances 
(Requires Medical Monitor Approval) ....................................... 71 
4.4.1.3 
Prohibited Therapies ................................................................ 72 
4.5 
Study Assessments ................................................................. 72 
4.5.1 
Definitions of Study Assessments ............................................ 72 
4.5.1.1 
Vital Signs ................................................................................ 72 
4.5.1.2 
Physical Examination ............................................................... 72 
4.5.1.3 
Neurological Examination ........................................................ 73 
4.5.1.4 
Electrocardiogram .................................................................... 73 
4.5.1.5 
Pharmacokinetic Assessments ................................................ 73 
4.5.1.6 
Pharmacodynamic Assessments ............................................. 74 
4.5.1.7 
Laboratory Assessments ......................................................... 74 
4.5.1.8 
Immunogenicity Sampling ........................................................ 75 
4.5.1.9 
Exploratory Blood Biomarker Assessments ............................. 75 
4.5.1.10 
Blood Sample for Exploratory Genetic Assessments ............... 75 
4.5.1.11 
Genetic Sampling of ADAD and APOE Genotype ................... 75 
4.5.1.12 
Lumbar Puncture ..................................................................... 75 
4.5.1.13 
lmaging Assessments .............................................................. 75 
4.5.1.14 
Cognitive, Functional, and Behavioral Assessments ............... 77 
4.5.1.15 
Clinical Progression ................................................................. 79 
4.5.1.16 
CDR Progression ..................................................................... 80 
4.5.1.17 
Medical History ........................................................................ 80 
4.5.2 
Screening and Pretreatment Assessments .............................. 80 
4.5.3 
Assessments During Treatment ............................................... 81 
4.5.4 
Remote Assessments .............................................................. 82 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
7/Protocol GN28352, Version 11 
4.5.5 
Study Completion .................................................................... 82 
4.5.6 
Early Termination Visit ............................................................. 82 
4.5.7 
Follow-Up Assessments .......................................................... 83 
4.5.8 
Study Period B Visits and Assessments .................................. 84 
4.5.9 
Samples for Roche and Other Clinical Repositories ................ 84 
4.5.9.1 
Overview of the Biological Sample Repositories...................... 84 
4.5.9.2 
Future Research ...................................................................... 85 
4.5.9.3 
Sample Collection .................................................................... 85 
4.5.9.4 
Confidentiality .......................................................................... 86 
4.5.9.5 
Participation in the RCR and NCRAD ...................................... 86 
4.5.9.6 
Withdrawal from the RCR and NCRAD ................................... 86 
4.5.9.7 
Monitoring and Oversight ......................................................... 87 
4.6 
Participant Discontinuation ...................................................... 87 
4.7 
Study Discontinuation .............................................................. 88 
4.8 
Post-Trial Access to Study Drug .............................................. 88 
4.9 
Assay Methods ........................................................................ 89 
4.10 
Statistical Methods ................................................................... 89 
4.10.1 
Analysis of the Conduct of the Study ....................................... 89 
4.10.2 
Analysis of Treatment Group Comparability ............................ 89 
4.10.3 
Efficacy Analyses ..................................................................... 90 
4.10.3.1 
Primary Efficacy Endpoints ...................................................... 90 
4.10.3.2 
Secondary Efficacy Endpoints ................................................. 90 
4.10.4 
Safety Analysis ........................................................................ 91 
4.10.4.1 
Adverse Events ........................................................................ 91 
4.10.4.2 
Clinical Laboratory Evaluations ................................................ 92 
4.10.4.3 
MRI Evaluations ....................................................................... 92 
4.10.4.4 
Vital Signs ................................................................................ 92 
4.10.4.5 
Electrocardiogram .................................................................... 92 
4.10.4.6 
Anti-Drug Antibodies ................................................................ 92 
4.10.5 
Pharmacokinetic and Pharmacodynamic Analyses ................. 92 
4.10.6 
Exploratory Analyses ............................................................... 93 
4.10.7 
Handling of Missing Data ......................................................... 93 
4.10.8 
Determination of Sample Size ................................................. 93 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
8/Protocol GN28352, Version 11 
4.10.9 
Interim Analysis ....................................................................... 94 
4.10.10 
Analyses for Study Period B .................................................... 94 
4.11 
Data Quality Assurance ........................................................... 94 
5. 
ASSESSMENT OF SAFETY ......................................................... 95 
5.1 
Safety Parameters and definitions ........................................... 95 
5.1.1 
Adverse Events ........................................................................ 95 
5.1.2 
Serious Adverse Event ............................................................ 96 
5.1.3 
Protocol-Defined Events of Special Interest/Non-Serious 
Expedited Adverse Events ....................................................... 97 
5.2 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 98 
5.2.1 
Adverse Event Reporting Period .............................................. 98 
5.2.2 
Eliciting Adverse Events .......................................................... 98 
5.2.3 
Assessment of Severity and Causality of Adverse Events ....... 98 
5.3 
Procedures for Recording Adverse Events ............................ 100 
5.3.1 
Recording Adverse Events on the eCRF ............................... 100 
5.3.1.1 
Diagnosis Versus Signs and Symptoms ................................ 101 
5.3.1.2 
Adverse Events Occurring Secondary to Other Events ......... 101 
5.3.1.3 
Persistent or Recurrent Adverse Events ................................ 101 
5.3.1.4 
Abnormal Laboratory Values ................................................. 102 
5.3.1.5 
Deaths ................................................................................... 102 
5.3.1.6 
Preexisting Medical Conditions .............................................. 102 
5.3.1.7 
Development or Worsening of Alzheimer’s Disease .............. 103 
5.3.1.8 
Hospitalization, Prolonged Hospitalization, or Surgery .......... 103 
5.3.1.9 
Pregnancy.............................................................................. 103 
5.3.1.10 
Pregnancies in Female Partners of Male Participants ........... 103 
5.3.1.11 
Congenital Anomalies/Birth Defects ...................................... 104 
5.3.1.12 
Abortions................................................................................ 104 
5.4 
Expedited Reporting Requirements for Serious 
Adverse Events (and Protocol-Defined Events of Special 
Interest) ................................................................................. 104 
5.4.1 
Reporting Requirements for Fatal/Life-Threatening Serious 
Adverse Events Related to Investigational Product ............... 104 
5.4.2 
Emergency Medical Contacts ................................................ 105 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
9/Protocol GN28352, Version 11 
5.4.3 
Reporting Requirements for All Serious Adverse Events 
and Protocol-Defined Events of Special Interest .................... 105 
5.5 
Type and Duration of Follow-Up of Participants after 
Adverse Events ...................................................................... 105 
5.6 
Post-Study Adverse Events ................................................... 106 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 106 
6. 
INVESTIGATOR REQUIREMENTS ............................................ 107 
6.1 
Study Initiation ....................................................................... 107 
6.2 
Study Completion .................................................................. 107 
6.3 
Informed Consent Form ......................................................... 108 
6.4 
Communication with the Institutional Review Board or 
Ethics Committee ................................................................... 109 
6.5 
Study Monitoring Requirements ............................................. 109 
6.6 
Electronic Case Report Forms ............................................... 110 
6.7 
Source Data Documentation .................................................. 110 
6.8 
Use of Computerized Systems .............................................. 110 
6.9 
Study Medication Accountability ............................................ 111 
6.10 
Disclosure of Data ................................................................. 111 
6.11 
Retention of Records ............................................................. 112 
7. 
REFERENCES............................................................................ 113 
 
 
LIST OF TABLES 
Table 1 
Adverse Event Grading (Severity) Scale ..................................... 99 
Table 2 
Causal Attribution Guidance ..................................................... 100 
 
 
LIST OF FIGURES 
Figure 1 
Study Design ............................................................................... 43 
Figure 2 
Study Schematic ......................................................................... 43 
Figure 3 
Pharmacokinetic Profile Based on Modeling and Simulation 
Data for 60 mg/kg Crenezumab Administered Intravenously 
Q4W Compared with 15 mg/kg Crenezumab Administered 
Intravenously Q4W ..................................................................... 47 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
10/Protocol GN28352, Version 11 
 
 
LIST OF APPENDICES 
APPENDIX 1  (SC Dosing) Study Flowchart (ScreeningWeek 104 jj)............ 118 
APPENDIX 2  (SC Dosing) Study Flowchart (Week 106End of 
Study(Period A) ......................................................................... 124 
APPENDIX 3  (IV Dosing) Study Flowchart (First IV DosingWeek 104 bb) .... 132 
APPENDIX 4  (IV Dosing) Study Flowchart (Week 108–End of Study 
Period A) ................................................................................... 136 
APPENDIX 5  Study Flow Chart for Study Period B: SC dosing ..................... 141 
APPENDIX 6  Study Flow Chart for Study Period B:  IV Dosing ..................... 145 
APPENDIX 7  Neurocognitive and Functional Assessments .......................... 149 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
11/Protocol GN28352, Version 11 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A DOUBLE-BLIND, PLACEBO-CONTROLLED 
PARALLEL-GROUP STUDY IN PRECLINICAL 
PSEN1 E280A MUTATION CARRIERS RANDOMIZED TO 
CRENEZUMAB OR PLACEBO, AND IN 
NON-RANDOMIZED, PLACEBO-TREATED 
NON-CARRIERS FROM THE SAME KINDRED, TO 
EVALUATE THE EFFICACY AND SAFETY OF 
CRENEZUMAB IN THE TREATMENT OF 
AUTOSOMAL-DOMINANT ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: GN28352 
VERSION NUMBER: 
11 
STUDY DRUG: 
Crenezumab (MABT5102A) 
NCT NUMBER 
NCT01998841 
MEDICAL MONITOR: 
, M.D., M.A.S. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
CH-4070 Basel, Switzerland 
 
In collaboration with: 
Banner Alzheimer’s Institute 
901 East Willetta St. 
Phoenix, AZ 85006 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to the contract research organization’s representative.  
Please retain the original for your study files. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
12/Protocol GN28352, Version 11 
PROTOCOL SYNOPSIS 
TITLE: 
A DOUBLE-BLIND, PLACEBO-CONTROLLED 
PARALLEL-GROUP STUDY IN PRECLINICAL PSEN1 E280A 
MUTATION CARRIERS RANDOMIZED TO CRENEZUMAB OR 
PLACEBO, AND IN NON-RANDOMIZED, PLACEBO-TREATED 
NON-CARRIERS FROM THE SAME KINDRED, TO EVALUATE 
THE EFFICACY AND SAFETY OF CRENEZUMAB IN THE 
TREATMENT OF AUTOSOMAL-DOMINANT ALZHEIMER’S 
DISEASE 
PROTOCOL NUMBER: 
GN28352 
VERSION NUMBER: 
11 
STUDY DRUG: 
Crenezumab (MABT5102A) 
NCT NUMBER 
NCT01998841 
PHASE: 
Phase II 
INDICATION: 
Alzheimer’s Disease 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
CH-4070 Basel, Switzerland 
 
In collaboration with: 
Banner Alzheimer’s Institute 
901 East Willetta St. 
Phoenix, AZ  85006 
 
OBJECTIVES 
PRIMARY EFFICACY OBJECTIVE 
The primary objectives of this Phase II trial are: 
 
To evaluate the efficacy of crenezumab treatment compared with placebo for at least 
260 weeks on change in cognitive function as measured by the Alzheimer’s Prevention 
Initiative (API) autosomal-dominant Alzheimer’s disease (ADAD) Cognitive Composite Test 
Battery in preclinical presenilin 1 (PSEN1) E280A autosomal-dominant mutation carriers 
 
To evaluate the efficacy of crenezumab treatment compared with placebo for at least 
260 weeks on change in episodic memory function as measured by the Free and Cued 
Selective Reminding Test (FCSRT) Cueing Index in preclinical PSEN1 E280A 
autosomal-dominant mutation carriers 
 
Additional details regarding the endpoints and analyses are in the Statistical Analysis Plan 
(SAP). 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
13/Protocol GN28352, Version 11 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives of this study (comparing crenezumab with placebo) will be to 
evaluate the following in PSEN1 E280A mutation carriers: 
 
Ability of crenezumab to affect clinical endpoints other than those in the primary endpoint 
family:  API ADAD Cognitive Composite Test Battery and FCSRT Cueing Index 
 
Ability of crenezumab to reduce cerebral fibrillar amyloid burden in a predefined region of 
interest (ROI) using florbetapir positron emission tomography (PET) 
 
Ability of crenezumab to reduce decline in regional cerebral metabolic rate of glucose 
(CMRgl) using fluorodeoxyglucose (FDG)-PET measurements in a predefined ROI 
 
Ability of crenezumab to reduce brain atrophy as measured by volumetric measurements 
using magnetic resonance imaging (MRI) 
 
Ability of crenezumab to affect a tau-based cerebrospinal fluid (CSF) biomarker 
 
Additional details regarding the endpoints and analyses are in the SAP. 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
 
To assess the safety and tolerability of crenezumab in preclinical PSEN1 E280A mutation 
carriers (comparing crenezumab with placebo) 
 
PHARMACOKINETIC/PHARMACODYNAMIC OBJECTIVES 
The pharmacokinetic (PK) and pharmacodynamic (PD) objectives for this study are as follows: 
 
Collect sparse PK samples to support confirmation of exposure to crenezumab and to 
explore the PD response (as measured by plasma total amyloid- [A] levels comparing 
crenezumab with placebo) in preclinical PSEN1 E280A mutation carriers 
 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
 
Assess further the effect of crenezumab in preclinical PSEN1 E280A mutation carriers on 
additional clinical measures of efficacy and biological markers of disease that have not been 
prespecified as primary or secondary endpoints in the SAP 
 
Explore pharmacogenetic effects, including but not limited to, a person’s apolipoprotein E 
(APOE) 4 carrier status on the active treatment’s cognitive, clinical, and adverse effects 
 
Explore effects of genetic variation, including but not limited to, how genes affect the biology 
of Alzheimer’s disease and related disorders and how genes influence biomarker responses 
 
Examine clinical and biomarker changes in non-carriers and to compare these changes with 
those seen in carriers treated with placebo 
 
Relate the treatment’s biomarker effects to clinical outcomes and to examine predictive and 
prognostic utility of baseline characteristics 
 
Assess the impact of treatment on brain tau load over time, as measured by tau PET 
imaging in an optional substudy (GN28352-1/BN40199) 
 
STUDY DESIGN 
DESCRIPTION OF THE STUDY 
Study Period A:  This is a prospective, randomized, double-blind, placebo-controlled, 
parallel-group study of crenezumab versus placebo in individuals who carry the PSEN1 E280A 
autosomal-dominant, mutation-causing early onset Alzheimer’s disease (AD) and do not meet 
criteria for mild cognitive impairment due to AD or dementia due to AD and are, thus, in a 
preclinical phase of AD.  The study also incorporates administration of placebo to individuals 
who are not PSEN1 E280A autosomal-dominant mutation carriers.  This efficacy and safety 
study will be conducted at a single primary site and approximately three satellite sites in 
Colombia. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
14/Protocol GN28352, Version 11 
In the Colombian study, PSEN1 E280A autosomal-dominant mutation carriers who meet study 
eligibility criteria will be randomized in a 1:1 ratio to one of two treatment groups:  crenezumab 
or placebo.  Crenezumab will be administered either SC (720 mg every 2 weeks [Q2W]) or IV 
(60 mg/kg every 4 weeks [Q4W]).  Matching placebo will be administered by the same routes at 
the same frequencies.  The switch to the higher IV dose (approximately 4-fold higher exposure 
to crenezumab) will be optional.  Participants may decide whether to change from the current 
SC dosing to the IV dose; however, once IV dosing in a given participant has occurred, it is not 
intended for a participant to switch back to the lower SC dose.  In order to maintain genotype 
blind and to have a genetic kindred control, a cohort of PSEN1 E280A mutation non-carrier 
kindred family members will also be enrolled in the study and dosed only with placebo. 
The study includes three arms with approximately 100 participants per arm; two arms of 
participants with a PSEN1 E280A mutation randomized in a 1:1 ratio to crenezumab or placebo 
and a third arm of non-carriers randomized to placebo.  Participants will receive the randomized 
treatment until the final participant has reached their final treatment visit at 260 weeks. 
The study duration for individual participants will be at least approximately 284 weeks, including 
an 8-week screening period, a double-blind treatment period of at least 260 weeks in length, a 
4-week final dose visit, and a final safety follow-up visit 16 weeks after the last dose of study 
drug (crenezumab or placebo) that will allow for clinical follow-up after treatment discontinuation 
for participants who do not to continue with study drug beyond the end of Study Period A or who 
terminate study drug early.  One or more interim analyses may be performed at the Sponsor’s 
discretion. 
Study Period B:  Following the completion of Study Period A, participants will be offered the 
opportunity to continue to receive study drug until regulatory approval or another mechanism 
for post-trial access to crenezumab is started (via an open-label extension [OLE] or other 
programs) or development of crenezumab is discontinued.  This is termed Study Period B).  
All PSEN1 mutation carriers will be provided crenezumab in Study Period B regardless of 
treatment allocation during Study Period A and all non-carriers will continue on placebo.  
Treatment allocation for both Study Periods A and B will remain blinded.  Study Period B may 
last up to approximately 33.5 years depending on when participants enter Study Period B and 
when crenezumab is granted regulatory approval or development of crenezumab is 
discontinued. 
OUTCOME MEASURES 
PRIMARY EFFICACY OUTCOME MEASURES 
The primary efficacy outcome measures for Study Period A are as follows: 
 
Annualized rate of change on the API ADAD Composite Cognitive Test total score, which is 
computed from the following five cognitive test scores: 
 Word List:  Recall 
 Multilingual Naming Test 
 Mini-Mental State Examination (MMSE) (for orientation to time) 
 Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Constructional 
Praxis (a measure of visuospatial ability) 
 Raven’s Progressive Matrices (a measure of nonverbal fluid reasoning and visuospatial 
abilities), Set A 
 
Annualized rate of change on the FCSRT Cueing Index 
 
SECONDARY EFFICACY OUTCOME MEASURE 
The final selection of secondary outcome measures will be based on the basis of baseline data 
from the study population, relevant completed trials, and other external data that will emerge 
prior to database unblinding.  The selected outcomes will be provided in the SAP to be 
submitted prior to database unblinding.  Secondary outcome measures will be selected from the 
following. 
Clinical 
 
Time to progression from preclinical AD to mild cognitive impairment (MCI) due to AD or 
from preclinical AD to dementia due to AD 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
15/Protocol GN28352, Version 11 
 
Time to progression to non-zero in the Clinical Dementia Rating (CDR) Scale global score 
 
Annualized rate of change in the CDRSum of Boxes SOB) 
 
Annualized rate of change in a measure of overall neurocognitive functioning:  
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
 
Biomarkers 
 
Imaging biomarkers 
 Annualized rate of change in mean cerebral fibrillar amyloid accumulation using 
florbetapir PET from a predefined ROI 
 Annualized rate of change in regional CMRgl using FDG-PET in a predefined ROI 
 Annualized rate of change in volumetric measurements using MRI  
 
CSF biomarkers 

Annualized rate of change in a tau-based CSF biomarker  
 
SAFETY OUTCOME MEASURES 
Safety will be assessed through regular neurological and physical examinations (including vital 
signs), prospective suicidality assessment (copyright Pfizer Inc. and Janssen Alzheimer 
Immunotherapy; used with permission), laboratory tests, ECGs, and MRI assessments.  
In addition, the following data will be collected and analyzed: 
 
Frequency and severity of treatment-emergent adverse events and serious adverse events 
 
Withdrawals due to adverse events 
 
Incidence of injection reactions and infusion-related reactions (IRRs) 
 
Incidence of anti-crenezumab antibodies 
 
Incidence of treatment-emergent adverse events of special interest, including: 
– 
Amyloid-related imaging abnormalitiesedema/effusion (ARIA-E, cerebral vasogenic 
edema [VE], sulcal effusion) 
– 
Amyloid-related imaging abnormalitieshemosiderin deposition (ARIA-H, superficial 
CNS siderosis, cerebral microhemorrhages) 
– 
Cerebral macrohemorrhages 
– 
Pneumonia 
 
PHARMACOKINETIC/PHARMACODYNAMIC OUTCOME MEASURES 
The PK outcome measures are CSF and serum crenezumab concentrations at 
protocol-specified timepoints.  In serum, crenezumab trough concentration at steady state 
(Ctrough, ss) will be assessed.  Additional PK analyses may be conducted, as appropriate. 
The PD outcome measures are as follows:  plasma A140 and A142 concentrations. 
EXPLORATORY OUTCOME MEASURES 
Exploratory outcome measures are listed in below.  In addition, any endpoints that are not 
prespecified in the SAP as secondary outcome measures may be analyzed as exploratory 
outcome measures. 
SAFETY PLAN 
Crenezumab has not been approved for use by global health authorities and is currently in 
clinical development.  Thus, the entire safety profile is not known at this time.  The crenezumab 
safety information is based on results from nonclinical and clinical studies, as well as published 
data on similar molecules.  The safety monitoring for this study is designed to ensure participant 
safety and will include specific eligibility criteria and monitoring assessments.  Any adverse 
events/serious adverse events or any other abnormalities (e.g., laboratory assessments, 
radiographs, physical examination findings) should be managed by the site investigators, as 
medically appropriate (unless otherwise specified in the protocol). 
The safety of participants in this trial will be ensured through the use of stringent inclusion and 
exclusion criteria and through close monitoring of participants.  Investigators will assess the 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
16/Protocol GN28352, Version 11 
occurrence of adverse events and serious adverse events at all participant evaluation 
timepoints during the study.  All adverse events and serious adverse events, whether 
volunteered by the participant, discovered by study personnel during questioning, or detected 
through physical examination, laboratory tests, or other means, will be recorded in the 
participant’s medical record and on the appropriate adverse event or serious adverse event 
electronic Case Report Form (eCRF). 
Each recorded adverse event or serious adverse event will include a description of its duration 
(i.e., start and end dates), severity, seriousness according to regulatory criteria, if applicable, 
and suspected relationship to the investigational product, as well as any actions taken. 
Participants will be followed carefully for adverse events during the study, including a 4-week 
postdose visit and a final safety follow-up visit 16 weeks after the last dose of study drug.  
Adverse events will be graded according to severity using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. 
An independent Data Monitoring Committee (iDMC) formerly known as the Data and Safety 
Monitoring Board (DSMB) will be used for this study during Study Period A.  
During Study Period B, an internal data monitoring committee comprised of Sponsor 
employees not affiliated with the trial will monitor safety. 
Please refer to the latest Crenezumab Investigator’s Brochure for additional safety information. 
Immunogenicity 
Immunogenicity, as determined by the presence of positive response in the anti-drug antibody 
(ADA) enzyme-linked immunosorbent assay (ELISA), will be assessed at specified timepoints 
during the course of the study.  Additional characterizations will be performed if necessary.   
Amyloid-Related Imaging Abnormalities 
Amyloid-related imaging abnormalities (ARIA) are a spectrum of image abnormalities detected 
on MRI.  Two types of ARIA have been described:  Amyloid-related imaging 
abnormalitieseffusion refers to the MRI alterations thought to represent VE and related 
extravasated fluid phenomena, and ARIA-H refers to the MRI alterations attributable to 
microhemorrhages and leptomeningeal hemosiderosis. 
The occurrence of imaging abnormalities believed to represent cerebral VE has been reported 
in association with the investigational use of compounds that are intended to treat AD by 
reducing A in the brain.  These imaging abnormalities have, in the majority of instances, been 
asymptomatic, and their presence has been detected by brain MRI.  Symptoms, when present 
in association with such imaging abnormalities, have been reported to include headache, 
worsening cognitive function, alteration of consciousness, seizures, unsteadiness, and vomiting. 
The clinical significance of ARIA-H is not yet fully understood. 
When anti-A antibodies bind to amyloid deposited around blood vessels, an FcR-mediated 
immune response may be elicited, compromising vascular integrity and resulting in ARIA-E or 
ARIA-H.  Crenezumab, a human IgG4, has reduced FcR binding compared with IgG1/2 and, 
thus, has reduced effector function that theoretically may lower the risk of ARIA-E.  This has 
been supported by emerging safety data observed in both clinical and nonclinical studies 
conducted to date.  A lack of binding to vascular amyloid, noted following in vivo dosing in 
PS2APP transgenic (Tg) mice (Study 15-2817B), may additionally reduce the risk of ARIA. 
To minimize the potential safety risks associated with ARIA-E and ARIA-H in this study, 
participants will be screened for ARIA-E and ARIA-H before enrollment and will be monitored for 
ARIA-E and ARIA-H by MRI during treatment.  Given the uncertainty of risk and concerns about 
cerebral amyloid angiopathy severity, participants with superficial siderosis of the CNS, more 
than 4 cerebral microhemorrhages, or evidence of a prior cerebral macrohemorrhage at 
screening will be excluded from this study. 
An overview of the monitoring and management guidelines for ARIA-E and ARIA-H is provided 
below. 
The cerebral microhemorrhage thresholds for study entry and treatment discontinuation allow 
for imaging measurement variability to be taken into account and reflect the uncertainty 
regarding the clinical relevance of small numbers of cerebral microhemorrhages.  This approach 
is intended to minimize potential safety risks associated with cerebral microhemorrhages but 
would not preclude participants from receiving potentially beneficial treatment. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
17/Protocol GN28352, Version 11 
Monitoring for Amyloid-Related Imaging Abnormalities  
In this Phase II study, a safety monitoring plan has been designed to mitigate and monitor the 
potential risk of ARIA-E and ARIA-H associated with anti-A immunotherapy.  This plan consists 
of the following key elements: 
 
Participants with evidence of one or more of the following abnormalities assessed by MRI 
during screening will be excluded from the trial: 
– 
Significant cerebral vascular pathology 
– 
Superficial siderosis of the CNS 
– 
More than 4 cerebral microhemorrhages 
– 
Evidence of a prior cerebral macrohemorrhage 
 
Participants enrolled in the study will regularly undergo neurological examinations to 
evaluate for any neurologic signs or symptoms that are suggestive of the presence of the 
following: 
Cerebral VE (e.g., confusion, dizziness, vomiting, and lethargy), superficial siderosis of the 
CNS (e.g., sensorineural deafness, cerebellar ataxia, and pyramidal signs), or cerebral 
microhemorrhages (e.g., transient or permanent focal motor or sensory impairment, ataxia, 
aphasia, and dysarthria) 
 
Brain MRI examinations for Study Period A (including fluid-attenuated inversion recovery 
[FLAIR] and T2 with additional in-homogeneous dephasing (T2*)-weighted gradient-recalled 
echo [GRE] sequences) will be performed for safety monitoring approximately every 
3 months for the first year and approximately every 6 months thereafter to detect potential 
safety risks noted below.  If switching to 60 mg/kg IV Q4W, MRI scans will be performed at 
3 months and 6 months after initiating the higher dose and then every 2428 weeks 
thereafter to detect the following:  ARIA-E, ARIA-H, and cerebral macrohemorrhages. 
Brain MRI examinations in Study Period B will be done at Week 105 and as directed by 
symptoms.  All safety MRI scans will be read for the evaluation of ARIA-E, ARIA-H, and 
cerebral macrohemorrhages by independent radiologists at a central reading facility 
 
Regardless of severity, all events of cerebral VE, sulcal effusion, superficial siderosis of the 
CNS, and cerebral micro- or macro-hemorrhage that occur at any time after receiving study 
drug are considered to be adverse events of special interest and will be reported in an 
expedited manner 
 
Management of Amyloid-Related Imaging Abnormalities 
Amyloid-Related Imaging AbnormalitiesEdema/Effusion (ARIA-E) 
The following rules for the management of MRI-related findings apply for ARIA-E: 
 
Asymptomatic ARIA-E with Size  4 Barkhof Grand Total Score (BGTS) 
– 
Continue study drug at the same dose (i.e., 60 mg/kg crenezumab) 
– 
Repeat MRI 4 weeks later 
– 
If ARIA-E is stable or decreased, continue study drug and monthly MRI monitoring until 
event resolves.  Once ARIA-E completely resolves, conduct MRI monitoring as per 
study flowchart. 
– 
If ARIA-E increases (BGTS  4) or symptoms develop, see the rules below. 
 
Symptomatic ARIA-E (of any size) or asymptomatic ARIA-E with size  4 BGTS: 
– 
Temporarily interrupt study drug and implement monthly MRI monitoring 
– 
Once symptoms and ARIA-E resolve, reintroduce study drug and perform an MRI after 
4 weeks of dosing.  If no new MRI abnormality is detected, resume MRI monitoring as 
per the study flowchart. 
 
For any new onset of ARIA-E: 
– 
Treat the same as the first event, on the basis of symptoms and BGTS 
 
If a participant is diagnosed with 3 recurrent, symptomatic ARIA-E events or exacerbations 
of previous events, permanently discontinue the study drug 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
18/Protocol GN28352, Version 11 
 
Implement monthly MRI monitoring until resolution of both symptoms and ARIA-E 
 
As per the protocol, maintain the participant in the study until study end and perform 
assessments as per the study flowcharts 
 
Amyloid-Related Imaging AbnormalitiesHemosiderin Deposition (ARIA-H) 
The following dose adjustments and discontinuation rules for MRI-related findings will apply to 
ARIA-H: 
 
Dose reduction:  Participants who develop  8 ARIA-H cumulatively will receive a lower dose 
of the study drug.  Cumulative is the sum of ARIA-H at baseline and newly detected ARIA-H 
during the study. 
 
Study drug discontinuation:  Participants who develop  10 ARIA-H cumulatively will be 
permanently discontinued from the study drug.  Cumulative is the sum of ARIA-H at 
baseline and newly detected ARIA-H during the study. 
 
The Sponsor believes that the above rules, coupled with frequent MRI monitoring and collection 
of CNS symptoms, will ensure safety while trying to maximize benefit for the participants. 
Pneumonia 
In the RPCP of Phase II clinical trials in mild to moderate AD (Studies ABE4869g and 
ABE4955g) there was an imbalance in the rates of total lower respiratory tract infection 
(TLRTI, including Preferred Terms [PT] of pneumonia, lower respiratory tract infection [LRTI], 
and bronchitis) driven by pneumonia.  However, this imbalance was not replicated in the pooled 
data of the two large Phase III studies (BN29552 and BN29553) where the pneumonia cases 
were balanced between the crenezumab treatment and placebo arms (13 and 15 cases). 
There is no clinical evidence of immunosuppression (e.g., effects on white blood cells or 
neutrophils; or pattern of infection type, e.g., opportunistic infections).  In addition, no evidence 
of immunosuppression or of a lung toxicity effect has been observed in nonclinical studies. 
Based on the currently available data, a causal relationship between the drug and events of 
pneumonia cannot be established or ruled out.  Pneumonia is considered a potential risk to be 
monitored closely, and is added to this protocol as an adverse event of special interest. 
Please refer to the latest Crenezumab Investigator’s Brochure for further information on the 
incidence of pneumonia in all completed and ongoing studies. 
Monitoring for Pneumonia 
 
It is of paramount importance to carefully document any pneumonia cases and other 
serious respiratory infections that occur in this study, by means of providing all relevant 
information required by the eCRF 
 
Participants with signs and/or symptoms suggestive of pneumonia (e.g., cough, fever, 
pleuritic chest pain) should undergo chest radiography for confirmation of diagnosis.  
Participants should be treated as per standard treatment care and any change to study drug 
should be considered within a benefitrisk assessment frame, and in agreement with the 
Medical Monitor.  
 
A chest X-ray is required under the following circumstances: 
– 
Serious and non-serious pneumonia 
– 
Serious and non-serious LRTIs 
– 
Serious upper respiratory tract infections 
 
In addition, whenever possible, additional relevant investigations should be conducted 
(e.g., WBC counts, pathogen identification by means of hemocultures, bronchoalveolar 
lavage) 
 
Injection and Infusion Reactions 
Administration of monoclonal antibodies may be associated with local reactions at the site of 
injection or infusion.  Systemic injection/infusion reactions as well as hypersensitivity or 
anaphylactic reactions may also occur. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
19/Protocol GN28352, Version 11 
Infusion and injection-related reactions are defined as any adverse event that occurs during or 
within 24 hours after the study drug injection or infusion. 
No relationship between treatment dose and the occurrence of infusion/injection related 
reactions has been observed.  The majority of IRRs in all ongoing and completed studies with 
crenezumab were of mild to moderate severity. 
Systemic Injection and Infusion-Related Reactions 
Crenezumab will be administered to participants under close medical supervision in a setting 
with access to appropriate emergency equipment and staff who are trained to monitor and 
respond to medical emergencies. 
In the event that a participant experiences a mild IRR, the infusion will be halted.  Once the 
reaction has resolved, the infusion rate will be resumed at half of the most recently used rate 
(e.g., 31.5 mL/min). 
Participants who experience a moderate IRR (e.g., fever or chills) should have the infusion 
stopped immediately and should receive aggressive symptomatic treatment.  The infusion 
should not be restarted before all symptoms have disappeared, and then it should be restarted 
at half the initial rate. 
Participants who experience serious or severe hypersensitivity reactions (e.g., hypotension, 
mucosal involvement) should not receive additional study drug.  In addition, in any case of 
anaphylaxis, anaphylactoid reaction, serious or severe hypersensitivity reaction, ADA and 
concurrent PK samples should be collected as close as possible to the event, and then at 4 and 
16 weeks postdose (see study flowcharts for further details).  Participants who receive the SC 
formulation of study drug will be observed for a minimum of 15 minutes following all injections. 
Participants who receive IV formulation of study drug, will be observed for a minimum of 
60 minutes following all infusions. 
ADDITIONAL SAFETY MONITORING 
Laboratory tests, including hematology, chemistry, coagulation, urinalysis, and ADAs will be 
performed throughout the study.  Electrocardiograms will be recorded regularly, including at 
baseline.  Physical and neurological examinations will be performed throughout the study to 
assess adverse events, particularly any neurological events that are not consistent with normal 
disease progression.  Suicidality assessments will be used to measure prospective suicidality.  
If the suicidality assessment reveals a concern about a significant level of suicidality, the 
participant will undergo a more detailed assessment by a qualified clinician who has experience 
in the evaluation of suicidal ideation and behavior, either at the site or by referral to an outside 
clinician. 
Serum pregnancy testing will be performed at screening for all female participants of 
childbearing potential.  Urine pregnancy testing will be performed prior to study drug 
administration or PET scan for all female participants of childbearing potential.  
Pregnancy testing will apply to all female participants of childbearing potential unless 
documented (by medical records or physician’s note) to be surgically sterile or postmenopausal, 
as defined in International Council for Harmonisation (ICH) Guidance M3 (R2), Section 11.2 
(12 months with no menses without an alternative medical cause).  If urine pregnancy testing 
returns a positive result, study drug will be held until pregnancy is verified.  If pregnancy is 
confirmed, the participant will not receive further doses of study drug. 
The incidence and nature of adverse events, serious adverse events, and laboratory 
abnormalities will be assessed on a regular basis by the iDMC.  The committee will recommend 
changes to study conduct or study termination, as required.  The responsibilities and operation 
of the committee will be documented in the iDMC Charter. 
NUMBER OF SUBJECTS 
Up to 300 people will take part in this study in Colombia. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
20/Protocol GN28352, Version 11 
TARGET POPULATION 
Inclusion Criteria 
Participants must meet the following criteria for study entry: 
 
Signed and dated written informed consents obtained from the participant and study partner 
in accordance with local regulations prior to the initiation of any protocol required 
procedures 
 
Membership in PSEN1 E280A mutation carrier kindred 
 
Agrees to conditions of, and is willing to undergo, genetic testing 
(e.g., APOE, PSEN1 E280A, and other genetic testing) 
 
PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during 
the screening period 
 
Males and females, age  30 years and  60 years 
 
MMSE of  24 for participants with less than 9 years of education or MMSE of  26 for 
participants with 9 or more years of education 
 
Does not meet criteria for dementia due to AD 
 
Does not meet criteria for MCI due to AD as defined by the following: 
– 
Cognitive concern in the judgment of the investigator, based in part on the average 
Subjective Memory Checklist (SMC) score  22 (average of participant and study 
partner component scores) 
– 
Word List:  Recall  3 for participants with less than 9 years of education 
– 
Word List:  Recall  5 for participants with 9 or more years of education 
– 
Preservation of independence in functional activities in the judgment of the investigator, 
based in part on review of the Functional Assessment Staging of Alzheimer’s Disease 
(FAST) 
 
Adequate vision and hearing in the investigator’s judgment to be able to complete testing 
 
If female, and not documented (by medical records or physician’s note) to be surgically 
sterile (absence of ovaries and/or uterus or tubal ligation) or postmenopausal, willing to 
undergo pregnancy tests at protocol-specific timepoints 
 
For female participants who are not documented (by medical records or physician’s note) to 
be surgically sterile (absence of ovaries and/or uterus or tubal ligation) or postmenopausal, 
agreement to remain abstinent or use two adequate methods of contraception, including at 
least 1 method with a failure rate of  1% per year (e.g., hormonal implants, combined oral 
contraceptives, vasectomized partner) during the treatment period and for at least 16 weeks 
(approximately 5 half-lives) after the last dose of study drug 
 
For male participants of reproductive potential with partners of childbearing potential 
(i.e., women who are not surgically sterile and are not postmenopausal), agreement to 
remain abstinent or use a condom as a method of contraception during the treatment period 
and for at least 8 weeks (approximately 2 half-lives) after the last dose of study drug 
– 
For male participants, a documented successful vasectomy (by medical records or 
physician documentation) is an acceptable alternative form of birth control. 
 
Study partner who agrees to participate in the study and is capable of and willing to: 
– 
Accompany the participant to all required visits 
– 
Provide information for required telephone assessments 
– 
Spend sufficient time with the participant to be familiar with his/her overall function and 
behavior, and be able to provide adequate information about the participant, including:  
Knowledge about domestic activities, hobbies, routines, social skills and basic activities 
of daily life. 
Work and educational history. 
Cognitive performance, including memory abilities, language abilities, temporal and 
spatial orientation, judgment, and problem solving. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
21/Protocol GN28352, Version 11 
Emotional and psychological state. 
General health status. 
 
Participant and study partner have evidence of the following: 
– 
Adequate premorbid functioning (e.g., intellectual, visual, and auditory)  
– 
Fluency in, and able to read, the language in which study assessments are 
administered 
 
Willing and able to undergo neuroimaging (PET and MRI) 
 
In the judgment of the investigator, no clinically significant thyroid dysfunction or B12 
deficiency, as determined by the following criteria: 
– 
Serum TSH and B12 levels within normal or expected ranges for the testing laboratory 
or, if TSH or B12 values are out of range, they are judged by the investigator not to be 
clinically significant 
– 
If the participant is undergoing thyroid replacement therapy, TSH levels must either be 
within normal or expected ranges for the testing laboratory or, if TSH values are out of 
range, they do not require any therapeutic actions (treatment or surveillance) 
– 
If the participant is receiving vitamin B12 injections or oral vitamin B12 therapy, B12 
levels must be at or above the lower limit of normal for the testing laboratory or, if B12 
values are out of range, they do not require any therapeutic actions (treatment or 
surveillance) 
 
In good general health with no known co-morbidities expected to interfere with participation 
in the study 
 
In the opinion of the investigator, the participant and study partner will be in accordance with 
the following:  
– 
Able to comply with the protocol 
– 
Able to participate in all scheduled evaluations 
– 
Have a high probability of completing all required tests and the study 
 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
 
Significant medical, psychiatric, or neurological condition or disorder documented by history, 
physical, neurological, laboratory, or ECG examination that would place the participant at 
undue risk in the investigator’s judgment or impact the interpretation of efficacy 
 
History of stroke 
– 
Participants with a history of transient ischemic attack may be enrolled if the event 
occurred  2 years prior to screening 
 
History of severe, clinically significant (persistent neurological deficit or structural brain 
damage) CNS trauma (e.g., cerebral contusion) 
 
Body weight  45 or  120 kg 
 
History or presence of atrial fibrillation that poses a risk for future stroke in the investigator’s 
judgment 
 
Clinically significant laboratory or ECG abnormalities (e.g., abnormally prolonged or 
shortened QTc interval) in the investigator’s judgment 
 
Current presence of bipolar disorder or other clinically significant major psychiatric disorder 
according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV)-TR or 
symptom (e.g., hallucinations, agitation, paranoia) that could affect the participant’s ability to 
complete evaluations  
– 
Recorded as an adverse event if diagnosed after study enrollment 
 
Clinically significant depression, based in part by a GDS (short form) (15-point scale) score 
 9 at screening 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
22/Protocol GN28352, Version 11 
 
History of seizures (excluding febrile seizures of childhood, or other isolated seizure 
episodes that were not due to epilepsy in the judgment of the investigator, and required at 
most time-limited anticonvulsant treatment, and which occurred more than 7 years prior to 
the screening visit) 
 
Myocardial infarction within 2 years, congestive heart failure, atrial fibrillation, or 
uncontrolled hypertension 
 
Female participants who are pregnant or intend to become pregnant during the conduct of 
this trial 
 
Female participants who are nursing infants or intend to nurse infants during the conduct of 
this trial  
 
History of cancer within 5 years with the exception of basal cell carcinoma, squamous cell 
cancer of the skin that has been previously excised with clean margins, or any cancer that 
is not actively being treated with anti-cancer drugs or radiotherapy, as well as cancers that 
are considered to have a low probability of recurrence (with supporting documentation of 
this from the treating oncologist if possible)  
 
Clinically significant infection within the last 30 days prior to screening 
(e.g., chronic, persistent, or acute infection [e.g., upper respiratory infection, urinary tract 
infection]) 
 
Brain MRI imaging results at baseline showing any of the following:   
– 
Evidence of any ARIA-E (cerebral VE, sulcal effusion), infection, significant cerebral 
vascular pathology, clinically significant lacunar infarct in a region important for 
cognition or multiple lacunes or a cortical infarct or focal lesions of clinical significance 
– 
More than 4 cerebral microhemorrhages (lesions with diameter  10 mm), regardless of 
their anatomical location or diagnostic characterization as "possible" or “definite” 
– 
Single area of superficial siderosis of the CNS or evidence of a prior cerebral 
macrohemorrhage (lesion with diameter  0 mm) 
 
Clinically significant screening blood or urine laboratory abnormalities requiring further 
evaluation or treatment, including the following: 
– 
Impaired hepatic function, as indicated by transaminases  2  the upper limit of normal 
(ULN) or abnormalities in synthetic function tests judged by the investigator to be 
clinically significant 
– 
Impaired coagulation (aPTT  1.2  ULN) 
– 
Platelet count  100,000/L 
– 
Glycosylated hemoglobin (HbA1c)  8.0% 
 
Positive urine test for drugs of abuse at screening 
– 
One additional screening may be performed; a positive test (except for cannabinoids) 
will result in exclusion.  Results of cannabinoid assays will not be used for the 
determination of eligibility. 
 
History of alcohol or substance dependence within the previous 2 years (DSM-IV TR 
criteria) 
 
Use of any other medications with the potential to significantly affect cognition (including but 
not limited to, sedatives, narcotics [e.g., opiates/opioids], hypnotics, over-the-counter [OTC] 
sleeping aids, sedating anti-allergy medications) 
– 
Intermittent or short-term use of these medications may be allowed if deemed medically 
necessary for the treatment of a non-excluded medical condition with approval from the 
Medical Monitor.  In addition, use of tricyclic antidepressants or benzodiazepines will be 
permitted if used in stable, low doses for the treatment of a non-excluded medical 
condition with approval from the Medical Monitor. 
 
Use of typical anti-psychotics or barbiturates 
 
Use of nonanti-cholinergic antidepressant medications or atypical anti-psychotics unless 
maintained on a stable dose regimen for at least 6 weeks prior to screening  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
23/Protocol GN28352, Version 11 
 
Use of any U.S. Food and Drug Administration/Instituto Nacional de Vigilancia de 
Medicamentos y Alimentos (INVIMA)-approved medications for treatment of late-onset AD 
(LOAD) at screening/baseline 
– 
Cholinesterase inhibitors and/or memantine are prohibited during the study except 
in participants enrolled in the study who develop AD dementia.  These participants will 
be permitted to take approved AD treatments (cholinesterase inhibitors and/or 
memantine). 
 
Use of anti-coagulant medication (e.g., heparanoids, heparin, warfarin, thrombin inhibitors, 
Factor Xa inhibitors), or known coagulopathy or platelet count  100,000 cells/L within 
4 weeks of the screening visit 
– 
Documentation required for normal PT, PTT, and INR during screening for discontinued 
anti-coagulants 
– 
Anti-platelet medications (e.g., aspirin, clopidigrel, dipyridamole) are permitted if on a 
stable dose for 4 or more weeks prior to screening 
– 
Short-term, perioperative use of anti-coagulants may not result in discontinuation from 
the study; however, any such use must be discussed with the Medical Monitor 
 
Treatment with any biologic therapy within 5 half-lives or 3 months prior to screening, 
whichever is longer, with the exception of routinely recommended vaccinations, which are 
allowed 
 
Use of anti-seizure medication (except in childhood for febrile seizures or if used for 
non-seizure indications), anti-Parkinsonian, or stimulant (e.g., methylphenidate) medications 
 
Use of investigational drug, device, or experimental medication within 60 days 
(or 5 half-lives, whichever is longer) of the screening visit 
 
Previous treatment with crenezumab (MABT5102A) or any other therapeutic that targets A 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, 
human, or humanized antibodies or fusion proteins 
 
Contraindication to MRI scan procedures, possibly including, but not limited to, the 
following: 
– 
Pacemakers, implantable cardioverter defibrillators, cochlear implants, cerebral 
aneurysm clips, implanted infusion pumps, implanted nerve stimulators, metallic 
splinters in the eye, other magnetic, electronic, or mechanical implants; metal 
fragments or foreign objects in the skin or body 
– 
Clinically significant claustrophobia that would contraindicate a brain MRI scan 
– 
Clinical history or examination finding that, in the judgment of the investigator, would 
pose a potential hazard in combination with MRI 
 
Contraindication to PET scan procedures, possibly including, but not limited to, the 
following:   
– 
Current or recent (within 12 months prior to screening) participation in studies involving 
radioactive agents, such that the total research-related radiation dose to the participant 
in any given year would exceed the limits set forth in the U.S. Code of Federal 
Regulations (CFR) Title 21 Section 361.1 
(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=361.1) 
 
Abnormal findings that, in the opinion of the investigator, may affect the participant’s 
response to the radiopharmaceutical and related testing procedures required for PET scans 
 
Unable to read and write in Spanish 
 
Any other clinical contraindications for safety or participation in lumbar punctures (optional) 
at the clinical judgment of the investigator 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
24/Protocol GN28352, Version 11 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
Primary efficacy analysis for the primary endpoint family in Study Period A will be based on a 
modified intent-to-treat (mITT) population.  The mITT population is defined as participants who 
are mutation carriers treated with any amount of study drug.  Participants in the efficacy 
analysis population will be grouped based on treatment assigned at randomization. 
Efficacy data from Study Period B will contribute to delayed start analyses and time-to-event 
analyses. 
Primary Efficacy Endpoint Family 
The primary efficacy analysis will be performed on the mITT population.  The primary endpoint 
family, 1) annualized rate of change on the API ADAD Composite Cognitive Test Battery total 
score and 2) annualized rate of change on the FCSRT Cueing Index, will be assessed using a 
mixed effects (ME) model.  The model will be used to test the treatment effect on annualized 
rate of change adjusting for selected baseline characteristics and randomization factors.  
Statistical tests for the primary endpoints will be two-sided and performed at an overall 
0.05 level:    04 for testing the treatment effect on the annualized rate of change on the 
API ADAD Composite Cognitive Test Battery total score;   0.01 for testing the treatment 
effect on the annualized rate of change on the FCSRT Cueing Index.  Estimated treatment 
effects and CIs will also be provided as an aid to interpretation of study results. 
In order to maximize the power, data beyond each participant's Week 260 assessment through 
the unblinding of the study will be included in the primary analysis or its sensitivity analysis. 
All details of the prespecified statistical analyses for the primary efficacy endpoints will be 
provided in the SAP.  
DETERMINATION OF SAMPLE SIZE 
This study will enroll up to 300 participants:  up to 200 participants will be enrolled in the carrier 
cohort and up to 100 participants will be enrolled in the non-carrier cohort. 
Participants in the carrier cohort will be randomized in a 1:1 randomization ratio of active to 
placebo participants.  The study was originally powered to compare the mean change from 
baseline over 260 weeks in the API ADAD Composite Cognitive Test total score between the 
crenezumab group and the placebo.  Assuming a 25% dropout rate, two-sided testing at an 
overall 0.05 level, a placebo group CV of 65% for the Week 260 change scores 
( 100%  standard deviation of placebo participant change scores/mean of placebo participant 
change scores) and 100 participants per arm, the study will have at least 80% power to detect a 
true effect of 30% reduction of the mean decline in the placebo group. 
Participants in the non-carrier cohort will all receive placebo and will be included in the study in 
order to maintain the genotype blind. 
The study was originally powered based on the API ADAD Composite Cognitive Test Battery 
total score.  However, due to concerns about learning effects and general lack of sensitivity to 
change in a cognitively normal population, before study unblinding, the Sponsor performed a 
blinded power analysis on the original primary endpoint API ADAD Composite Cognitive Test 
Battery Total Score and the secondary clinical endpoints.  The Sponsor decided to promote the 
FCSRT Cueing Index from a secondary endpoint to part of a primary endpoint family (along with 
the API ADAD Composite) due to its favorable statistical properties and clinical relevance as a 
sensitive measure of episodic memory dysfunctionthe hallmark of emerging symptomatic AD 
and the most commonly observed, early, and consistent neuropsychological marker of AD.  
In the SAP, the Sponsor will provide details of the blinded power analysis along with the 
evidence of type I error control. 
INTERIM ANALYSIS 
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct one or more interim analyses.  Sites are to be informed prior to an interim 
analysis.  Below are the specifications to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed. 
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis will be 
conducted by an external statistical group and reviewed by the iDMC.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC Charter.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
25/Protocol GN28352, Version 11 
The decision to conduct the optional interim analysis, along with the rationale, timing, and 
statistical details for the analysis, will be documented in the SAP.  The iDMC Charter will be 
updated to document potential recommendations the iDMC can make to the Sponsor as a result 
of the analysis (e.g., stop the study for positive efficacy, stop the study for futility), and the 
iDMC Charter will also be made available to relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the interim 
analysis, the type I error rate of the primary analysis will be controlled to ensure statistical 
validity is maintained.  If the study continues beyond the interim analysis, the critical value at the 
final analysis would be adjusted accordingly to maintain the protocol-specified overall type I 
error rate, per standard Lan-DeMets methodology. 
ANALYSES FOR STUDY PERIOD B 
All efficacy analyses will include data from Study Period A and Study Period B.  The analysis 
population will be based on mITT population.  The delayed-start efficacy analyses and 
rank-preserving structural failure time analyses will be triggered 2 years after the last 
efficacy visit in Study Period A.  
Summaries of conduct of study and summaries of treatment group 
comparability/demographics and baseline characteristics will also be presented.  
The population is based on the Study Period B ITT population.  The analyses are similar to 
what are specified for Study Period A and are specified in the SAP. 
Pharmacokinetic and PD analyses will be handled in a similar fashion to Study Period A. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
26/Protocol GN28352, Version 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
A 
amyloid 
AD 
Alzheimer’s disease 
ADA 
anti-drug antibody 
ADAD 
autosomal-dominant Alzheimer's disease 
API 
Alzheimer’s Prevention Initiative 
APOE 
apolipoprotein E 
ARIA 
amyloid-related imaging abnormalities 
ARIA-E 
amyloid-related imaging abnormalitiesedema/effusion 
ARIA-H 
amyloid-related imaging abnormalitieshemosiderin 
deposition 
BGTS 
Barkhof Grand Total Score 
CDR 
Clinical Dementia Rating 
CDR-SOB 
Clinical Dementia RatingSum of Boxes 
CERAD 
Consortium to Establish a Registry for Alzheimer’s Disease 
CFR 
Code of Federal Regulations 
CMRgl 
cerebral metabolic rate for glucose 
CREAD 
Crenezumab for Early Alzheimer’s Disease  
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
Clinical Study Report 
Ctrough, ss 
trough concentration at steady state 
DANA 
D265A and N297A (mutations) 
DSMB 
Data and Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders IV 
EC50 
half maximal effective concentration 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
enzyme-linked immunosorbent assay 
EOAD 
early-onset Alzheimer's disease 
ET 
early termination 
FAST 
Functional Assessment Staging of Alzheimer’s Disease 
FcR 
fragment crystallizable  receptor 
FCSRT 
Free and Cued Selective Reminding Test 
FDA 
U.S. Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FLAIR 
fluid-attenuated inversion recovery 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
27/Protocol GN28352, Version 11 
Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GRE 
gradient-recalled echo 
GTP1 
[18F] Genentech Tau Probe 1 
hAPP 
human amyloid precursor protein 
HbA1c 
glycosylated hemoglobin 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IND 
Investigational New Drug 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IxRS 
interactive voice or Web-based response system 
LOAD 
late-onset Alzheimer’s disease 
LRTI 
lower respiratory tract infection 
MCI 
mild cognitive impairment 
ME 
mixed effects 
mITT 
modified intent-to-treat (population) 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NCRAD 
National Cell Repository for Alzheimer's Disease 
NPI 
Neuropsychiatric Inventory 
OLE 
open-label extension 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PSEN (1, 2) 
presenilin (1, 2) gene 
PT 
Preferred Term 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
RBANS 
Repeatable Battery for the Assessment of 
Neuropsychological Status 
RCR 
Roche Clinical Repository 
ROI 
region of interest 
RPCP 
randomized, placebo-controlled portion 
SAP 
Statistical Analysis Plan 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
28/Protocol GN28352, Version 11 
Abbreviation 
Definition 
SDV 
source data verification 
SMC 
Subjective Memory Checklist 
SPCQ 
Study Partner Characterization Questionnaire 
T2* 
T2 with additional in-homogeneous dephasing 
Tg 
transgenic 
TLRTI 
total lower respiratory tract infection 
ULN 
upper limit of normal 
VE 
vasogenic edema 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
29/Protocol GN28352, Version 11 
1. 
BACKGROUND 
1.1 
BACKGROUND ON DISEASE 
Alzheimer’s disease (AD) is the most common form of disabling cognitive impairment in 
older people, and it takes a devastating toll on patients and families.  Due to the 
growing number of people living to older ages, AD will lead to a significant increase in 
the number of clinically affected individuals and will have an overwhelming economic 
impact around the world by the time today’s young adults become senior citizens 
(Evans et al. 1989; Corrada et al. 2010). 
The cardinal neuropathological features of AD include amyloid plaques and 
neurofibrillary tangles.  The major component of amyloid plaques is a form of the 
amyloid- (A) peptide with 42 amino acids (A142), and the major component of 
neurofibrillary tangles is the microtubule-associated protein, tau.  Postulated elements 
of the pathogenic cascade include the accumulation of A peptides in monomeric, 
oligomeric, and fibrillar A species, the aggregation and phosphorylation of tau, 
neuroinflammation, synaptic dysfunction, and neuronal loss.  The amyloid hypothesis 
proposes that the accumulation of certain A species (e.g., soluble A142 oligomers 
or A142 fibrils) play a critical, early role in the development of AD.  
Amyloid-modifying medication and immunization therapies have been developed to 
target the production, accumulation, or clearance of these A species. 
More than 200 mutations of the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and 
amyloid precursor protein (APP) genes exist and are inherited as fully penetrant, 
autosomal-dominant traits which almost always result in the clinical onset of AD before 
the age of 65 (www.molgen.ua.ac.be/admutations/).  Given this early age of onset, 
autosomal-dominant AD (ADAD) is frequently referred to as autosomal-dominant early 
onset AD (EOAD).  In contrast to this early onset of disease, the vast majority of AD, 
known as late-onset AD (LOAD), is characterized by symptom onset after the age of 65.  
In LOAD, neither the certainty nor the timing of the onset of clinical symptoms can be 
predicted reliably and, therefore, LOAD is frequently referred to as “sporadic AD.”  
While there are several genetic, mechanistic, and other biological differences between 
ADAD and sporadic AD, these forms of AD have very similar neuropathological and 
clinical features.  Sporadic AD may be associated with reduced A142 clearance, 
while ADAD has been associated with increased A142 production.  However, the 
biochemical consequences of these alterations in clearance and production in ADAD 
and sporadic AD, respectively, are similar, namely A accumulation in the brain.  It has 
been proposed that accumulation of the same A species in the brain plays an early 
role in the pathobiology of ADAD as well as sporadic AD, and that both forms of the 
disease might respond to A-modifying treatments (Bateman et al. 2011). 
There is a growing belief that AD-modifying treatments targeting A may need to be 
started before the onset of overt symptoms, when fibrillar Aβ has already plateaued, tau 
(neurofibrillary) pathology is apparent, and there has been irreversible synaptic or 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
30/Protocol GN28352, Version 11 
neuronal loss, in order to have their most profound benefit (Hardy and Selkoe 2002).  
Because progression to mild cognitive impairment (MCI) and dementia is certain, 
people inheriting ADAD mutations offer a scientifically compelling group for assessing 
the efficacy of putative prevention strategies in smaller and shorter trials.  A large 
PSEN1 E280A autosomal-dominant EOAD kindred in Colombia provides what may be 
a unique opportunity to conduct a study large enough to address both clinical and 
biomarker outcomes in a well-characterized population at virtually certain risk for AD 
dementia. 
This population offers the opportunity to study mutation carriers in a stage of 
“preclinical AD,” that is, they are at certain risk of developing AD dementia but do not 
yet have overt symptoms and do not meet criteria for MCI or dementia 
(Reiman et al. 2010; Sperling et al. 2011a). 
There is a high unmet medical need in the ADAD population for a treatment that will 
slow disease progression. 
1.2 
BACKGROUND ON CRENEZUMAB 
Crenezumab (RO5490245; MABT5102A), is a fully humanized IgG4 monoclonal 
antibody to A selected for its ability to bind monomeric, oligomeric, and fibrillar forms 
of A in vitro (Adolfsson et al. 2012).  Crenezumab binds both A140 and A142, 
inhibits A aggregation, and promotes A disaggregation.  Because crenezumab is a 
human IgG4 backbone antibody, it has reduced fragment crystallizable  receptor 
(FcR)-binding affinity compared with human IgG1 or IgG2, which is predictive of 
reduced immune-effector response.  These properties, combined with the ability of 
systemically delivered crenezumab to decrease A CNS levels in a murine model of 
AD, suggest that this anti-A therapeutic approach may offer clinical efficacy while 
reducing the risk of toxicity, with the ultimate goal of modifying disease progression in 
patients with AD with lower risk of amyloid-related imaging abnormalities 
(ARIA)edema/effusion (ARIA-E), including cerebral vasogenic edema (VE) and sulcal 
effusion, or ARIAhemosiderin deposition (ARIA-H), including cerebral 
microhemorrhages and superficial siderosis (Sperling et al. 2011a).  The encouraging 
safety profile to date offers the opportunity to administer high doses of the agent and 
achieve high brain concentrations relative to alternative monoclonal antibodies. 
Crenezumab is a fully humanized IgG4 monoclonal antibody that binds to the 
A peptides, A140 and A142, in multiple forms (monomers, oligomers, fibers, and 
plaques), notably with high affinity to oligomers, and is hypothesized to reduce oligomer 
neurotoxicity and accumulation (Adolfsson et al. 2012; Ultsch et al. 2016).  In vitro 
studies demonstrated the ability of crenezumab to block A aggregation, promote 
A disaggregation, and protect neurons from oligomer-induced cytotoxicity 
(Adolfsson et al. 2012).  Its IgG4 backbone confers reduced activation of FcRs in 
comparison with IgG1 and was shown to minimize FcR-mediated activation of 
microglia and release of inflammatory cytokines upon oligomer engagementwhich 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
31/Protocol GN28352, Version 11 
has also been proposed to contribute to neurotoxicity (Xing et al. 2011; 
Heneka et al. 2015)while preserving FcR-mediated microglial phagocytosis of 
oligomers (Adolfsson et al. 2012).  Following in vivo dosing in PS2APP transgenic (Tg) 
mice, crenezumab localizes to brain areas with putative high concentrations of A 
oligomers, i.e., hippocampal mossy fibers and the periphery of amyloid plaques 
(Koffie et al. 2009; Liu et al. 2015) but not to the dense core of plaques or vascular 
amyloid (Study 15-2817B). 
Amyloid-related imaging abnormalities, indicative of VE or effusions (ARIA-E) and 
microhemorrhages or leptomeningeal hemosiderosis (ARIA-H), have been reported in 
recent AD trials involving monoclonal antibodies that bind aggregated forms of A and 
have IgG1 backbones with fully preserved FcR-mediated effector function 
(Salloway et al. 2009; Ostrowitzki et al. 2012; Fuller et al. 2014; Sevigny et al. 2015).  
As these molecules demonstrated increases in ARIA-E incidence with increasing dose 
and apolipoprotein (APOE) E4 (APOE4) allele frequency, the dose levels administered 
in past trials have been constrained to limit these events (Salloway et al. 2009).  
Crenezumab was designed as an IgG4 based on the hypothesis that reducing effector 
function would lower the risk of inducing ARIA-E/H, possibly by minimizing inflammation 
at brain vasculature (Wilcock et al. 2006).  A lack of binding to vascular amyloid, noted 
following in vivo dosing in PS2APP Tg mice (Study 15-2817B), may additionally reduce 
the risk of ARIA.  This safety finding on crenezumab allows for the evaluation of 
relatively higher dose levels compared with other monoclonal antibodies that bind 
aggregated forms of A. 
The safety profile of crenezumab to date (see the Crenezumab Investigator’s Brochure 
for details on nonclinical and clinical studies) allows doses higher than 720 mg SC 
every 2 weeks (Q2W) to be studied in participants.  Specifically, the dose of 60 mg/kg 
IV every 4 weeks (Q4W) was included as an option for participants in this study 
(GN28352, amendment 6).  This dose was also evaluated in a Phase Ib study 
(GN29632), in the global Phase III studies (BN29552 and BN29553) in sporadic 
prodromal to mild AD, and the open-label extension (OLE) Study BN40031. 
Crenezumab has been investigated in patients with early (prodromal to mild [sporadic]) 
AD in two Phase III studies (Study BN29552, Crenezumab for Early Alzheimer’s 
Disease [CREAD] and Study BN29553 [CREAD 2]) that were discontinued because a 
preplanned interim analysis indicated that Study BN29553 was unlikely to meet its 
primary endpoint of change from baseline in Clinical Dementia RatingSum of Boxes 
(CDR-SOB) score.  No new safety signals for crenezumab were observed in this 
analysis and the overall safety profile was similar to that observed in previous trials. 
More details on all clinical studies conducted with crenezumab, including the Phase III 
studies, can be found in the Crenezumab Investigator’s Brochure. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
32/Protocol GN28352, Version 11 
1.2.1 
Summary of Nonclinical Studies 
In vivo pharmacology and CNS distribution studies were conducted in human amyloid 
precursor protein (hAPP) Tg mouse models of AD.  Crenezumab was detected in both 
brain homogenates and cerebrospinal fluid (CSF) following a single IV dose.  
Furthermore, administration of 2 weekly doses of 5 mg/kg crenezumab to hAPP Tg 
mice decreased total A levels in soluble fractions of brain homogenates while 
increasing plasma total A levels. 
An in vivo pharmacology study in PS2APP Tg mice showed on immunofluorescence 
microscopy that crenezumab localized to brain areas with putative high concentrations 
of A oligomers (i.e., hippocampal mossy fibers and the periphery of amyloid plaques; 
Koffie et al. 2009; Liu et al. 2015) but not to the dense core of plaques or vascular 
amyloid, consistent with higher binding affinity of crenezumab for oligomers over 
aggregated fiber and plaque forms. 
In a study to further evaluate the pharmacology of crenezumab, hAPP Tg mice received 
weekly or monthly intraperitoneal (IP) crenezumab administrations for 16 weeks (total of 
17 weekly or 5 monthly doses) at doses of up to 50 mg/kg.  When given at  10 mg/kg 
for more than 2 weekly or monthly doses, unexpected deaths were observed.  
No microscopic findings were identified in the CNS (specifically, no evidence of cerebral 
microhemorrhage) or peripheral tissues to explain the mortalities.  A high incidence of 
anti-crenezumab antibodies was observed (93% of samples collected from animals 
given crenezumab), which resulted in attenuation of both serum crenezumab 
concentrations and pharmacodynamic (PD) responses (plasma total A140 and 
A142).  Taken together, these data suggest that these deaths are likely the result of 
an adverse immunogenic response to the xenogenic crenezumab antibody; that is, 
native mouse antibodies are produced in response to the humanized form of the 
antibody, and are, therefore, not predictive of human safety. 
Weekly IP administration of two human/mouse chimeric anti-A monoclonal antibodies 
to hAPP Tg mice for 24 weeks (total of 25 doses) was well-tolerated at doses of up to 
50 mg/kg.  Specifically, no changes in the cerebral microvasculature 
(e.g., microhemorrhage or amyloid deposition) were observed, despite evidence of 
sustained antibody exposure and PD activity (plasma total A140).  These chimeric 
antibodies share a humanized variable domain with crenezumab but contain a murine 
IgG2a Fc region with either wild-type or D265A and N297A (DANA) mutations.  
The murine IgG2a Fc region was selected to decrease immunogenic potential in mice.  
The Fc DANA mutations were designed to decrease binding to murine FcRs and to 
more closely approximate the reduced effector function of an IgG4 antibody 
(i.e., crenezumab). 
Weekly SC administrations of crenezumab to cynomolgus monkeys for 39 weeks 
(total of 40 doses) was well-tolerated at doses of up to 100 mg/kg (highest dose tested).  
No findings related to crenezumab administration were seen on expanded 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
33/Protocol GN28352, Version 11 
neurohistopathology of the brain.  Subcutaneous injection volumes of up to 5.2 mL were 
well-tolerated.  A slight increase in microscopic findings (multifocal perivascular 
mononuclear cell infiltrates) was observed at injection sites in crenezumab groups 
compared with the control group.  These changes reversed following the 14-week 
dose-free period. 
A single, 1.5-mL, SC injection of 225 mg of crenezumab (150 mg/mL) administered to 
New Zealand White rabbits to evaluate local tolerance was considered to be 
well-tolerated at a concentration of 150 mg/mL.  The study results supported the 
SC administration of 1.0 mL of crenezumab per injection site to humans in 
Study ABE4662g (SC bioavailability study) and in the 3 ongoing, Phase II studies. 
Additional information on the nonclinical studies with crenezumab is provided in the 
Crenezumab Investigator’s Brochure. 
Overall, results from nonclinical safety and pharmacology studies supported the clinical 
development program of crenezumab in sporadic AD, as well as this Phase II study in 
ADAD. 
1.2.2 
Clinical Experience 
As of May 2021, crenezumab had been investigated in a total of 13 completed studies 
and 1 ongoing study in Phase I, Phase II, and Phase III clinical trials.  
Approximately 1789 patients and healthy volunteers have been exposed to crenezumab 
in these studies. 
Thirteen studies have been completed, including Phase I studies 
(ABE4427g, AB4662g, GP29172, GP29523, GN29632, GP40201, and JP29973), 
Phase II studies (ABE4869g, ABE4955g and GN28525) and Phase III studies 
(BN29552, BN29553 and BN40031).  Study GN28352 is ongoing. 
Study ABE4427g studied the safety, tolerability, and pharmacokinetics of single- and 
multiple-ascending doses of crenezumab IV in patients with mild to moderate AD who 
were 5086 years of age.  Study ABE4662g studied the pharmacokinetics of IV and SC 
dosing and the relative bioavailability of crenezumab (SC dosing) in healthy volunteers 
who were 18–50 years of age.  Study GP29172 evaluated the pharmacokinetics of SC 
dosing and the bioequivalence of 2 formulations of crenezumab (SC dosing) in healthy 
volunteers who were 18–65 years of age.  Study GP29523 assessed the tolerability and 
pharmacokinetics of a single, dose-escalated, SC administration of crenezumab in 
healthy volunteers.  Study GN29632 evaluated the safety and tolerability of multiple 
doses of crenezumab in patients with mild to moderate AD with doses of 30, 45, 60, 
and 120 mg/kg IV Q4W.  The 13-week double-blinded, dose-escalation part of the study 
was followed by an OLE part. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
34/Protocol GN28352, Version 11 
Study GP40201 was a Phase I, multicenter, partially blinded, placebo-controlled study 
designed to assess the safety, tolerability, and pharmacokinetics of SC administered 
crenezumab while varying dose, injection volume, flow rate, and the use of recombinant 
human hyaluronidase in healthy volunteers. 
Study JP29973 was a Phase I, double-blind, placebo-controlled, randomized, 
dose-escalation study investigating the safety of repeated doses of crenezumab for 
13 weeks in 8 Japanese patients with mild to moderate AD. 
The Phase II program (Studies ABE4869g, ABE4955g, and GN28352), including an 
OLE study (GN28525), was designed to study safety and tolerability, as well as clinical 
and biomarker effects of crenezumab in two populations within the AD spectrum:  
an AD dementia population (50–80 years of age) with mild to moderate disease severity 
(Mini-Mental State Examination [MMSE]; 18–26); and a younger population of 
participants (30–60 years of age) at risk for autosomal dominant AD due to a mutation 
(E280A) in the PSEN1 gene.  Studies ABE4869g and ABE4955g and the OLE study 
(GN28525) in patients who previously participated in either Study ABE4869g or 
ABE4955g have been completed. 
The Phase III studies BN29552 and BN29553, which were designed to evaluate the 
efficacy, safety, and tolerability of 60 mg/kg IV crenezumab in the sporadic AD 
population (pAD-mAD; MMSE 22–30; 5085 years of age), were stopped early on 
30 January 2019 after a preplanned interim analysis of Study BN29552 found that the 
study was unlikely to meet its primary endpoint of change from baseline in CDR-SOB 
score.  No new safety signals were found.  The Phase III OLE Study BN40031 that 
included patients who completed Studies BN29552 and BN29553 was also stopped. 
Please refer to the Crenezumab Investigator’s Brochure for more details. 
1.2.2.1 
Safety Experience in Patients with Sporadic AD 
Overall, in all ongoing and completed studies in patients with sporadic AD, crenezumab 
was well-tolerated.  Adverse events occurred across different MedDRA System Organ 
Class (SOC) groups and were predominantly of mild to moderate severity.  No dose 
relationship was observed with respect to the nature, severity, and frequency of 
adverse events across crenezumab studies.  In patients with sporadic AD, the most 
commonly reported adverse events were as expected in elderly patients with 
prodromal, mild, or moderate AD. 
A high-level summary of safety data is provided below.  Up-to-date safety information 
from crenezumab studies, including the Phase II and Phase III studies, is provided in 
the most recent Crenezumab Investigator’s Brochure. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
35/Protocol GN28352, Version 11 
Amyloid-Related Imaging Abnormalities 
Overall, in the completed studies with a control arm, the frequency of ARIA-H was 
balanced between treatment arms and was as expected in an AD population.  
The majority of ARIA-H findings were asymptomatic.  
Overall, the incidence of ARIA-E in crenezumab studies was low.  Across all 
crenezumab studies, as of 12 December 2019, 5 patients were diagnosed with new 
ARIA-E.  All events were mild with a low Barkhof Grand Total Score (BGTS).  In the two 
Phase III Studies BN29552 and BN29553, 2 ARIA-E were reported in the active arms 
and 1 ARIA-E in the placebo arm.  One event of ARIA-E was symptomatic 
(worsening of headache, in a patient in the active arm of Study BN29552).  One patient 
who was diagnosed with ARIA-E during the double-blind part of the Phase II program 
(Study ABE4869g) developed recurrent ARIA-E during the OLE phase 
(Study GN28525).  In the 4 other patients, ARIA-E resolved within 5 weeks without 
recurrence. 
Please refer to the current Crenezumab Investigator’s Brochure for further details on 
the incidence of ARIA in crenezumab studies. 
Pneumonia 
An imbalance in serious adverse events of total lower respiratory tract infections 
(TLRTI) (including the MedDRA Preferred Terms (PT) of pneumonia, lower respiratory 
tract infection [LRTI], and bronchitis) driven by pneumonia was observed in the 
randomized, placebo-controlled portion (RPCP) of the Phase II program.  However, this 
imbalance was not replicated in the pooled data of the two large Phase III Studies 
(BN29552 and BN29553) where the pneumonia cases were balanced between the 
active treatment and placebo arms (13 and 15 cases, respectively). 
In addition, the rate of pneumonia in crenezumab-treated patients was within the 
expected ranges for an elderly AD population (Chong and Street 2008).  Details on the 
incidence of pneumonia in the different crenezumab studies are provided in the most 
recent Crenezumab Investigator’s Brochure. 
Injection and Infusion-Related Reactions 
Across all crenezumab studies in patients with sporadic AD, the vast majority of local 
and systemic injection and infusion-related reactions (IRRs) were non-serious, of mild 
or moderate severity, and did not lead to changes in study treatment.  An overview of 
the nature of IRRs and a description of the serious and severe IRRs are provided in the 
most recent Crenezumab Investigator’s Brochure. 
In the Phase Ib Study GN29632 investigating treatment doses of up to 120 mg/kg, there 
was no relationship between the treatment dose and the incidence or type of injection 
and infusion-related adverse events. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
36/Protocol GN28352, Version 11 
1.2.2.2 
Clinical Pharmacokinetics 
The pharmacokinetics of crenezumab after IV administration in patients with mild to 
moderate AD were dose proportional across the dose range tested in both the 
single-dose (0.310 mg/kg) and multiple-dose (0.55 mg/kg weekly for 4 doses) phases 
of Study ABE4427g and were characterized by slow clearance (2.53.3 mL/day/kg) and 
a long elimination half-life (t1/2) (1726 days) following a single IV dose.  Overall, the 
observed clearance and volume of distribution in the Phase I studies are consistent with 
those for other humanized IgG monoclonal antibodies that exhibit kinetics in the linear 
range (Mould and Sweeney 2007; Dirks and Meibohm 2010; Deng et al. 2011).  
The steady-state pharmacokinetics of crenezumab were assessed in patients with mild 
to moderate AD in the Phase II studies (ABE4869g and ABE4955g).  
Crenezumab trough concentration at steady state (Ctrough, ss) for the SC and IV cohorts 
were reached between Week 13 and Week 25 (after 612 SC doses or 36 IV doses).  
A dose-dependent increase in crenezumab Ctrough, ss was observed with a mean (SD) 
crenezumab Ctrough, ss concentration of 69 (30) g/mL following administration of 300 mg 
SC Q2W and 118 (72) g/mL following 15 mg/kg IV Q4W. 
In Study GN29632 in patients with mild to moderate AD, crenezumab pharmacokinetics 
at higher doses of 30120 mg/kg IV Q4W increased proportionally to doses of up to 
120 mg/kg, as demonstrated by the proportional increase in the pharmacokinetic (PK) 
parameters peak concentration at steady state (Cpeak, ss) and area under the 
concentrationtime curve (AUC) extrapolated to infinity (AUCinf), following the first 
administered dose.  The pharmacokinetics in this study appear to be consistent with 
those in prior studies. 
In two Phase III Studies BN29552 and BN29553, at a crenezumab dose of 
60 mg/kg IV Q4W, the serum crenezumab mean [SD] Ctrough, ss concentrations 
(345 [146] g/mL and 360 [162] g/mL respectively, at Week 13 predose) in patients 
with prodromal to mild AD were consistent with those achieved in Study GN29632, and 
approximately 4-fold higher than the mean Ctrough, ss concentrations in Phase II 
Studies ABE4869g and ABE4955g at 15 mg/kg IV Q4W. 
Penetration into CSF was similar between doses and routes of administration, with a 
mean crenezumab CSF/serum ratio of approximately 0.3%.  Overall, the steady-state 
crenezumab concentrations in CSF were low, with mean (SD) concentrations of 
0.25 (0.12) g/mL after 15 mg/kg IV Q4W and 0.19 (0.14) g/mL after 300 mg SC Q2W 
in Studies ABE4955g and ABE4869g and approximately 1.0 g/mL after 60 mg/kg IV 
Q2W in Studies BN29552 and BN29553. 
Additional PK information is provided in the Crenezumab Investigator’s Brochure.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
37/Protocol GN28352, Version 11 
1.2.2.3 
Immunogenicity 
The immunogenicity of crenezumab was assessed in the completed Phase I, Phase II, 
and Phase III Studies ABE4427g, ABE4662g, ABE4869g, ABE4955g, GN28525, 
GP29172, GP29523, GN29632, GP40201, and BN29552. 
In the two Studies GN29632 and BN29552 in patients with sporadic AD, the same dose 
of 60 mg/kg BW was investigated as in this study, with the following findings: 
 
Study GN29632:  anti-drug antibody (ADA) incidence was 0% (0 of 75 patients) 
 
Study BN29552:  The incidence of ADAs was 0.5% with 2 of 397 patients exposed 
to crenezumab having transient ADAs throughout the study.  In these 2 patients, 
the presence of ADAs did not appear to have an effect on the exposure to 
crenezumab, based on PK data. 
 
See the Crenezumab Investigator’s Brochure for additional details on nonclinical and 
clinical studies. 
1.3 
RATIONALE FOR DOING THIS STUDY 
1.3.1 
Rationale for the Alzheimer’s Prevention Initiative 
The Alzheimer’s Prevention Initiative (API) is helping to launch a new era in 
AD prevention research by a) evaluating suitable investigational AD-modifying 
treatments in cognitively normal people who, on the basis of their age and genetic 
background, are at the highest imminent risk of AD symptoms; b) helping to establish 
the biomarker endpoints and accelerated regulatory approval pathway needed for the 
field to rapidly evaluate promising preclinical AD treatments; c) providing a better test of 
the amyloid hypothesis than clinical trials in the symptomatic stages of AD; and d) 
providing unusually large prevention registries as a shared resource for enrollment into 
these and other preclinical AD trials. 
These programs have been designed in an effort to provide the greatest possible 
benefit to the field.  For instance, the trial described in this protocol will provide an 
opportunity to explore the effects of an anti-amyloid treatment on well-studied AD 
biomarkers, and the extent to which the treatment’s biomarker effects predicts a clinical 
benefit.  Furthermore, data and biological samples from the trial will be made available 
to the research community within specified times after the last participant’s last study 
visit to help the field develop better ways to test preclinical AD treatments. 
1.3.2 
Rationale for Study 
Currently approved treatments for established AD dementia are of modest efficacy.  
Investigational AD-modifying treatments targeting postulated elements of the 
pathogenic cascade include those intended to interfere with the production, 
accumulation, or toxic sequelae of A species (Kramp and Herrling 2011).  There is a 
growing concern that AD-modifying treatments may need to be started before the onset 
of overt symptoms, when fibrillar A has already plateaued, tau (neurofibrillary) 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
38/Protocol GN28352, Version 11 
pathology is apparent, and there has been irreversible synaptic or neuronal loss, in 
order to have their most profound benefit (Hardy and Selkoe 2002).  There is a poor 
correlation between fibrillar A and the severity of cognitive impairment in clinically 
affected patients; trials so far suggest that A-modifying treatments may have limited 
benefits; and an A immunization therapy has been shown to retard progression of both 
A and tau pathology in a triple Tg mouse model only if introduced before the onset of 
tau pathology (Oddo et al. 2004).  If one or more forms of A play an early role in the 
development of AD (Selkoe 2008), and if an appropriately specific treatment is safe and 
tolerated and is started early enough, this treatment could have a profound clinical and 
public health impact, helping to stave off the clinical stages of AD.  There is, therefore, 
an urgent need to study investigational agents in people who do not yet have dementia 
symptoms. 
It is imperative to find effective “preclinical” AD treatments, that is, therapeutic 
interventions initiated in people who have not yet developed MCI or dementia and 
aimed at postponing the onset of, reducing the risk of, or completely preventing the 
clinical stages of AD (Reiman and Langbaum 2009).  Even modestly effective 
treatments could have public health benefit.  For example, delaying the onset of 
symptoms by 5 years, without increasing lifespan, may reduce the number of AD 
dementia cases by 50% (Brookmeyer et al. 1998).  However, preclinical AD treatment 
trials using progression to dementia as the endpoint require too many cognitively 
normal people and too many years.  New and improved methods and outcomes are 
needed. 
Because progression to MCI and dementia is certain, people inheriting ADAD mutations 
offer a scientifically compelling group for assessing the efficacy of putative prevention 
strategies in smaller and shorter trials.  An extraordinarily large PSEN1 E280A 
autosomal-dominant EOAD kindred in Colombia provides what may be a unique 
opportunity to conduct a study large enough to address both clinical and biomarker 
outcomes in a well-characterized population at virtually certain risk for AD dementia.  
This population offers the opportunity to study mutation carriers in a stage of 
“preclinical AD,” that is, they are at certain risk of developing AD dementia but do not 
yet have overt symptoms and do not meet criteria for MCI or dementia 
(Reiman et al. 2010; Sperling et al. 2011b). 
Sensitive cognitive endpoints have been proposed that may allow subtle cognitive 
decline to be tracked years before manifest dementia symptoms—measurements that 
aim to distinguish ADAD mutation carriers without MCI or dementia from non-carriers 
and also to distinguish between cognitively normal persons who did and did not 
progress to the clinical stages of “sporadic” LOAD (Ayutyanont et al. 2014; 
Langbaum et al. 2014).  Capitalizing on this development, the primary aim of this study 
is to evaluate whether treatment with crenezumab will result in better cognitive 
performance over time, in comparison with placebo treatment, in individuals without 
MCI or dementia but who are at high risk for developing symptomatic AD.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
39/Protocol GN28352, Version 11 
With effective preventive AD treatments being needed urgently, ADAD families hold a 
key by permitting shorter and smaller trials to be conducted so that critical answers can 
be found sooner. 
Another important goal of the study is to further develop biomarkers that can be used to 
predict and monitor the progress of disease, as well as predict and monitor treatment 
effects (Reiman and Langbaum 2009; Reiman et al. 2010).  Brain imaging and fluid 
biomarkers of AD pathology and progression (e.g., positron emission tomography [PET] 
measurements of cerebral metabolic rate for glucose [CMRgl] decline in AD-affected 
regions, magnetic resonance imaging [MRI] measurements of regional or whole brain 
volume loss, PET measurements of fibrillar A or of tau deposition, CSF A142 
reductions, and total-tau [t-tau] and phospho-tau [p-tau] increases) offer promising 
endpoints for the accelerated evaluation of AD treatments in people in the preclinical 
stages of AD who are at increased risk for MCI and dementia due to AD.  
However, these biomarkers need to be studied in therapeutic trials to clarify the extent 
to which they are moved by AD-modifying treatments. 
There is no precedent that indicates which outcome measures are likely to change with 
treatment or which changes during a preclinical state of AD are meaningful for 
preventing functional deficits in symptomatic stages of AD.  Because of this lack of 
precedent, and the scarcity of participants with ADAD, health authorities have 
suggested there may be flexibility when considering outcome measures in a rare clinical 
trial opportunity in nonclinical ADAD 
(https://www.alzforum.org/sites/default/files/legacy/new/pdf/ColombianSeries.pdf).  
Additionally, AD biomarker development is rapidly evolving.  Therefore, this trial in 
preclinical ADAD will incorporate multiple objectives and outcome measures that reflect 
some flexibility on the part of health authorities in the approaches used to assess 
treatment effects. 
Despite the futility of the recently discontinued Phase III program of crenezumab in 
sporadic AD (see Section 1.2), Study GN28352 continues given that this at-risk ADAD 
population differs from the sporadic prodromal to mild AD population in the following 
ways:  the population is much younger, clinically asymptomatic at study entry, and 
carries a mutation that is specifically linked to amyloid metabolism. 
2. 
OBJECTIVES 
Sections 2.12.4 describe the objectives of Study Period A.  The objectives of 
Study Period B are described in Section 2.5. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
40/Protocol GN28352, Version 11 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary objectives of this Phase II trial are: 
 
To evaluate the efficacy of crenezumab treatment compared with placebo for at 
least 260 weeks on change in cognitive function as measured by the API ADAD 
Cognitive Composite Test Battery in preclinical PSEN1 E280A autosomal-dominant 
mutation carriers 
 
To evaluate the efficacy of crenezumab treatment compared with placebo for at 
least 260 weeks on change in episodic memory function as measured by the 
Free and Cued Selective Reminding Test (FCSRT) Cueing Index in preclinical 
PSEN1 E280A autosomal-dominant mutation carriers 
 
Additional details regarding the endpoints and analyses are in the Statistical Analysis 
Plan (SAP). 
2.1.2 
Secondary Efficacy Objectives 
The secondary efficacy objectives of this study (comparing crenezumab with placebo) 
will be to evaluate the following in PSEN1 E280A mutation carriers: 
 
Ability of crenezumab to affect clinical endpoints other than those in the primary 
endpoint family:  API ADAD Cognitive Composite Test Battery (see Section 3.3.2.1 
for details on clinical endpoints) and FCSRT Cueing Index 
 
Ability of crenezumab to reduce cerebral fibrillar amyloid burden in a predefined 
region of interest (ROI) using florbetapir PET 
 
Ability of crenezumab to reduce decline in regional CMRgl using 
fluorodeoxyglucose (FDG)-PET measurements in a predefined ROI 
 
Ability of crenezumab to reduce brain atrophy as measured by volumetric 
measurements using MRI 
 
Ability of crenezumab to affect a tau-based CSF biomarker 
 
Additional details regarding the endpoints and analyses are in the SAP. 
2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
 
To assess the safety and tolerability of crenezumab in preclinical PSEN1 E280A 
mutation carriers (comparing crenezumab with placebo) 
 
2.3 
PHARMACOKINETIC/PHARMACODYNAMIC OBJECTIVES 
The PK and PD objectives for this study are as follows: 
 
Collect sparse PK samples to support confirmation of exposure to crenezumab and 
to explore the PD response (as measured by plasma total A levels comparing 
crenezumab with placebo) in preclinical PSEN1 E280A mutation carriers 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
41/Protocol GN28352, Version 11 
2.4 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
 
Assess further the effect of crenezumab in preclinical PSEN1 E280A mutation 
carriers on additional clinical measures of efficacy and biological markers of 
disease that have not been prespecified as primary or secondary endpoints in the 
SAP 
 
Explore pharmacogenetic effects, including but not limited to, a person’s APOE4 
carrier status on the active treatment’s cognitive, clinical, and adverse effects 
 
Explore effects of genetic variation, including but not limited to, how genes affect 
the biology of AD and related disorders and how genes influence biomarker 
responses 
 
Examine clinical and biomarker changes in non-carriers and to compare these 
changes with those seen in carriers treated with placebo 
 
Relate the treatment’s biomarker effects to clinical outcomes and to examine 
predictive and prognostic utility of baseline characteristics 
 
Assess the impact of treatment on brain tau load over time, as measured by tau 
PET imaging in an optional substudy (GN28352-1/BN40199) 
 
2.5 
STUDY PERIOD B OBJECTIVES 
The objectives of Study Period B are: 
 
Provide continued drug access to study participants until the regulatory approval 
of crenezumab or another mechanism of post-trial access to crenezumab is 
initiated 
 
Assess the long-term safety, efficacy, and PK and PD effects of crenezumab   
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Study Period A:  This is a prospective, randomized, double-blind, placebo-controlled, 
parallel-group study of crenezumab versus placebo in individuals who carry the 
PSEN1 E280A autosomal-dominant, mutation-causing EOAD and do not meet criteria 
for MCI due to AD (Albert et al. 2011) or dementia due to AD (McKhann et al. 2011) and 
are, thus, in a preclinical phase of AD (Sperling et al. 2011b).  The study also 
incorporates administration of placebo to individuals who are not PSEN1 E280A 
autosomal-dominant mutation carriers.  This efficacy and safety study will be conducted 
at a single primary site and approximately three satellite sites in Colombia. 
In the Colombian study, PSEN1 E280A autosomal-dominant mutation carriers who 
meet study eligibility criteria will be randomized in a 1:1 ratio to one of two treatment 
groups:  crenezumab or placebo.  Crenezumab will be administered either SC 
(720 mg Q2W) or IV (60 mg/kg Q4W).  Matching placebo will be administered by the 
same routes at the same frequencies.  The switch to the higher IV dose 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
42/Protocol GN28352, Version 11 
(approximately 4-fold higher exposure to crenezumab) will be optional.  
Participants may decide whether to change from the current SC dosing to the IV dose; 
however, once IV dosing in a given participant has occurred, it is not intended for a 
participant to switch back to the lower SC dose.  In order to maintain genotype blind 
and to have a genetic kindred control, a cohort of PSEN1 E280A mutation non-carrier 
kindred family members will also be enrolled in the study and dosed only with placebo. 
The study includes three arms with approximately 100 participants per arm; two arms of 
participants with a PSEN1 E280A mutation randomized in a 1:1 ratio to crenezumab or 
placebo and a third arm of non-carriers randomized to placebo.  Participants will receive 
the randomized treatment until the final participant has reached their final treatment visit 
at 260 weeks (see Figure 1). 
The study duration for individual participants will be at least approximately 284 weeks, 
including an 8-week screening period, a double-blind treatment period of at least 
260 weeks in length, a 4-week final dose visit, and a final safety follow-up visit 
16 weeks after the last dose of study drug (crenezumab or placebo) that will allow for 
clinical follow-up after treatment discontinuation for participants who do not to continue 
with study drug beyond the end of Study Period A or who terminate study drug early.  
One or more interim analyses may be performed at the Sponsor’s discretion 
(see Sections 3.2 and 4.10.9). 
Study Period B:  Following the completion of Study Period A, participants will be offered 
the opportunity to continue to receive study drug until regulatory approval or another 
mechanism for post-trial access to crenezumab is started (via an OLE or other 
programs) or development of crenezumab is discontinued.  This is termed 
Study Period B (see Sections 3.2.1, 4.5.5, 4.5.8).  All PSEN1 mutation carriers will be 
provided crenezumab in Study Period B regardless of treatment allocation during 
Study Period A and all non-carriers will continue on placebo.  Treatment allocation for 
both Study Periods A and B will remain blinded.  Study Period B may last up to 
approximately 33.5 years depending on when participants enter Study Period B and 
when crenezumab is granted regulatory approval or development of crenezumab is 
discontinued.  See Figure 2. 
See Appendix 1 and Appendix 2 for the study flowchart for SC dosing. 
See Appendix 3 and Appendix 4 for the study flowchart for IV dosing. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
43/Protocol GN28352, Version 11 
Figure 1 Study Design 
 
PSEN1  presenilin 1; RCT  randomized, controlled trial. 
 
Figure 2 Study Schematic 
 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
44/Protocol GN28352, Version 11 
3.2 
RATIONALE FOR STUDY DESIGN 
Study Period A:  The study will utilize a common-close design.  All participants will be 
enrolled in the double-blind portion of the study until the last ongoing participant who is 
enrolled in the study and remains on treatment (i.e., ongoing enrolled participant) has 
received approximately 260 weeks of treatment, as far as is practical 
(see Section 4.5.4).  All participants will not have the same amount of follow-up after 
enrollment but all will have at least 5 years of double-blind treatment.  
The common-close design will increase the power of detecting a difference between 
crenezumab and placebo by utilizing the data obtained from each participant, including 
those data from participants with more than 5 years’ treatment duration, in the overall 
analysis.  Furthermore, the common-close design allows similar duration of treatment 
with the higher IV dose (60 mg/kg IV) or matching placebo, for analysis of treatment at 
a higher dose. 
The rationale for changing the study design is to maintain statistical power of 80% to 
detect a treatment effect (see Section 4.10 for further details)despite the fact that only 
252 participants of the 300 originally planned could be recruited from this kindredand 
to allow reasonable duration of treatment for assessment of benefit at the higher dose. 
Study Period A will be continued until the last ongoing enrolled participant has reached 
260 weeks, as far as is practical (see Section 4.5.4). 
One or more interim analyses may be conducted at the Sponsor’s discretion at any 
point during the study.  Such an analysis may be triggered by, for example, the 
availability of results from another clinical study with crenezumab. 
3.2.1 
Rationale for Study Period B 
For the first participants reaching the final efficacy visit in Study Period A 
(End of Treatment-A or End of Treatment-B visit), several months will pass before 
results from Study Period A are available and a longer period of time until regulatory 
approval or a mechanism of post-trial access is set up.  To honor the long commitment 
of participants and not to force a treatment gap in the case crenezumab is effective in 
slowing disease progression, participants will be offered the opportunity to continue to 
receive blinded study drug until regulatory approval or post-trial drug access is started 
(via an OLE or other program) or there is a decision to terminate the development of 
crenezumab on the basis of the results in Study GN28352.  Data collected in 
Study Period B will be used to assess the long term safety and efficacy of crenezumab.  
Continuation into Study Period B is optional. 
Treatment and Dosing 
After completing the final efficacy visit in Study Period A, all mutation carriers who enter 
Study Period B will receive crenezumab and all non-carriers entering Study Period B 
will continue to receive placebo.  Participants, site staff, vendor staff, and Sponsor will 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
45/Protocol GN28352, Version 11 
remain blinded to study drug treatment assignment during the blinded treatment period 
in Study Period A as well as during the Study Period B (see Section 3.8 for details on 
blinding).  Following the data snapshot date for the Study Period A primary readout, 
selected members of the Sponsor team may become unblinded for the purpose of 
analysis and interpretation of Study Period A data.  During Study Period B, after the 
results of Study Period A are available, study participants may choose to learn their 
mutation carrier status (see Sections 3.8 and 3.9 for additional information). 
Participants will have the option to receive the same dose (720 mg SC Q2W or 
60 mg/kg IV Q4W) they were receiving at the end of the Study GN28352 Period A or 
switch to the higher dose of 60 mg/kg IV Q4W if they have not already switched.  
See Section 3.2.2 for rationale for crenezumab dosage. 
3.2.2 
Rationale for Crenezumab Dosage 
In this Phase II study, crenezumab 720 mg SC Q2W was selected as the dose and 
dosing regimen, following the results of the Phase II studies in sporadic AD; this dose 
provides similar exposures as the 15 mg/kg IV Q4W dose in Phase II that suggested a 
trend for efficacy in sporadic AD dementia.  This SC dose has been administered in this 
study since August 2015 and has so far been well-tolerated.  Since July 2019, a higher 
dose of 60 mg/kg IV Q4W is being offered to study participants as this is assumed to 
have a higher potential for efficacy and was also being investigated in Phase III studies 
in sporadic AD. 
The Phase III studies (BN29552 [CREAD] and BN29553 [CREAD 2]) in patients with 
prodromal or mild (sporadic) AD tested a 4-fold higher dose (i.e., 60 mg/kg IV Q4W) of 
crenezumab than in Phase II compared with placebo.  Based on results from a 
preplanned interim analysis of Study BN29552 assessing the safety and efficacy of 
crenezumab indicating that Study BN29552 was unlikely to meet its primary endpoint of 
change from baseline in CDR-SOB score, both Phase III studies were discontinued. 
Study GN28352 continues given that this at-risk ADAD population differs from the 
sporadic prodromal to mild AD population in the following ways:  the population is much 
younger, clinically asymptomatic at study entry, and carries a mutation that is 
specifically linked to amyloid metabolism.  Approximately half of the carrier participants 
have been reported to have negative amyloid PET scans at baseline 
(Reiman et al. 2018).  In addition, this PSEN1 E280A mutation is reported to be 
associated with an increased rate of amyloid accumulation in brain, as measured by 
amyloid PET compared with sporadic AD (Fleisher et al. 2015), suggesting the potential 
for crenezumab in delaying the progression of amyloid pathology may provide greater 
benefit in this patient population compared with sporadic AD.  Furthermore, a 
quantitative systems pharmacology model of AD has been developed by Genentech 
and calibrated to both the ADAD (PSEN1 E280A mutation) and sporadic AD 
populations.  Simulations from this model predict that both the 720 mg SC Q2W and 
60 mg/kg IV crenezumab Q4W dosing regimens will delay the progression of amyloid 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
46/Protocol GN28352, Version 11 
accumulation in the brain in the ADAD population, as measured by amyloid PET 
standard uptake ratio, with a greater effect associated with the 60 mg/kg IV Q4W 
regimen (internal data). 
Both doses of crenezumab offered in this study are predicted to result in drug 
concentrations in the brain above the in vitro half maximal effective concentration (EC50) 
in the brain (see Figure 3).  Higher doses of crenezumab are predicted to increase 
concentrations in the brain compared with the concentrations resulting from the 
15 mg/kg IV Q4W dose, and therefore, to maintain drug concentrations above the in 
vitro EC50 in the brain throughout the treatment period.  In vitro, the EC50 for 
crenezumab binding to A142 monomers and aggregates was approximately 
0.2 g/mL, and higher target engagement of soluble A was observed with higher 
crenezumab concentrations (Adolfsson et al. 2012).  Crenezumab binds to both A140 
and A142 with high affinity (7.3  0.6 nM and 11.1  1.2 nM, respectively), inhibits A 
aggregation and promotes A disaggregation. 
Doses of crenezumab up to 120 mg/kg IV Q4W have been safe and well-tolerated 
(Phase Ib Study GN29632) and Phase III studies investigated the dose of 60 mg/kg IV 
Q4W.  No safety signals for crenezumab were observed in the Study BN29552 interim 
analysis and the overall safety profile was similar to that observed in previous trials.  
Nonclinical safety data provide 2-, 3-, and 6-fold safety factors for the 60 mg/kg dose at 
steady state on the basis of human equivalent dose, the maximum observed 
concentration (Cmax), and average exposure (AUC), respectively, relative to the 
maximum tested dose of 100 mg/kg/week administered by SC injection in cynomolgus 
monkeys (for more details, refer to the Crenezumab Investigator’s Brochure). 
In summary, based on available in vitro affinity, clinical PK and PD data, the dose of 
720 mg SC Q2W remains a dose with the potential to result in meaningful efficacy in 
this at risk population (ADAD) that has not previously been studied.  The higher dose of 
60 mg/kg IV Q4W is predicted to yield higher target engagement and has been found to 
be safe and well-tolerated in patients with sporadic AD. 
In the current study, beginning with protocol Version 6, use of a higher dose 
(60 mg/kg IV Q4W) than previously used in this study will be offered to participants in 
addition to the dose already available (720 mg SC Q2W) as it provides participants with 
an opportunity to receive a dose that may provide greater efficacy.  Participation in the 
study with treatment at a higher dose is at the discretion of the participant after 
discussion of the different dosing options. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
48/Protocol GN28352, Version 11 
In order to maximize the chances of observing a change in clinical and biomarker 
outcomes during the  5-year treatment period of this trial, the enrolled participant 
population will be 30 years of age or older.  The preclinical population  30 years of age 
was the population in which the empirically derived API ADAD Composite Cognitive 
Test Battery was developed and determined to be sensitive in tracking decline.  
Furthermore, imaging data in Colombian PSEN1 E280 mutation carriers suggests that 
amyloid accumulation begins around the age of 30 (Fleisher et al. 2012).  
Therefore, this preclinical population may be optimal for detecting cognitive changes, 
the emergence of symptoms indicative of MCI due to AD, and amyloid-related 
biomarker changes. 
A non-carrier group from the same kindred in Colombia will also be enrolled.  
The primary rationale for including non-carriers is to maintain blinding to genotype 
status to study participants, blinded study site personnel, and the Sponsor.  
The community standard in Colombia is to not be apprised of one’s mutation carriage 
status in either research or clinical contexts.  The inclusion of mutation non-carriers will 
also provide a genetic kindred control against which to explore the rate of clinical 
progression and biomarker changes in ADAD mutation carriers.  The mutation 
non-carriers will be dosed only with placebo. 
3.3 
OUTCOME MEASURES IN STUDY PERIOD A 
3.3.1 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measures for Study Period A are as follows: 
 
Annualized rate of change on the API ADAD Composite Cognitive Test total score, 
which is computed from the following five cognitive test scores: 
– 
Word List:  Recall (Rosen et al. 1984; Morris et al. 1989; Mohs et al. 1997) 
– 
Multilingual Naming Test (Gollan et al. 2012) 
– 
MMSE (Folstein et al. 1975) (for orientation to time) 
– 
Consoritum to Establish a Registry for Alzheimer’s Disease (CERAD) 
Constructional Praxis (Morris et al. 1989) (a measure of visuospatial ability) 
– 
Raven’s Progressive Matrices (a measure of nonverbal fluid reasoning and 
visuospatial abilities), Set A (Raven 1976) 
 
Annualized rate of change on the FCSRT Cueing Index 
 
3.3.2 
Secondary Efficacy Outcome Measures 
The final selection of secondary outcome measures will be based on the basis of 
baseline data from the study population, relevant completed trials, and other external 
data that will emerge prior to database unblinding.  The selected outcomes will be 
provided in the SAP to be submitted prior to database unblinding.  Secondary outcome 
measures will be selected from the following. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
49/Protocol GN28352, Version 11 
3.3.2.1 
Clinical 
 
Time to progression from preclinical AD to MCI due to AD (Albert et al. 2011) or 
from preclinical AD to dementia due to AD (McKhann et al. 2011) 
(see Section 4.5.1) 
 
Time to progression to non-zero in the Clinical Dementia Rating (CDR) Scale 
global score (Morris 1993) 
 
Annualized rate of change in the CDRSOB (Morris 1993) 
 
Annualized rate of change in a measure of overall neurocognitive functioning: 
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
(Randolph 1998) 
 
3.3.2.2 
Biomarkers 
 
Imaging biomarkers 
– 
Annualized rate of change in mean cerebral fibrillar amyloid accumulation 
using florbetapir PET from a predefined ROI 
– 
Annualized rate of change in regional CMRgl using FDG-PET in a predefined 
ROI 
– 
Annualized rate of change in volumetric measurements using MRI 
 
CSF biomarkers 
– 
Annualized rate of change in a tau-based CSF biomarkers 
 
3.3.3 
Safety Outcome Measures 
Safety will be assessed through regular neurological and physical examinations 
(including vital signs), prospective suicidality assessment (copyright Pfizer Inc. and 
Janssen Alzheimer Immunotherapy; used with permission), laboratory tests, ECGs, and 
MRI assessments.  In addition, the following data will be collected and analyzed: 
 
Frequency and severity of treatment-emergent adverse events and serious 
adverse events 
 
Withdrawals due to adverse events 
 
Incidence of injection reactions and IRRs 
 
Incidence of anti-crenezumab antibodies 
 
Incidence of treatment-emergent adverse events of special interest, including: 
– 
ARIA-E (cerebral VE, sulcal effusion) 
– 
ARIA-H (superficial CNS siderosis, cerebral microhemorrhages) 
– 
Cerebral macrohemorrhages 
– 
Pneumonia 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
50/Protocol GN28352, Version 11 
3.3.4 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
The PK outcome measures are CSF and serum crenezumab concentrations at 
protocol-specified timepoints.  In serum, crenezumab Ctrough, ss will be assessed.  
Additional PK analyses may be conducted, as appropriate. 
The PD outcome measures are as follows:  plasma A140 and A142 concentrations. 
3.3.5 
Exploratory Outcome Measures 
Exploratory outcome measures are listed below.  In addition, any endpoints 
(among those listed in Section 3.3.2) that are not prespecified in the SAP as secondary 
outcome measures may be analyzed as exploratory outcome measures. 
3.3.5.1 
Clinical 
 
Changes from baseline over time in the following cognitive measures: 
– 
Trail Making Test (Armitage 1946) 
– 
MMSE (Folstein et al. 1975  
– 
RBANS Index Scores (Randolph 1998) 
– 
Scores of each of the components of the API ADAD Composite Cognitive Test 
Battery 
– 
Preclinical Alzheimer’s Cognitive Composite (PACC) (Donohue et al. 2014), 
which for this trial will include the FCSRT free and cued recall, MMSE, RBANS 
story recall, and RBANS coding score 
– 
Clinical endpoints not examined in secondary outcome measures 
 
Changes in the Neuropsychiatric Inventory (NPI) (Cummings et al. 1994; 
Cummings 1997) total score, items, and factors 
 
Changes in the Geriatric Depression Scale (GDS) (Sheikh and Yesavage 1986) 
total score 
 
Changes in Functional Assessment Staging of Alzheimer’s Disease (FAST) 
(Sclan and Reisberg 1992) total score  
 
Changes in Subjective Memory Checklist (SMC, Acosta-Baena et al. 2011) 
 
3.3.5.2 
Fluid Biomarkers 
 
CSF levels of Aβ species 
 
Changes in other blood and CSF measures 
 
3.3.5.3 
Imaging Biomarkers 
 
Analysis of ROIs not selected in secondary outcome measures  
 
Other imaging outcome measures and analytic methods, alone, or in conjunction 
with other imaging modalities not explored in secondary outcome measures  
 
Change in tau burden over time, as measured by [18F]-Genentech Tau Probe 1 
(GTP1) PET in an optional substudy (GN28352-1/BN40199) 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
51/Protocol GN28352, Version 11 
3.3.5.4 
Other Outcome Measures 
 
Changes in primary, secondary, and exploratory outcomes in mutation non-carriers 
treated with placebo 
 
Comparisons of clinical and biomarker outcomes between carriers treated with 
placebo and non-carriers 
 
Changes in primary, secondary, and exploratory outcomes in carriers and 
non-carriers as functions of APOE genotype and other genetic variations  
 
Short-term changes in imaging measures as functions of initiation (e.g., baseline to 
12 weeks)  
 
Analyses of outcome measures in relation to one another and in relation to 
baseline characteristics 
 
3.4 
OUTCOME MEASURES IN STUDY PERIOD B 
The same safety, efficacy, and PK and PD measures will be collected in Study Period B 
with the exception of FDG-PET (see Appendix 5 and Appendix 6 for frequency of 
assessments).  The safety outcome measures are as described for Study Period A.  
Efficacy and PK/PD outcome measures will be assessed as change over time for 
continuous outcome measures or time to event for time to progression to non-zero in 
the CDR Scale global score and for progression from preclinical AD to MCI due to AD 
or from preclinical AD to Dementia due to AD. 
3.5 
SAFETY PLAN 
See Section 5 for complete details of the safety evaluation for this study. 
Crenezumab has not been approved for use by global health authorities and is currently 
in clinical development.  Thus, the entire safety profile is not known at this time.  
The crenezumab safety information is based on results from nonclinical and clinical 
studies, as well as published data on similar molecules.  The safety monitoring for this 
study is designed to ensure participant safety and will include specific eligibility criteria 
and monitoring assessments.  Any adverse events/serious adverse events or any other 
abnormalities (e.g., laboratory assessments, radiographs, physical examination 
findings) should be managed by the site investigators, as medically appropriate 
(unless otherwise specified in the protocol). 
The safety of participants in this trial will be ensured through the use of stringent 
inclusion and exclusion criteria and through close monitoring of participants.  
Investigators will assess the occurrence of adverse events and serious adverse events 
at all participant evaluation timepoints during the study.  All adverse events and serious 
adverse events, whether volunteered by the participant, discovered by study personnel 
during questioning, or detected through physical examination, laboratory tests, or other 
means, will be recorded in the participant’s medical record and on the appropriate 
adverse event or serious adverse event electronic Case Report Form (eCRF). 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
52/Protocol GN28352, Version 11 
Each recorded adverse event or serious adverse event will include a description of its 
duration (i.e., start and end dates), severity, seriousness according to regulatory 
criteria, if applicable, and suspected relationship to the investigational product, as well 
as any actions taken. 
Participants will be followed carefully for adverse events during the study, including a 
4-week postdose visit and a final safety follow-up visit 16 weeks after the last dose of 
study drug (for the list of study assessments, see the study flowcharts in Appendix 1 to 
Appendix 4).  Adverse events will be graded according to severity using the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.0. 
An independent Data Monitoring Committee (iDMC) formerly known as the Data and 
Safety Monitoring Board (DSMB) will be used for this study during Study Period A.  
During Study Period B, an internal data monitoring committee comprised of Sponsor 
employees not affiliated with the trial will monitor safety. 
Please refer to the latest Crenezumab Investigator’s Brochure for additional safety 
information. 
3.5.1 
Immunogenicity 
Immunogenicity, as determined by the presence of a positive response in the ADA 
enzyme-linked immunosorbent assay (ELISA), will be assessed at specified timepoints 
during the course of the study.  Additional characterizations will be performed if 
necessary. 
3.5.2 
Amyloid-Related Imaging Abnormalities 
Amyloid-related imaging abnormalities are a spectrum of image abnormalities detected 
on MRI.  Two types of ARIA have been described:  Amyloid-related imaging 
abnormalitieseffusion refers to the MRI alterations thought to represent VE and related 
extravasated fluid phenomena, and ARIA-H refers to the MRI alterations attributable to 
microhemorrhages and leptomeningeal hemosiderosis. 
The occurrence of imaging abnormalities believed to represent cerebral VE has been 
reported in association with the investigational use of compounds that are intended to 
treat AD by reducing A in the brain.  These imaging abnormalities 
(Salloway et al. 2009; Sperling et al. 2011a) have, in the majority of instances, been 
asymptomatic, and their presence has been detected by brain MRI.  Symptoms, when 
present in association with such imaging abnormalities, have been reported to include 
headache, worsening cognitive function, alteration of consciousness, seizures, 
unsteadiness, and vomiting. 
The clinical significance of ARIA-H is not yet fully understood. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
53/Protocol GN28352, Version 11 
When anti-A antibodies bind to amyloid deposited around blood vessels, an 
FcγR-mediated immune response may be elicited, compromising vascular integrity and 
resulting in ARIA-E or ARIA-H.  Crenezumab, a human IgG4, has reduced FcR binding 
compared with IgG1/2 and, thus, has reduced effector function that theoretically may 
lower the risk of ARIA-E.  This has been supported by emerging safety data observed in 
both clinical and nonclinical studies conducted to date.  A lack of binding to vascular 
amyloid, noted following in vivo dosing in PS2APP Tg mice (Study 15-2817B), may 
additionally reduce the risk of ARIA. 
To minimize the potential safety risks associated with ARIA-E and ARIA-H in this study, 
participants will be screened for ARIA-E and ARIA-H before enrollment and will be 
monitored for ARIA-E and ARIA-H by MRI during treatment (see Section 3.5.2.1).  
Given the uncertainty of risk and concerns about cerebral amyloid angiopathy (CAA) 
severity, participants with superficial siderosis of the CNS, more than 4 cerebral 
microhemorrhages, or evidence of a prior cerebral macrohemorrhage at screening will 
be excluded from this study. 
An overview of the monitoring and management guidelines for ARIA-E and ARIA-H is 
provided in the following sections. 
The cerebral microhemorrhage thresholds for study entry and treatment discontinuation 
allow for imaging measurement variability to be taken into account and reflect the 
uncertainty regarding the clinical relevance of small numbers of cerebral 
microhemorrhages.  This approach is intended to minimize potential safety risks 
associated with cerebral microhemorrhages but would not preclude participants from 
receiving potentially beneficial treatment (see Section 3.5.2.2). 
3.5.2.1 
Monitoring for Amyloid-Related Imaging Abnormalities 
In this Phase II study, a safety monitoring plan has been designed to mitigate and 
monitor the potential risk of ARIA-E and ARIA-H associated with anti-A 
immunotherapy.  This plan consists of the following key elements: 
 
Participants with evidence of one or more of the following abnormalities assessed 
by MRI during screening will be excluded from the trial: 
– 
Significant cerebral vascular pathology 
– 
Superficial siderosis of the CNS 
– 
More than 4 cerebral microhemorrhages 
– 
Evidence of a prior cerebral macrohemorrhage 
 
Participants enrolled in the study will regularly undergo neurological examinations 
to evaluate for any neurologic signs or symptoms that are suggestive of the 
presence of the following: 
Cerebral VE (e.g., confusion, dizziness, vomiting, and lethargy), superficial 
siderosis of the CNS (e.g., sensorineural deafness, cerebellar ataxia, and 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
54/Protocol GN28352, Version 11 
pyramidal signs), or cerebral microhemorrhages (e.g., transient or permanent 
focal motor or sensory impairment, ataxia, aphasia, and dysarthria) 
 
Brain MRI examinations for Study Period A (including fluid-attenuated inversion 
recovery [FLAIR] and T2 with additional in-homogeneous dephasing 
(T2*)-weighted gradient-recalled echo [GRE] sequences) will be performed for 
safety monitoring approximately every 3 months for the first year and 
approximately every 6 months thereafter to detect potential safety risks noted 
below.  If switching to 60 mg/kg IV Q4W, MRI scans will be performed at 3 months 
and 6 months after initiating the higher dose and then every 2428 weeks 
thereafter to detect the following:  ARIA-E, ARIA-H, and cerebral 
macrohemorrhages (see study flowchart in Appendix 1, Appendix 2, Appendix 3, 
and Appendix 4 for MRI schedule). 
Brain MRI examinations in Study Period B will be done at Week 105 and as 
directed by symptoms. 
All safety MRI scans will be read for the evaluation of ARIA-E, ARIA-H, and 
cerebral macrohemorrhages by independent radiologists at a central reading 
facility 
 
Regardless of severity, all events of cerebral VE, sulcal effusion, superficial 
siderosis of the CNS, and cerebral micro- or macro-hemorrhage that occur at any 
time after receiving study drug are considered to be adverse events of special 
interest and will be reported in an expedited manner (see Section 5.4) 
 
3.5.2.2 
Management of Amyloid-Related Imaging Abnormalities 
 
Amyloid-Related Imaging AbnormalitiesEdema/Effusion (ARIA-E) 
The following rules for the management of MRI-related findings apply for ARIA-E: 
 
Asymptomatic ARIA-E with Size  4 BGTS (Barkhof et al. 2013) 
– 
Continue study drug at the same dose (i.e., 60 mg/kg crenezumab) 
– 
Repeat MRI 4 weeks later 
– 
If ARIA-E is stable or decreased, continue study drug and monthly MRI 
monitoring until event resolves.  Once ARIA-E completely resolves, conduct 
MRI monitoring as per study flowchart. 
– 
If ARIA-E increases (BGTS  4) or symptoms develop, see the rules below. 
 
Symptomatic ARIA-E (of any size) or asymptomatic ARIA-E with size  4 BGTS: 
– 
Temporarily interrupt study drug and implement monthly MRI monitoring 
– 
Once symptoms and ARIA-E resolve, reintroduce study drug and perform an 
MRI after 4 weeks of dosing.  If no new MRI abnormality is detected, resume 
MRI monitoring as per the study flowchart. 
 
For any new onset of ARIA-E: 
– 
Treat the same as the first event, on the basis of symptoms and BGTS 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
55/Protocol GN28352, Version 11 
 
If a participant is diagnosed with 3 recurrent, symptomatic ARIA-E events or 
exacerbations of previous events, permanently discontinue the study drug 
 
Implement monthly MRI monitoring until resolution of both symptoms and ARIA-E 
 
As per the protocol, maintain the participant in the study until study end and 
perform assessments as per the study flowcharts 
 
Amyloid-Related Imaging AbnormalitiesHemosiderin Deposition (ARIA-H) 
The following dose adjustments and discontinuation rules for MRI-related findings will 
apply to ARIA-H: 
 
Dose reduction:  Participants who develop  8 ARIA-H cumulatively will receive a 
lower dose of the study drug.  Cumulative is the sum of ARIA-H at baseline and 
newly detected ARIA-H during the study. 
 
Study drug discontinuation:  Participants who develop  10 ARIA-H cumulatively 
will be permanently discontinued from the study drug.  Cumulative is the sum of 
ARIA-H at baseline and newly detected ARIA-H during the study. 
 
The Sponsor believes that the above rules, coupled with frequent MRI monitoring and 
collection of CNS symptoms, will ensure safety while trying to maximize benefit for the 
participants. 
3.5.3 
Pneumonia 
In the RPCP of Phase II clinical trials in mild to moderate AD (Studies ABE4869g and 
ABE4955g) there was an imbalance in the rates of TLRTI (including PTs of pneumonia, 
LRTI, and bronchitis) driven by pneumonia.  However, this imbalance was not 
replicated in the pooled data of the two large Phase III studies (BN29552 and BN29553) 
where the pneumonia cases were balanced between the crenezumab treatment and 
placebo arms (13 and 15 cases). 
There is no clinical evidence of immunosuppression (e.g., effects on white blood cells or 
neutrophils; or pattern of infection type, e.g., opportunistic infections).  In addition, no 
evidence of immunosuppression or of a lung toxicity effect has been observed in 
nonclinical studies. 
Based on the currently available data, a causal relationship between the drug and 
events of pneumonia cannot be established or ruled out.  Pneumonia is considered a 
potential risk to be monitored closely, and is added to this protocol as an adverse event 
of special interest. 
Please refer to the latest Crenezumab Investigator’s Brochure for further information on 
the incidence of pneumonia in all completed and ongoing studies. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
56/Protocol GN28352, Version 11 
3.5.3.1 
Monitoring for Pneumonia 
 
It is of paramount importance to carefully document any pneumonia cases and 
other serious respiratory infections that occur in this study, by means of providing 
all relevant information required by the eCRF 
 
Participants with signs and/or symptoms suggestive of pneumonia 
(e.g., cough, fever, pleuritic chest pain) should undergo chest radiography for 
confirmation of diagnosis.  Participants should be treated as per standard treatment 
care and any change to study drug should be considered within a benefitrisk 
assessment frame, and in agreement with the Medical Monitor.  
 
A chest X-ray is required under the following circumstances: 
– 
Serious and non-serious pneumonia 
– 
Serious and non-serious LRTIs 
– 
Serious upper respiratory tract infections 
 
In addition, whenever possible, additional relevant investigations should be 
conducted (e.g., WBC counts, pathogen identification by means of hemocultures, 
bronchoalveolar lavage) 
 
3.5.4 
Injection and Infusion Reactions 
Administration of monoclonal antibodies may be associated with local reactions at the 
site of injection or infusion.  Systemic injection/infusion reactions as well as 
hypersensitivity or anaphylactic reactions may also occur. 
Infusion and injection-related reactions are defined as any adverse event that occurs 
during or within 24 hours after the study drug injection or infusion. 
No relationship between treatment dose and the occurrence of infusion/injection related 
reactions has been observed.  The majority of IRRs in all ongoing and completed 
studies with crenezumab were of mild to moderate severity. 
3.5.4.1 
Systemic Injection and Infusion-Related Reactions 
Crenezumab will be administered to participants under close medical supervision in a 
setting with access to appropriate emergency equipment and staff who are trained to 
monitor and respond to medical emergencies. 
In the event that a participant experiences a mild IRR, the infusion will be halted.  
Once the reaction has resolved, the infusion rate will be resumed at half of the most 
recently used rate (e.g., 31.5 mL/min). 
Participants who experience a moderate IRR (e.g., fever or chills) should have the 
infusion stopped immediately and should receive aggressive symptomatic treatment.  
The infusion should not be restarted before all symptoms have disappeared, and then it 
should be restarted at half the initial rate. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
57/Protocol GN28352, Version 11 
Participants who experience serious or severe hypersensitivity reactions 
(e.g., hypotension, mucosal involvement) should not receive additional study drug.  
In addition, in any case of anaphylaxis, anaphylactoid reaction, serious or severe 
hypersensitivity reaction, ADA and concurrent PK samples should be collected as close 
as possible to the event, and then at 4 and 16 weeks postdose (see study flowcharts for 
further details).  Participants who receive the SC formulation of study drug will be 
observed for a minimum of 15 minutes following all injections. 
Participants who receive IV formulation of study drug, will be observed for a minimum of 
60 minutes following all infusions. 
3.5.5 
Additional Safety Monitoring  
Laboratory tests, including hematology, chemistry, coagulation, urinalysis, and ADAs 
will be performed throughout the study.  Electrocardiograms will be recorded regularly, 
including at baseline.  Physical and neurological examinations will be performed 
throughout the study to assess adverse events, particularly any neurological events that 
are not consistent with normal disease progression.  Suicidality assessments will be 
used to measure prospective suicidality (see Appendix 7).  If the suicidality assessment 
reveals a concern about a significant level of suicidality, the participant will undergo a 
more detailed assessment by a qualified clinician who has experience in the evaluation 
of suicidal ideation and behavior, either at the site or by referral to an outside clinician. 
Serum pregnancy testing will be performed at screening for all female participants of 
childbearing potential (see the footnotes to the study flowcharts in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4).  Urine pregnancy testing will be performed 
prior to study drug administration or PET scan for all female participants of childbearing 
potential.  Pregnancy testing will apply to all female participants of childbearing potential 
unless documented (by medical records or physician’s note) to be surgically sterile or 
postmenopausal, as defined in International Council for Harmonisation (ICH) Guidance 
M3 (R2), Section 11.2 (12 months with no menses without an alternative medical 
cause).  If urine pregnancy testing returns a positive result, study drug will be held until 
pregnancy is verified.  If pregnancy is confirmed, the participant will not receive further 
doses of study drug. 
The incidence and nature of adverse events, serious adverse events, and laboratory 
abnormalities will be assessed on a regular basis by the iDMC.  The committee will 
recommend changes to study conduct or study termination, as required.  
The responsibilities and operation of the committee will be documented in the 
iDMC Charter. 
3.6 
STUDY PARTICIPANTS AND ANALYSIS GROUPS  
The Study Period A primary efficacy analysis will be based on a modified intent-to-treat 
(mITT) population.  This consists of participants who are mutation carriers treated with 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
58/Protocol GN28352, Version 11 
any amount of study drug.  Participants in the efficacy analysis population will be 
grouped based on treatment assigned. 
Safety assessments will be performed for safety-evaluable participants, defined as all 
randomized participants who have received at least 1 dose of study drug.  Because of 
the importance of assessing safety on the basis of actual drug received by a participant 
(especially with respect to cerebral VE, superficial siderosis of the CNS, and cerebral 
micro- or macrohemorrhages), participants will be grouped for all safety analyses 
according to the treatment they actually received rather than the treatment assigned at 
randomization and mutation-carrier status. 
The Study Period B safety population is based on all randomized participants that 
received at least 1 dose of study drug in Study Period B.  Participants will be grouped 
according to the actual treatment received. 
3.7 
CONTROL GROUPS 
Mutation carriers who receive placebo treatment will comprise the primary control 
comparison group. 
3.8 
MINIMIZATION OF BIAS 
The trial is a Phase II, single-center, randomized, double-blinded, placebo-controlled 
study of the effects of crenezumab on clinical outcomes and biomarkers, in ADAD 
mutation carriers, with a non-randomized study of the effects of placebo in carriers and 
non-carriers. 
In Study Period A, eligible carrier participants for the randomized clinical trial will be 
randomized in a 1:1 ratio (active to placebo) using an interactive voice or Web-based 
response system (IxRS) to prevent bias in treatment assignment.  
Randomization among carriers will be stratified by age, education, APOE4 carrier 
status (carrier vs. non-carrier), and baseline CDR zero versus CDR non-zero in order to 
maximize treatment group comparability.  In Study Period B, all carrier participants will 
receive crenezumab and non-carrier participants will receive placebo. 
Participants, study site personnel who will evaluate participant status, contract research 
organization (CRO) personnel who will review participant eCRFs, other Sponsor agents 
(with the exception of the IxRS provider), and Sponsor personnel involved in study 
conduct will be blinded to treatment assignments at least through the end of 
Study Period A.  Because of the physical characteristics of the study drug, 
investigators and study drug administrators should implement strategies to maintain the 
blind, which are outlined in the pharmacy manual.  Pharmacists and drug administrators 
will be unblinded to study drug allocation due to slight variations in color of active drug 
and placebo.  Pharmacists and study drug administrators will not participate in any 
portion of the study outside requirements of drug preparation and administration.  
For further details, please refer to the pharmacy manual. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
59/Protocol GN28352, Version 11 
The investigator will be unblinded to study drug allocation only if the identity of the study 
drug is essential for participant management in the case of an serious adverse event.  
The investigator will contact the Sponsor, or medical designee, to discuss the medical 
details and options for unblinding.  The iDMC will be unblinded to treatment assignment 
(see Section 3.10). 
After Study Period A, following the data snapshot date for the Study Period A primary 
readout, selected members of the Sponsor team may become unblinded for the 
purpose of analysis and interpretation of Study Period A data.  In addition, once genetic 
results are made available, participants who choose to learn their genetic status would 
infer their treatment allocation in Study Period B since all carriers will be receiving 
crenezumab in Study Period B.  Participants will be asked not to share their mutation 
status results with the cognitive or global raters (see Section 3.9 for additional 
information). 
3.9 
ETHICAL CONSIDERATIONS 
This study will comply with laws and guidelines as discussed in the following sections:  
Compliance with Laws and Regulations (see Section 3.11), Informed Consent Form 
(see Section 6.3), Communication with the Institutional Review Board (IRB) or 
Ethics Committee (EC) (see Section 6.4), and Disclosure of Data (see Section 6.10). 
Currently, there is no approved treatment to delay or prevent the onset of symptoms of 
AD.  Crenezumab is an investigational drug that is being studied in patients at high risk 
for AD due to an autosomal-dominant genetic mutation (PSEN1 E280A).  This is the 
first preclinical trial in individuals who do not have MCI or dementia but are at high risk 
for developing clinical AD.  The inclusion of two placebo groups is considered 
necessary and justifiable in the double-blind design of this study.  A placebo mutation 
carrier group is necessary to allow for unbiased assessment of efficacy, safety, and 
tolerability of crenezumab.  In order to maintain genotype blind and to have a genetic 
kindred control, a cohort of ADAD mutation non-carriers will also be enrolled into the 
study from the kindreds in a double-blinded fashion and placed only on placebo.  
All participants in the study will be allowed standard of care medications for AD 
(e.g., memantine and acetylcholinesterase inhibitors) if they develop symptomatic AD. 
In Study Period B, all carriers will receive crenezumab and all non-carriers will 
receive placebo.  At the request of the site and participants, non-carriers will be 
allowed to continue receiving placebo injections or infusions in Study Period B so that 
no one is required to receive genetic results before crenezumab receives market 
approval in order to participate in Study Period B.  Genetic counselling and results 
will be made available after all participants have completed the Week 260 assessments 
and Study Period A results are available.  If non-carriers choose to learn their carrier 
status, no further placebo injections or infusions will be administered. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
60/Protocol GN28352, Version 11 
3.10 
ADMINISTRATIVE STRUCTURE  
The study is sponsored by F. Hoffmann-La Roche Ltd (hereafter referred to as Roche).  
A joint leadership team comprised of the Banner Alzheimer’s Institute and Roche will be 
responsible for governance, operating in partnership with the Neurosciences Group of 
the University of Antioquia.  Crenezumab was in-licensed from AC Immune and is being 
developed by Roche.  This trial will be managed by a primary CRO.  A total of up to 
300 participants will be enrolled in Colombia.  
The randomization of participants will be managed by a central IxRS vendor using 
dynamic hierarchical randomization.  
All laboratory tests of blood specimens will be performed by central laboratories or 
Roche, as appropriate. 
A central imaging reader will determine the presence of cerebral VE and sulcal effusion 
by FLAIR MRI, and the presence of superficial siderosis of the CNS and cerebral 
micro- or macrohemorrhages by T2*-weighted GRE MRI scans. 
An iDMC formerly referred to as the DSMB will be utilized during the conduct of this trial 
to periodically review unblinded safety and efficacy data during Study Period A.  
In addition to periodic review of safety and efficacy data, the iDMC may make 
recommendations regarding study conduct.  Details of the iDMC membership and roles 
are detailed in the iDMC Charter.  During Study Period B, an internal monitoring 
committee comprised of Sponsor employees not affiliated with the conduct of the trial 
will monitor safety. 
3.11 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with the U.S. Food and Drug Administration 
(FDA) regulations, the ICH E6 Guideline for Good Clinical Practice (GCP), and 
applicable local, state, and federal laws, as well as other applicable country laws. 
4. 
MATERIALS AND METHODS  
4.1 
PARTICIPANTS 
4.1.1 
Participant Selection 
Written informed consent will be obtained prior to initiation of any study procedure.  
All participants volunteering and eligible for participation in the study will be screened 
for conformance with the following inclusion and exclusion criteria.  In Study Period A, 
approximately 200 participants who are PSEN1 E280A mutation carriers will be 
randomized to receive crenezumab or placebo; approximately 100 mutation 
non-carriers will be enrolled and will receive only placebo.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
61/Protocol GN28352, Version 11 
4.1.2 
Inclusion Criteria 
Participants must meet the following criteria for study entry: 
 
Signed and dated written informed consents obtained from the participant and 
study partner in accordance with local regulations prior to the initiation of any 
protocol required procedures 
 
Membership in PSEN1 E280A mutation carrier kindred 
 
Agrees to conditions of, and is willing to undergo, genetic testing 
(e.g., APOE, PSEN1 E280A, and other genetic testing) 
 
PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or 
during the screening period 
 
Males and females, age  30 years and  60 years 
 
MMSE of  24 for participants with less than 9 years of education or MMSE of 
 26 for participants with 9 or more years of education 
 
Does not meet criteria for dementia due to AD (McKhann et al. 2011) 
 
Does not meet criteria for MCI due to AD (Albert et al. 2011) as defined by the 
following: 
– 
Cognitive concern in the judgment of the investigator, based in part on the 
average SMC score  22 (average of participant and study partner component 
scores) 
– 
Word List:  Recall  3 for participants with less than 9 years of education 
– 
Word List:  Recall  5 for participants with 9 or more years of education 
– 
Preservation of independence in functional activities in the judgment of the 
investigator, based in part on review of the FAST (Sclan and Reisberg 1992) 
 
Adequate vision and hearing in the investigator’s judgment to be able to complete 
testing 
 
If female, and not documented (by medical records or physician’s note) to be 
surgically sterile (absence of ovaries and/or uterus or tubal ligation) or 
postmenopausal (as defined in Section 3.5.5), willing to undergo pregnancy tests at 
protocol-specific timepoints 
 
For female participants who are not documented (by medical records or physician’s 
note) to be surgically sterile (absence of ovaries and/or uterus or tubal ligation) or 
postmenopausal (as defined in Section 3.5.5), agreement to remain abstinent or 
use two adequate methods of contraception, including at least 1 method with a 
failure rate of  1% per year (e.g., hormonal implants, combined oral 
contraceptives, vasectomized partner) during the treatment period and for at least 
16 weeks (approximately 5 half-lives) after the last dose of study drug 
 
For male participants of reproductive potential with partners of childbearing 
potential (i.e., women who are not surgically sterile and are not postmenopausal, 
as defined in Section 3.5.5), agreement to remain abstinent or use a condom as a 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
62/Protocol GN28352, Version 11 
method of contraception during the treatment period and for at least 8 weeks 
(approximately 2 half-lives) after the last dose of study drug 
– 
For male participants, a documented successful vasectomy (by medical 
records or physician documentation) is an acceptable alternative form of birth 
control. 
 
Study partner who agrees to participate in the study and is capable of and willing 
to: 
– 
Accompany the participant to all required visits, as specified in the footnotes to 
the study flowcharts provided in Appendix 1 and Appendix 2 for SC 
administration and Appendix 3 and Appendix 4 for IV administration 
– 
Provide information for required telephone assessments 
– 
Spend sufficient time with the participant to be familiar with his/her overall 
function and behavior, and be able to provide adequate information about the 
participant, including:  
Knowledge about domestic activities, hobbies, routines, social skills and basic 
activities of daily life. 
Work and educational history. 
Cognitive performance, including memory abilities, language abilities, 
temporal and spatial orientation, judgment, and problem solving. 
Emotional and psychological state. 
General health status. 
 
Participant and study partner have evidence of the following: 
– 
Adequate premorbid functioning (e.g., intellectual, visual, and auditory)  
– 
Fluency in, and able to read, the language in which study assessments are 
administered 
 
Willing and able to undergo neuroimaging (PET and MRI) 
 
In the judgment of the investigator, no clinically significant thyroid dysfunction or 
B12 deficiency, as determined by the following criteria: 
– 
Serum TSH and B12 levels within normal or expected ranges for the testing 
laboratory or, if TSH or B12 values are out of range, they are judged by the 
investigator not to be clinically significant 
– 
If the participant is undergoing thyroid replacement therapy, TSH levels must 
either be within normal or expected ranges for the testing laboratory or, if TSH 
values are out of range, they do not require any therapeutic actions 
(treatment or surveillance) 
– 
If the participant is receiving vitamin B12 injections or oral vitamin B12 
therapy, B12 levels must be at or above the lower limit of normal for the 
testing laboratory or, if B12 values are out of range, they do not require any 
therapeutic actions (treatment or surveillance) 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
63/Protocol GN28352, Version 11 
 
In good general health with no known co-morbidities expected to interfere with 
participation in the study 
 
In the opinion of the investigator, the participant and study partner will be in 
accordance with the following:  
– 
Able to comply with the protocol 
– 
Able to participate in all scheduled evaluations 
– 
Have a high probability of completing all required tests and the study 
 
4.1.3 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
 
Significant medical, psychiatric, or neurological condition or disorder documented 
by history, physical, neurological, laboratory, or ECG examination that would place 
the participant at undue risk in the investigator’s judgment or impact the 
interpretation of efficacy 
 
History of stroke 
– 
Participants with a history of transient ischemic attack may be enrolled if the 
event occurred  2 years prior to screening 
 
History of severe, clinically significant (persistent neurological deficit or structural 
brain damage) CNS trauma (e.g., cerebral contusion) 
 
Body weight  45 or  120 kg 
 
History or presence of atrial fibrillation that poses a risk for future stroke in the 
investigator’s judgment 
 
Clinically significant laboratory or ECG abnormalities (e.g., abnormally prolonged or 
shortened QTc interval) in the investigator’s judgment 
 
Current presence of bipolar disorder or other clinically significant major psychiatric 
disorder according to the Diagnostic and Statistical Manual of Mental Disorders IV 
(DSM-IV)-TR or symptom (e.g., hallucinations, agitation, paranoia) that could affect 
the participant’s ability to complete evaluations  
– 
Recorded as an adverse event if diagnosed after study enrollment 
 
Clinically significant depression, based in part by a GDS (short form) 
(15-point scale) score  9 at screening 
 
History of seizures (excluding febrile seizures of childhood, or other isolated 
seizure episodes that were not due to epilepsy in the judgment of the investigator, 
and required at most time-limited anticonvulsant treatment, and which occurred 
more than 7 years prior to the screening visit) 
 
Myocardial infarction within 2 years, congestive heart failure, atrial fibrillation, or 
uncontrolled hypertension 
 
Female participants who are pregnant or intend to become pregnant during the 
conduct of this trial 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
64/Protocol GN28352, Version 11 
 
Female participants who are nursing infants or intend to nurse infants during the 
conduct of this trial  
 
History of cancer within 5 years with the exception of basal cell carcinoma, 
squamous cell cancer of the skin that has been previously excised with clean 
margins, or any cancer that is not actively being treated with anti-cancer drugs or 
radiotherapy, as well as cancers that are considered to have a low probability of 
recurrence (with supporting documentation of this from the treating oncologist if 
possible)  
 
Clinically significant infection within the last 30 days prior to screening 
(e.g., chronic, persistent, or acute infection [e.g., upper respiratory infection, urinary 
tract infection]) 
 
Brain MRI imaging results at baseline showing any of the following:   
– 
Evidence of any ARIA-E (cerebral VE, sulcal effusion), infection, significant 
cerebral vascular pathology, clinically significant lacunar infarct in a region 
important for cognition or multiple lacunes or a cortical infarct or focal lesions 
of clinical significance 
– 
More than 4 cerebral microhemorrhages (lesions with diameter  10 mm), 
regardless of their anatomical location or diagnostic characterization as 
"possible" or “definite” 
– 
Single area of superficial siderosis of the CNS or evidence of a prior cerebral 
macrohemorrhage (lesion with diameter  0 mm) 
 
Clinically significant screening blood or urine laboratory abnormalities requiring 
further evaluation or treatment, including the following: 
– 
Impaired hepatic function, as indicated by transaminases  2  the upper limit 
of normal (ULN) or abnormalities in synthetic function tests judged by the 
investigator to be clinically significant 
– 
Impaired coagulation (aPTT  1.2  ULN) 
– 
Platelet count  100,000/L 
– 
Glycosylated hemoglobin (HbA1c)  8.0% 
 
Positive urine test for drugs of abuse at screening 
– 
One additional screening may be performed; a positive test (except for 
cannabinoids) will result in exclusion (see Section 4.5.2).  Results of 
cannabinoid assays will not be used for the determination of eligibility. 
 
History of alcohol or substance dependence within the previous 2 years 
(DSM-IV TR criteria) 
 
Use of any other medications with the potential to significantly affect cognition 
(including but not limited to, sedatives, narcotics [e.g., opiates/opioids], hypnotics, 
over-the-counter [OTC] sleeping aids, sedating anti-allergy medications) 
– 
Intermittent or short-term use of these medications may be allowed if deemed 
medically necessary for the treatment of a non-excluded medical condition 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
65/Protocol GN28352, Version 11 
with approval from the Medical Monitor (see Section 4.4.1.2 for additional 
details).  In addition, use of tricyclic antidepressants or benzodiazepines will 
be permitted if used in stable, low doses for the treatment of a non-excluded 
medical condition with approval from the Medical Monitor (see Section 4.4 for 
additional details). 
 
Use of typical anti-psychotics or barbiturates 
 
Use of non-anti-cholinergic antidepressant medications or atypical anti-psychotics 
unless maintained on a stable dose regimen for at least 6 weeks prior to screening  
 
Use of any FDA/Instituto Nacional de Vigilancia de Medicamentos y Alimentos 
(INVIMA)-approved medications for treatment of LOAD at screening/baseline 
– 
Cholinesterase inhibitors and/or memantine are prohibited during the study 
except in participants enrolled in the study who develop AD dementia.  
These participants will be permitted to take approved AD treatments 
(cholinesterase inhibitors and/or memantine). 
 
Use of anti-coagulant medication (e.g., heparanoids, heparin, warfarin, thrombin 
inhibitors, Factor Xa inhibitors), or known coagulopathy or platelet count 
 100,000 cells/L within 4 weeks of the screening visit 
– 
Documentation required for normal PT, PTT, and INR during screening for 
discontinued anti-coagulants 
– 
Anti-platelet medications (e.g., aspirin, clopidigrel, dipyridamole) are permitted 
if on a stable dose for 4 or more weeks prior to screening 
– 
Short-term, peri-operative use of anti-coagulants may not result in 
discontinuation from the study; however, any such use must be discussed with 
the Medical Monitor 
 
Treatment with any biologic therapy within 5 half-lives or 3 months prior to 
screening, whichever is longer, with the exception of routinely recommended 
vaccinations, which are allowed 
 
Use of anti-seizure medication (except in childhood for febrile seizures or if used 
for non-seizure indications), anti-Parkinsonian, or stimulant (e.g., methylphenidate) 
medications 
 
Use of investigational drug, device, or experimental medication within 60 days 
(or 5 half-lives, whichever is longer) of the screening visit 
 
Previous treatment with crenezumab (MABT5102A) or any other therapeutic that 
targets A 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins 
 
Contraindication to MRI scan procedures, possibly including, but not limited to, the 
following: 
– 
Pacemakers, implantable cardioverter defibrillators, cochlear implants, 
cerebral aneurysm clips, implanted infusion pumps, implanted nerve 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
66/Protocol GN28352, Version 11 
stimulators, metallic splinters in the eye, other magnetic, electronic, or 
mechanical implants; metal fragments or foreign objects in the skin or body 
– 
Clinically significant claustrophobia that would contraindicate a brain MRI scan 
– 
Clinical history or examination finding that, in the judgment of the investigator, 
would pose a potential hazard in combination with MRI 
 
Contraindication to PET scan procedures, possibly including, but not limited to, the 
following:   
– 
Current or recent (within 12 months prior to screening) participation in studies 
involving radioactive agents, such that the total research-related radiation 
dose to the participant in any given year would exceed the limits set forth in 
the U.S. Code of Federal Regulations (CFR) Title 21 Section 361.1 
(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=
361.1) 
 
Abnormal findings that, in the opinion of the investigator, may affect the 
participant’s response to the radiopharmaceutical and related testing procedures 
required for PET scans 
 
Unable to read and write in Spanish 
 
Any other clinical contraindications for safety or participation in lumbar punctures 
(optional) at the clinical judgment of the investigator 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Both PSEN1 E280A mutation carriers and non-carriers are being enrolled.  The majority 
of individuals in the PSEN1 E280A kindred from Colombia do not wish to know their 
PSEN1 genotype.  In most cases, the participant will not know whether he or she is a 
mutation carrier or a non-carrier.  Participants who have their mutation carrier status 
disclosed by a physician in conjunction with genetic counseling outside of the auspices 
of this study and are mutation carriers will be eligible for the study.  Genetic disclosure 
performed independent of this study is not required for a mutation carrier to be eligible 
to participate.  Non-carriers who receive information about their genetic status prior to 
the study will not be included.  In view of methods being used to balance groups at 
enrollment, some otherwise potentially eligible participants may not be included in the 
study.  In cases of genetic disclosure performed independent of this study, some 
otherwise potentially eligible non-carriers may also not be included in the study. 
Participants, blinded study personnel, and the Sponsor will not know if a participant has 
been assigned to the active treatment or one of the two placebo treatment groups in 
Study Period A.  In Study Period B, participants and blinded study personnel will 
continue to be blinded to treatment assignment (following database lock for 
Study Period A, selected members of the Sponsor team may become unblinded for the 
purpose of analysis and interpretation of the Period A data). 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
67/Protocol GN28352, Version 11 
In Study Period A, a dynamic randomization design will be used with treatment 
allocation assigned by the IxRS vendor.  Mutation carriers will be randomized to 
crenezumab and placebo arms in a 1:1 ratio.  A smaller group of mutation non-carriers 
will be assigned to placebo to conduct the study, such that ADAD family members are 
not required to receive information about their genetic risk and to help distinguish those 
changes related to the predisposition to AD from those associated with normal aging in 
the two placebo groups (in Study Period B, all carrier participants will be assigned 
crenezumab by the IxRS vendor and non-carrier participants will be assigned placebo). 
While PK samples should be collected from participants assigned to the placebo arms 
to maintain the blinding of treatment assignment, PK assay results for these participants 
are generally not needed for the safe conduct or proper interpretation of this trial.  
A defined set of personnel responsible for performing PK assays and not otherwise 
involved in the conduct of the trial will be unblinded to participants’ treatment 
assignments to identify appropriate PK samples to be analyzed.  Samples from 
participants assigned to the placebo arms will not be analyzed except by request 
(i.e., to evaluate a possible error in dosing).  In addition, PK and plasma PD assay 
results will not be released to blinded personnel until the study is unblinded. 
If unblinding is necessary for participant management (e.g., in the case of an serious 
adverse event for which participant management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  Treatment codes should not be broken except in emergency 
situations.  If the investigator wishes to know the identity of the study drug for any other 
reason, he or she should contact the Medical Monitor directly.  The investigator should 
document and provide an explanation for any premature unblinding 
(e.g., accidental unblinding, unblinding due to an serious adverse event). 
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected, and suspected 
adverse reactions that are considered by the investigator or Sponsor to be related to 
study drug. 
4.3 
STUDY TREATMENT 
4.3.1 
Crenezumab and Placebo 
4.3.1.1 
Formulation 
Crenezumab is produced using Chinese hamster ovary cells—purified and formulated.  
It is subjected to a series of quality-control tests to confirm its identity, purity, potency, 
quality, and sterility.  The drug product is a sterile, preservative-free liquid intended for 
SC or IV administration and is formulated as 180 mg/mL crenezumab in 200 mM 
arginine succinate, 0.05% (w/v) polysorbate 20, pH 5.5.  Placebo will consist of the 
same formulation but without the active drug.  Placebo and active drug are supplied in 
6-mL glass vials, with 4 mL of liquid per vial. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
68/Protocol GN28352, Version 11 
For further details, see the Crenezumab Investigator’s Brochure and the 
Study GN28352 pharmacy manual. 
4.3.1.2 
Dosage, Administration, and Storage 
Crenezumab will be administered to participants under close medical supervision in a 
setting with access to appropriate emergency equipment and staff who are trained to 
monitor and respond to medical emergencies.   
Subcutaneous dosing:  Crenezumab has been formulated for SC injection, and no 
dilution of the drug product or placebo is necessary prior to administration. 
Administration:  Study drug will be administered SC into the back of the arm, the thigh, 
or the abdomen via polypropylene syringe.  The total volume of drug will be 2  2.0 mL 
(2  360 mg), administered in 2 injections.  Vital signs will be measured prior to the 
injection.  Study participants will be observed for a minimum of 30 minutes following the 
first 4 administrations of study drug (180 mg/mL formulation) and for a minimum of 
15 minutes subsequently. 
Intravenous dosing:  IV infusions will be administered by appropriately trained staff in 
the clinic. 
The IV drug or placebo will be prepared and infused from the IV bag by infusion pump.  
The bag size, drug preparation, and infusion rates are all described in the pharmacy 
manual guidance.  For the IV dose calculation, the participant’s weight should be used.  
If the current weight changes by  10% from the previous reference weight, the current 
weight should become the new reference weight for subsequent dosing.  If the 
participant’s weight changes again by  10% from the reference weight, the IV dose 
should again be recalculated.  See the pharmacy manual for further information. 
Administration:  Vital signs will be measured just prior to study drug administration, at 
the end of the IV infusion, and  60 minutes after the end of the infusion. 
Study participants will be observed for a minimum of 60 minutes following IV 
administration of study drug. 
Participants who experience a moderate IRR (e.g., fever or chills) should have the 
infusion stopped immediately and should receive aggressive symptomatic treatment.  
The infusion should not be restarted before all symptoms have disappeared, and then it 
should be restarted at half the initial rate. 
Participants who experience serious or severe hypersensitivity reactions 
(e.g., hypotension, mucosal involvement) should not receive additional study drug.  
In addition, in any case of anaphylaxis, anaphylactoid reaction, serious or severe 
hypersensitivity reaction, ADA and concurrent PK samples should be collected as close 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
69/Protocol GN28352, Version 11 
as possible to the event, and then at 4 and 16 weeks postdose (see the study 
flowcharts for further details). 
Collection of all relevant clinical data, including vital signs, any change to infusion 
speeds, etc., should be recorded on the eCRF.  
Storage:  Vials of study drug should be refrigerated at 2°C–8°C and protected from 
direct sunlight.  Vials should not be frozen or stored at room temperature.  
Additional storage details are provided in the pharmacy manual.  The pharmacy manual 
addresses procedures for temperature excursions.  
4.3.1.3 
Dosage Modification 
Participants with a serious, life-threatening adverse event or who meet the criteria for 
dose discontinuation in Section 3.5.4 must not receive additional doses of study drug 
(crenezumab or placebo) but will be invited to, and should, remain in the study and 
complete study assessments per the protocol (see the study flowcharts in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4) if this is deemed to be safe and clinically 
appropriate by the investigator.  
Participants who experience serious or severe hypersensitivity reactions 
(e.g., hypotension, mucosal involvement) should not receive additional study drug.  
In addition, in any case of anaphylaxis, anaphylactoid reaction, serious or severe 
hypersensitivity reaction, ADA and concurrent PK samples should be collected as close 
as possible to the event, and then at 4 and 16 weeks postdose (see the study 
flowcharts for further details). 
Study drug will be held for participants experiencing other clinically significant 
neurologic deterioration attributed to the study drug, as judged by the investigator, or 
other adverse events (including ARIA-E is associated with neurologic symptoms or if 
BGTS  4, without symptoms).  Status will be assessed by MRI follow-up every 4 weeks 
until symptoms and ARIA-E resolve.  Reintroduce study drug and perform an MRI scan 
after 4 weeks of dosing.  If no new ARIA-E is detected, resume MRI monitoring as per 
study flowcharts.  
Any new onset of ARIA-E:  Treat the same as the first event, on the basis of symptoms 
and BGTS.  However, in the case where a participant is diagnosed with three recurrent, 
symptomatic ARIA-E events or exacerbations of previous events, permanently 
discontinue the study drug.  Implement monthly MRI monitoring until resolution of both 
symptoms and ARIA-E. 
ARIA-H 
Dose reduction:  Participants who develop   8 ARIA-H cumulatively will receive a lower 
dose of the study drug.  Cumulative is the sum of ARIA-H at baseline and newly 
detected ARIA-H during the study. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
70/Protocol GN28352, Version 11 
Study drug discontinuation:  Participants who develop  10 ARIA-H deposition 
cumulatively will be permanently discontinued from the study drug.  Cumulative is the 
sum of ARIA-H at baseline and newly detected ARIA-H during the study. 
The participant will be invited to remain in the study and complete study assessments 
per the protocol.  All such cases should be discussed with the Medical Monitor.  
4.3.2 
PET Tracers 
All patients that are enrolled using PET amyloid evaluation and those in the optional tau 
PET substudy will be assessed using appropriate PET ligands. 
Details of the optional tau PET substudy are described in a separate protocol. 
Those participants who have participated in the tau PET substudy (Study BN40199) 
as part of Study GN28352 are eligible to have an optional tau PET scan performed in 
Study Period B (see Section 4.5.1.13).  A separate consent signature is required for this 
optional assessment. 
The florbetapir and GTP1 PET ligands used in the context of this study (and the 
associated substudy) have been designated as investigational products. 
For information on the safety profile (reference safety information) of and reporting 
requirements for the PET ligands administered in this study (and the associated 
substudy), please see Section 5.7. 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES  
4.4.1 
Concomitant Therapy 
Concomitant therapy includes any prescription medications or OTC preparations being 
taken by a participant at any time from screening through the last study visit.  
All concomitant medications should be reported to the investigator and recorded in the 
eCRF.  The following is a list of medications that are permitted, permitted under special 
circumstances with Medical Monitor approval, and prohibited therapies.  
4.4.1.1 
Permitted Therapies 
The following are permitted therapies: 
 
Stable doses of maintenance medications except for medications that may 
significantly affect cognition (see below)  
 
During the study, any treatment deemed necessary by the investigator for the 
management of a participant’s disease, with the following exception: 
Participants requiring initiation of excluded therapies may not be able to receive 
further doses of study drug if initiation of the excluded medication increases the 
risk of receiving study drug (such as anticoagulants). 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
71/Protocol GN28352, Version 11 
 
Non-tricyclic antidepressants (including trazodone, selective serotonin reuptake 
inhibitors, and serotonin norepinephrine reuptake inhibitors), benzodiazepines, and 
atypical anti-psychotic medications if the participant is on a stable dose regimen for 
at least 6 weeks prior to screening   
Initiation during the trial is permitted if necessary to treat an adverse event and 
is expected to have stable dose regimen for at least 6 weeks prior to any 
cognitive and functional assessments. 
 
Short- or intermediate-acting benzodiazepines for the mandatory MRI procedure 
and the amyloid PET scan if the participant requires it 
Some of the imaging data (e.g., functional MRI data) would be excluded from 
relevant exploratory analyses. 
 
OTC stimulants such as caffeine, nicotine, and those found in cold and flu 
preparations (e.g., pseudoephedrine)  
 
Anti-platelet therapies during study conduct if the dose and dose regimen have 
been stable for 4 or more weeks prior to screening and are expected to remain 
stable after screening  
Initiation of antiplatelet therapy during the trial is permitted if needed to treat an 
adverse event. 
 
4.4.1.2 
Permitted Therapies under Special Circumstances 
(Requires Medical Monitor Approval) 
 
The following are permitted therapies under special circumstance and require 
Medical Monitor approval: 
– 
Short-term or intermittent use of medications that may significantly affect 
cognition (including but not limited to, sedatives, narcotics 
[e.g., opiates/opioids], hypnotics, anti-psychotic medications, OTC sleeping 
aids, sedating anti-allergy medications)  
These medications should, if possible, be suspended for 2 days or 
5 half-lives, whichever is longer, prior to any cognitive assessment, FDG-PET 
scan, or MRI scan. 
 
Anti-cholinergic antidepressants, such as tricyclic antidepressants, and 
benzodiazepines, only if used at low doses that are stable for at least 6 weeks prior 
to screening, and if deemed medically necessary for the treatment of a 
non-excluded medical condition 
 
Non-sedating anti-seizure drugs (e.g., pregabalin) use for a non-seizure indication  
 
Anticoagulation therapy (e.g., temporary usage during surgery, for treatment of 
deep vein thrombosis) 
In these circumstances, appropriate safety assessments should be made if 
occurring prior to a lumbar puncture.  The investigator should discuss with the 
Medical Monitor all individual participant cases that require anticoagulant 
therapy. 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
72/Protocol GN28352, Version 11 
4.4.1.3 
Prohibited Therapies 
The following are prohibited therapies: 
 
Typical anti-psychotic medications  
 
Barbiturates 
 
Anti-seizure medication for seizure indication   
Non-sedating anti-seizure drugs (e.g., pregabalin) use for non-seizure indication 
are permitted with Medical Monitor approval.  
 
Anti-Parkinsonian medications  
 
Prescription stimulant medications (e.g. methylphenidate, 
dextroamphetamine, etc.) 
Over-the-counter stimulants, such as caffeine, nicotine, and those found in cold 
and flu preparations (e.g., pseudoephedrine), are allowed. 
 
Long term use of anticoagulants   
 
Cholinesterase inhibitors and/or memantine, with the following exception: 
Participants enrolled in the study who develop AD dementia will be permitted to 
take approved AD treatments (cholinesterase inhibitors and/or memantine). 
 
During the study, participants will be permitted to receive any treatment deemed 
necessary by the investigator for the management of their disease.  
However, participants requiring commencement of excluded therapies may not be able 
to receive further doses of study drug if initiation of the excluded medication increases 
the risk of receiving study drug (such as anticoagulants).  Participants who are 
withdrawn from study drug during Study Period A will be invited to continue to be 
followed at the evaluation visits for safety, clinical and biomarker assessments, selected 
PK, exploratory PD, and ADA status, as specified in the study flowchart 
(see Appendix 1, Appendix 2, Appendix 3, and Appendix 4).  
4.5 
STUDY ASSESSMENTS 
4.5.1 
Definitions of Study Assessments 
4.5.1.1 
Vital Signs 
Vital signs will include measurements of heart rate, respiratory rate, temperature, and 
systolic and diastolic blood pressure while the participant has been supine for 
 3 minutes.  In addition, height should be obtained only at screening.  Weight should 
be obtained at screening and at weeks indicated on the appropriate study flowchart or 
early termination (ET).  On dosing days, record vital signs prior to the SC injection.  
For IV administration, vital signs will be measured just prior to study drug 
administration, at the end of the IV infusion, and  60 minutes after the end of infusion. 
4.5.1.2 
Physical Examination 
A complete physical examination should include an evaluation of the head, eye, ear, 
nose, throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, and 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
73/Protocol GN28352, Version 11 
gastrointestinal systems.  Changes from baseline abnormalities should be recorded at 
each subsequent physical examination.  New or worsened abnormalities should be 
recorded as adverse events if considered clinically significant in the investigator’s 
judgment. 
4.5.1.3 
Neurological Examination 
A complete neurological examination should include the evaluation of consciousness, 
cranial nerves, motor and sensory system, coordination and gait, and reflexes.  
Changes from baseline abnormalities should be recorded at each subsequent 
neurological examination.  New or worsened abnormalities should be recorded as 
adverse events if considered clinically significant in the investigator’s judgment. 
4.5.1.4 
Electrocardiogram 
To minimize variability in autonomic tone and heart rate, it is important that participants 
are resting quietly and in a supine position prior to recording ECGs.  Blood draws and 
other procedures should be avoided during the period immediately before ECG 
measurement, and activity should be controlled as much as possible to minimize 
variability due to the effects of physiologic stress.  If possible, ECGs should be recorded 
on the same type of machine for each site involved in the study, and the same machine 
should be used for all ECGs for a specific participant.  For safety monitoring purposes, 
the investigator must review, sign, and date all ECG tracings.  Two paper copies of 
ECG tracings will be kept as part of the participant's permanent study file at the site for 
all timepoints.  Single ECGs for only baseline, Week 4, and Week 12 should be 
submitted to the ECG vendor for all participants. 
In an optional substudy, participants will have an additional ECG assessment prior to 
dosing at the Week 16 visit and 7 days ( 3 days) following the Week 16 study drug 
administration in order to collect ECG results at steady state peak and Ctrough, ss drug 
levels.  Triplicate ECGs at baseline (two additional than for non-substudy participants), 
Week 16, and Week 17 will be submitted to the ECG vendor for all substudy 
participants, in addition to submitting the single ECG from Weeks 4 and 12.  Two paper 
copies of ECG tracings will be kept as part of the participant's permanent study file at 
the site.  Please refer to the ECG vendor manual for additional details. 
During this substudy, each ECG assessment was to be accompanied by additional PK, 
PD, and exploratory plasma, serum, and RNA blood samples as well as vital signs 
(blood pressure, heart rate, respiratory rate) after the ECG assessment 
(see Appendix 1 [SC]) for additional details). 
4.5.1.5 
Pharmacokinetic Assessments 
At specified timepoints, blood or (optional) CSF samples will be collected for 
measurement of serum or CSF crenezumab concentrations.  On dosing days, PK blood 
samples will be collected prior to study drug administration unless otherwise specified. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
74/Protocol GN28352, Version 11 
4.5.1.6 
Pharmacodynamic Assessments 
Blood samples will be collected from all participants at baseline and other timepoints for 
determination of plasma total A140 and total A142 levels as a measure of PD 
response to crenezumab treatment.  On dosing days, blood samples will be collected 
prior to study drug administration unless otherwise specified.   
4.5.1.7 
Laboratory Assessments 
Samples for the following laboratory tests will be collected for analysis per the study 
flowcharts (see Appendix 1, Appendix 2, Appendix 3, and Appendix 4): 
 
Urine samples and blood samples will be obtained for screening and/or clinical 
safety laboratory tests, including hematology, serum chemistry, and urinalysis 
– 
Urinalysis:  pH, protein, glucose, ketones, bilirubin, blood, specific gravity, 
leukocyte esterase, urobilinogen, and nitrite, as well as microscopic analysis 
on the basis of dipstick results 
– 
Urine test for drugs of abuse, including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opioids 
– 
Urine pregnancy test (for all female participants of childbearing potential 
unless documented by medical records or physician’s note to be surgically 
sterile or postmenopausal as defined in Section 3.5.5) prior to study drug 
administration and PET scans unless there are 2 PET scans in 1 day 
 
Blood samples will be obtained in the fasting state at screening only.  The tests will 
be performed by a central laboratory and will include the following: 
– 
Hematology:  hematocrit, hemoglobin, RBC count, and WBC count with 
differential and platelets  
– 
Serum chemistry:  sodium, potassium, BUN, bicarbonate, estimated 
glomerular filtration rate, calcium, AST, ALT, -glutamyl transpeptidase, total 
and direct bilirubin, alkaline phosphatase, lactate dehydrogenase, total protein, 
albumin, glucose, cholesterol, triglycerides, uric acid, creatine phosphokinase, 
HbA1c, and, at screening only, vitamin B12, ultrasensitive TSH, and thyroxine 
– 
Coagulation:  aPTT and INR 
– 
Serum -human chorionic gonadotropin (-hCG) pregnancy test for all female 
participants of childbearing potential unless documented by medical records or 
physician’s note to be surgically sterile or postmenopausal (defined in 
Section 3.5.5) will be performed at screening and to confirm a positive urine 
pregnancy test during the trial 
 
All laboratory abnormalities assessed as clinically significant by the investigator 
should be reported as adverse events (Section 5.3.1.4). 
 
All participants with clinically significant abnormal laboratory values will be followed 
until the event is resolved or stabilized, the participant is lost to follow-up, or it has 
been determined that the study treatment or participation is not the cause of the 
event 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
75/Protocol GN28352, Version 11 
4.5.1.8 
Immunogenicity Sampling  
Blood samples will be collected to assess the possible development of ADAs in all 
participants as noted in the Study Flowchart (see Appendix 1, Appendix 2, Appendix 3, 
and Appendix 4) and in case of anaphylaxis, anaphylactoid, or serious hypersensitivity 
reactions.  In addition, for any participant suspected of developing anaphylaxis, 
anaphylactoid, or serious hypersensitivity reactions warranting discontinuation of 
dosing, an ADA sample and a concurrent PK sample must be collected as close as 
possible to the event, and then at the 4-week end of treatment visit and at the 16-week 
safety follow-up visit after the final dose.  Serum samples will be analyzed for antibodies 
to crenezumab using a bridging ELISA.  Samples may be tested for antibodies against 
other drug product substances. 
4.5.1.9 
Exploratory Blood Biomarker Assessments 
Additional plasma, serum, and RNA samples will be collected from all participants at 
baseline and other timepoints to enable exploratory analysis of biomarkers, their 
response to crenezumab, and their association with clinical efficacy.  These biomarkers 
may include proteins of the amyloid pathway, inflammatory mediators, and other 
markers associated with the pathophysiology of AD.  On dosing days, blood samples 
will be collected prior to study drug administration unless otherwise specified. 
4.5.1.10 
Blood Sample for Exploratory Genetic Assessments 
Blood samples will be collected from participants for exploratory studies conducted by 
the investigators conducting this study and as a resource to other investigators in the 
scientific community.  Samples may be used during this trial and up to 15 years after 
study results are reported to help improve the early detection and/or tracking of AD; to 
improve the understanding of the biology of AD and related disorders; for 
pharmacogenetic purposes; to help in the discovery of new treatments; and/or to 
provide a resource for genome-wide association, sequencing, epigenetic, and gene 
expression studies. 
4.5.1.11 
Genetic Sampling of ADAD and APOE Genotype 
A blood sample will be collected from all participants at screening, and ADAD mutation 
and APOE genotyping will be performed prior to randomization.  
4.5.1.12 
Lumbar Puncture 
Participation in the CSF Substudy is optional.  If the participant chooses to participate in 
this substudy, CSF levels of A142, total tau, ptau-181, and other CSF biomarkers will 
be assessed to evaluate the treatment effect of crenezumab on these markers. 
4.5.1.13 
lmaging Assessments 
Radiologic evaluation will be performed using a standardized MRI protocol at screening 
and for safety and efficacy assessments.  The data acquisition protocol includes pulse 
sequences for use in clinical safety evaluation performed by a central reading facility.  
It also includes pulse sequences for secondary and exploratory efficacy analyses and 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
76/Protocol GN28352, Version 11 
for future use by members of the research community.  Dosing will not be withheld if 
MRI scans are delayed or missed in the case where no new or unexplained 
neurological symptoms are present as confirmed by the treating clinician via standard 
medical assessments. 
Cerebral amyloid burden and the effect of crenezumab on cerebral amyloid will be 
assessed using 18F florbetapir PET.  Regional CMRgl and the effect of crenezumab on 
regional CMRgl will be assessed using FDG-PET.  The rationale for including 12-week 
FDG-PET measures is to explore short-term changes in glucose metabolism and to 
address potentially confounding effects unrelated to possible target engagement or 
possible slowing of the disease process. 
Use of cannabinoids is prohibited for the 24 hours prior to any FDG-PET scan or MRI 
scan.  
During Study Period B, participants who participated in the tau PET 
Substudy BN40199, which evaluated the effect of crenezumab on tau burden as 
measured by GTP1tau PET in this study population, will have one more assessment 
at Week 105 in Study Period B.  The results of this assessment are expected to help 
understand the effects of crenezumab on the longitudinal progression of tau burden as 
well as the relationship between changes in GTP1tau PET and changes in other 
endpoints. 
As with the [18F]-FDG and [18F]-florbetapir PET scans, GTP1tau PET scans should 
only be performed if the investigator has determined that the total annual radiation 
exposure from all PET and CT scans (including any other scans involving radiation 
that may have been acquired outside of this study) does not exceed local safety 
guidelines.  Radiation exposure for GTP1 doses can be found in the 
GTP1 Investigator’s Brochure.  Radiation exposure for [ 18F]-florbetapir doses can be 
found in the Amyvid U.S. Package Insert (0.019 mSv/MBq whole-body Effective 
Dose).  Radiation exposure for [18F]-FDG can be found in Quinn et al. (2016) 
(7.4 mSv whole-body Effective Dose for a 10 mCi [18F]-FDG dose).  
Available safety data from the initial clinical studies with GTP1 show that exposure to 
GTP1 and imaging procedures are generally well-tolerated.  There have been no 
deaths, no adverse events of special interest, and no hypersensitivity reactions.  
Currently there are no adverse drug reactions identified for GTP1.  Refer to the 
GTP1 Investigator's Brochure for more details of these studies and for a full 
nonclinical evaluation of the tracer and the clinical experience to date. 
The effects of low levels of ionizing radiation on a conceived fetus are unknown; there 
are no known data to suggest there is a risk.  It is recommended, but not required, to 
use effective contraception during sexual intercourse occurring within 24 hours 
following a male or female participant receiving a PET scan. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
77/Protocol GN28352, Version 11 
Specific details about the acquisition, processing, clinical interpretation, and quantitative 
analysis of all imaging exams will be included in the imaging charter.  In addition, each 
modality will have a procedures manual that will be provided to the scanning centers 
with specific instructions for the execution of each imaging examination. 
4.5.1.14 
Cognitive, Functional, and Behavioral Assessments 
In this trial, a number of cognitive, functional, and behavioral assessments will be 
administered; some will be administered only to the participant, some only to the study 
partner, and some to both.  These assessments will be administered by independent, 
blinded raters with either a psychometrician role or a global rater role.  
Suicidality assessments will be performed by a clinician qualified to perform such 
assessments.  The psychometrician and global rater will not have access to study 
results other than those related to the specific assessments they administer.  
The investigator may access any necessary study results needed for the evaluation of 
criteria for MCI/AD dementia. 
All cognitive, functional, and behavioral assessments administered to the participant are 
not to be performed immediately after dosing or any potentially stressful procedures 
(e.g., blood draws, imaging requiring a sedative).  In addition, participants should not 
perform these tests while fasting.  For each participant, best efforts should be made to 
have subsequent cognitive, functional, and behavioral assessments performed at the 
same time of day as the baseline assessments to minimize the effect of diurnal 
variation in cognitive performance.  Best efforts should be made for assessments of a 
given participant or study partner to be administered by the same psychometrician and 
the same global rater at each of the study visits.  This will minimize measurement error 
due to inter-rater variability. 
A Study Partner Characterization Questionnaire (SPCQ) will be completed prior to the 
administration of the study partner assessments at each interaction at which study 
partner assessments are performed.  The study partner must be present at the clinic for 
completion of the study partner assessments at screening and at baseline (Day 1).  
Subsequently, best efforts should be exerted to ensure that the study partner is present 
at all visits requiring study partner assessments.  In rare instances, when the study 
partner cannot be present in person, the study partner-based assessments may be 
administered by telephone (see Section 4.5.4). 
If, during the course of the trial, the investigator determines that the participant has lost 
capacity to provide informed consent to participate in research, the study partner will be 
required to accompany the participant to visits involving the study partner.  It is strongly 
preferred that the designated study partner is the same individual throughout the entire 
study.  However, if the study partner role has been reassigned, and the original study 
partner again becomes available, the role should be reassigned to the original study 
partner.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
78/Protocol GN28352, Version 11 
If a participant is started on prolonged therapy with a permitted medication known to 
affect cognitive function (e.g., antidepressants, atypical antipsychotics) after enrollment 
into the trial, the dose of that medication must be maintained for at least 6 weeks prior 
to the administration of any cognitive assessments.  If a participant is started on a 
short-term therapy with a permitted medication known to affect cognitive function after 
enrollment into the trial, that medication must be stopped 2 days or 5 half-lives, 
whichever is longer, prior to any cognitive, functional, or behavioral assessment.  Use of 
cannabinoids is prohibited for the 24 hours prior to any cognitive assessment.  
The cognitive test batteries include a Screening Battery, the API ADAD Composite 
Cognitive Test Battery, and an Extended Cognitive Battery.  Additional functional and 
behavioral assessments and other self-reported questionnaires will also be 
administered.  
Cutoff scores for some tests may be lower than what is traditionally used in U.S. studies 
because of differences in population demographics.  Assessment scores obtained from 
participants with low levels of education should be interpreted thoughtfully.  
Screening Battery 
The Screening Battery consists of the Word List and the MMSE.  The scores obtained 
on these assessments will be used in determining eligibility. 
API ADAD Composite Cognitive Test Battery 
The API ADAD Composite Cognitive Test Battery was chosen for its sensitivity to 
measure clinical change in this and other at-risk populations after controlling for practice 
effects.  The battery consists of the Word List, Multilingual Naming Test, MMSE, 
CERAD Constructional Praxis; and Raven’s Progressive Matrices. 
Extended Cognitive Test Battery 
The Extended Cognitive Test Battery consists of additional neuropsychological 
assessments that measure verbal and non-verbal episodic memory, executive function, 
psychomotor speed, and other cognitive abilities.  The Extended Cognitive Test Battery 
consists of the FCSRT, the Trail Making Test, and the RBANS. 
Other Assessments 
The following other assessments will be administered to the participant: 
 
SMC 
 
CDR 
 
GDS 
 
Suicidality assessment 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
79/Protocol GN28352, Version 11 
Study Partner Assessments 
The following assessments will be administered to the study partner: 
 
SPCQ 
 
SMC 
 
CDR 
 
NPI 
 
FAST 
 
See Appendix 7 for complete details regarding the neurocognitive, functional, and 
behavioral assessments. 
4.5.1.15 
Clinical Progression 
Ascertainment of AD dementia or MCI progression will be made by the investigator.  
Any ascertainment of AD dementia or MCI progression will be reviewed by an external 
adjudication committee. 
For AD dementia progression ascertainment, the following will be required: 
 
Investigator review of medical history; interview of participant and study partner 
that establishes significant deterioration in the participant’s cognitive and functional 
status since baseline; and review of the following:  CDR, Word List:  Recall, MMSE 
total, RBANS, FAST, and NPI 
– 
Elective review of any other clinical and cognitive test results in rendering this 
judgment (except for the API ADAD Composite Cognitive Test total score or 
the CERAD total score) 
 
Documentation that dementia criteria are met 
 
Agreement by an external adjudication committee that the above criteria have been 
met 
 
For MCI progression ascertainment, the following will be required: 
 
Cognitive concern in the judgment of the investigator, based in part on the average 
SMC score  22 (average of participant and study partner component scores) 
 
Objective evidence of impairment in the judgment of the investigator in one or more 
cognitive domains, on the basis of review of the following:  CDR, Word List:  Recall, 
MMSE total, and RBANS 
– 
Elective review of any other clinical and cognitive test results in rendering this 
judgment (except for the API ADAD Composite Cognitive Test total score or 
the CERAD total score) 
 
Preservation of functional abilities in the judgment of the investigator, based in part 
on review of the FAST 
 
Documentation that MCI criteria have been met 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
80/Protocol GN28352, Version 11 
 
Agreement by an external adjudication committee that the above criteria have 
been met 
 
4.5.1.16 
CDR Progression 
When a change from the prior visit’s global CDR score is recorded, a review of that 
participant’s CDR scoring sheets from that visit will automatically be triggered and 
performed by the CRO responsible for quality assurance of cognitive assessments in 
order to confirm that the total CDR score was derived correctly. 
4.5.1.17 
Medical History 
A complete medical history should include a negative or positive history for risk factors 
for pneumonia, including asthma, chronic obstructive pulmonary disease (COPD), heart 
disease, and smoking; and any other potential risk factor considered significant in the 
investigator’s judgment. 
4.5.2 
Screening and Pretreatment Assessments 
Participants must sign an Informed Consent Form before any screening evaluations or 
measurements are performed.  Participants must satisfy all of the inclusion criteria and 
none of the exclusion criteria prior to randomization.  Information regarding consented 
participants, who are not subsequently randomized, will be kept in a screening log. 
All screening evaluations must be completed within 56 days and reviewed to confirm 
that participants meet all eligibility criteria before the first injection of study drug.  
Informed consent for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations.  Informed Consent Forms for participants 
who are not subsequently enrolled will be maintained at the study site.  In addition, the 
randomization in IxRS will not occur until the participant’s eligibility has been confirmed 
by the Medical Monitor or designated staff.  
Participants who are found to be ineligible for entry into the study, on the basis of 
inclusion/exclusion criteria, will not be re-screened with the following exceptions:  
 
Participants who fail to meet criteria based on TSH levels may be re-screened 
once after initiation of treatment for the underlying disease and maintenance of 
treatment at a stable dose for  1 month prior to Day 1 
 
Participants who fail to meet criteria based on vitamin B12 levels may be 
re-screened once after initiation of treatment for the underlying disease and 
maintenance of treatment at a stable dose for  1 month prior to Day 1 
 
Participants who test positive for drugs of abuse (except cannabinoids) in their 
urine at screening may be re-screened one additional time 
 
Participants who are ineligible because of need for medical treatment of infection or 
need for medical treatment of minor, non-excluded medical condition(s) diagnosed 
during screening, or who have minor but clinically significant blood or urine 
laboratory abnormalities requiring intervention (for example, stopping a 
medication), may be re-screened once, after the condition(s) have stabilized and 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
81/Protocol GN28352, Version 11 
after doses of treatment medications for these condition(s) have been discontinued 
for at least 30 days, or have been stabilized for at least 30 days 
 
Participants who are ineligible because of cognitive screening results may be 
re-screened once, but not earlier than 3 months after the first assessment.  
Screening evaluations must be repeated in these participants.  
Screening, pretreatment tests, and evaluations will be performed within 56 days 
prior to Day 1 of Week 1, unless otherwise specified.  
 
Participants who previously withdrew consent for study participation during the 
screening period, but are otherwise eligible, may be re-screened once but not 
earlier than 3 months after the first assessment.  Screening evaluations must be 
repeated in these participants.  Screening, pretreatment tests, and evaluations will 
be performed within 56 days prior to Day 1 of Week 1, unless otherwise specified. 
 
A participant may be re-screened once, for any of the exceptions just described, at 
which time the exception must be addressed.  Upon screening, if a different exception 
arises, 1 additional re screening is possible, at which time all exceptions must be 
addressed; however, a participant may be re-screened a total of 2 times, at most, for 
the exceptions listed above.  
In addition to this re-screen limit, participants who are ineligible because of 
unavailability of a study partner may be re-screened multiple times to attempt to find an 
available study partner but not earlier than 1 month after the first assessment of the 
most recent screening period.  Screening, pretreatment tests, and evaluations will be 
performed within 56 days prior to Day 1 of Week 1, unless otherwise specified. 
Laboratory testing, cognitive/functional assessments or imaging assessments that are 
repeated for administrative or technical issues (e.g., breakage of a sample vial, not 
evaluable images) are not considered to constitute “re-screening.”  In these cases, the 
screening window may be extended if approved by the Medical Monitor.  
Please see the study flowchart provided in Appendix 1 for the screening and 
pretreatment assessments. 
4.5.3 
Assessments During Treatment 
All assessments will be performed on the day of the specified visit unless a time window 
is specified.  Assessments scheduled on the day of study drug administration should be 
performed prior to study drug injection or infusion, unless otherwise noted.  For SC 
administration, please see the study flowcharts provided in Appendix 1 and Appendix 2 
for the schedule of treatment assessments.  For participants who decide to switch to IV 
dosing, the study flowcharts provided in Appendix 3 and Appendix 4 should be followed, 
starting from the visit when the first IV dose is administered.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
82/Protocol GN28352, Version 11 
4.5.4 
Remote Assessments  
In the case of coronavirus disease 2019 (COVID-19) or similar events where in-person 
assessments are not possible, remote assessments may be allowed (Appendix 1 and 
Appendix 2).  Any assessments that could not be collected remotely should be collected 
in-person as soon as feasible, even if out of the protocol-defined assessment window, 
particularly those related to the primary outcome or safety assessments. 
4.5.5 
Study Completion  
The common-close study design requires that all participants should remain on their 
randomized treatment allocation until the last participant completes their Week 260 visit 
(subject to practical considerations regarding scheduling of final study visits that are 
outlined below).  An end of treatment or ET visit (ET-A or ET-B), including all 
assessments scheduled per study flowchart should be completed at the end of the 
blinded treatment period, 4 weeks after the final dose.  Following the completion of the 
randomized, placebo-controlled, double-blinded treatment period in Study Period A, 
participants will be offered the opportunity to continue to receive study drug until the 
results of the study are known and post-trial access to crenezumab is started (via an 
OLE or other program) or development of crenezumab is discontinued.  For participants 
who do not choose to continue study drug in Study Period B, a final safety follow-up 
visit will be completed 16 weeks after the final dose. 
In order to minimize site burden and to facilitate scheduling, sites will be notified at least 
4 months prior to the date of the common close and as such will be able to utilize 
upcoming planned visits to schedule the study completion assessments.  
Participants who enrolled early in the study and have been in the study longer should 
have their study completion visits scheduled earlier where possible.  The Sponsor will 
provide guidance to sites to facilitate scheduling when they are notified that the end of 
study is approaching. 
Please see the study flowchart provided in Appendix 2 or Appendix 4 for assessments 
to be performed at the study completion visit (ET-A or ET-B) and the safety follow-up 
visit. 
4.5.6 
Early Termination Visit 
Participants who discontinue from blinded treatment prior to completion 
of Study Period A (early treatment discontinuation) will be asked to stay in the study for 
continued safety and efficacy assessments at selected evaluation visits following 
completion of an ET visit (see study flowchart in Appendix 1, Appendix 2, Appendix 3, 
and Appendix 4).  Participants who discontinue from the study (ET), or who discontinue 
from blinded treatment and elect to no longer remain in the study, will be asked to 
return to the clinic for an ET visit (see the study flowchart in Appendix 2 for participants 
receiving SC study drug and Appendix 4 for participants receiving IV study drug).  
The ET visit should be 4 weeks from last dose.  In addition, a final safety follow-up visit 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
83/Protocol GN28352, Version 11 
should be completed 16 weeks after last dose to ensure adequate washout of study 
drug but may be scheduled sooner if needed. 
Please see the study flowchart provided in Appendix 2 or Appendix 4 for assessments 
to be performed at the study completion/ET visit. 
Participants that are study drug non-compliant may be withdrawn from study treatment.  
As standard guidance, this refers to the following:  Participant misses more than 
2 doses within a single, 6-month period; a one-time exception of 3 missed doses within 
a 6-month period will be allowed.  In rare circumstances (e.g., hospitalization), the 
Medical Monitor has the discretion to allow additional missed doses. 
In order to maximize the opportunity for all active trial participants to receive the higher 
dose (60 mg/kg IV) of study drug, participants who have withdrawn from study 
treatment in Study Period A, but remain in the study for safety and efficacy 
assessments will be permitted a one-time opportunity to return to the study and to 
receive the higher IV dose, provided they did not discontinue treatment due to an 
adverse event related to study drug, the investigator judges it is safe to restart study 
drug, and the participant consents to receive IV administration of study drug going 
forward.  If the participant has not completed a complex visit within 6 months of 
restarting study drug, a complex visit should be completed prior to reinitiating study 
drug.  The investigator may also order unscheduled laboratory assessments as 
necessary to ensure safety and appropriateness to resume study drug. 
If a participant discontinues from the study (ET) or discontinues from study drug 
treatment and elects to no longer stay in the study, ET Visit A should be completed if 
the last visit occurred more than 12 weeks after functional, behavioral and cognitive 
assessments were performed; ET Visit B should be performed if the last visit occurred 
within 12 weeks of functional, behavioral and cognitive assessments.  The final safety 
follow-up visit should be scheduled 16 weeks from last dose. 
Study Period B:  If a participant enters Study Period B, but wishes to stop study 
treatment before the end of Study Period B, a safety follow-up visit should be completed 
16 weeks from the last dose. 
4.5.7 
Follow-Up Assessments 
Participants who complete the treatment phase of the study will return to the clinic for 
an end of treatment visit 4 weeks after the last dose (ET-A or ET-B).  Following the 
completion of Study Period A, participants will be offered the opportunity to continue to 
receive study drug until the results of the study are known and post-trial access to 
crenezumab is started (via an OLE or other program) or development of crenezumab is 
discontinued (see Section 4.5.8).  For those participants that do not choose to continue 
study drug in Study Period B, a final safety follow-up visit will occur 16 weeks after the 
last dose (see Appendix 2 or Appendix 4). 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
84/Protocol GN28352, Version 11 
Any adverse event (including a clinically significant laboratory abnormality) that is 
unresolved at the end of the study will continue to be followed until the event is resolved 
or stabilized, the participant is lost to follow up, or it has been determined that the study 
treatment or participation is not the cause of the event.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or study 
procedures until a final outcome can be reported. 
Please see the study flowchart provided in Appendix 2 or Appendix 4 for specified 
follow-up assessments. 
4.5.8 
Study Period B Visits and Assessments 
All assessments will be performed on the day of the specified visit unless a time window 
is specified.  Assessments scheduled on the day of study drug administration should be 
performed prior to study drug injection or infusion, unless otherwise noted.  
Study conduct and procedures during Study Period B are the same as for 
Study Period A (see Section 4.5.1), though the frequency may be different.  For SC 
administration, please see the study flowcharts provided in Appendix 5.  For IV 
administration, please see the study flowchart provided in Appendix 6.  If participants 
terminate participation in Study Period B, or Study Period B is terminated by the 
Sponsor due to discontinuation of the development of crenezumab, or participants 
complete Study Period B and do not enter an OLE or otherwise continue on 
crenezumab, participants will be asked to complete a final safety follow-up visit 
16 weeks after their last dose of study drug (Appendix 5 and Appendix 6).  
4.5.9 
Samples for Roche and Other Clinical Repositories 
4.5.9.1 
Overview of the Biological Sample Repositories 
Blood and CSF samples will be stored at two central sample repositories, the Roche 
Clinical Repository (RCR) and the National Cell Repository for Alzheimer’s Disease 
(NCRAD).  The NCRAD is a national repository funded by the National Institute on 
Aging in the United States.  The RCR and NCRAD are facilities used for the long-term 
storage of human biologic specimens, including body fluids, solid tissues, and 
derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and analysis of 
repository specimens will facilitate the rational design of new pharmaceutical agents 
and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.  Additionally, research on the basis of these samples 
may lead to an enhanced understanding of AD and related disorders. 
Specimens for the biological sample repositories will be collected from participants who 
consent to participate in this study.  Repository specimens may be used to achieve the 
following objectives: 
 
To help improve the early detection of AD 
 
To increase knowledge and understanding of AD biology and risk factors 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
85/Protocol GN28352, Version 11 
 
To provide a resource for genome-wide association, sequencing, epigenetic, and 
gene expression studies related to AD or crenezumab 
 
To develop biomarker or diagnostic assays for AD and related disorders and 
establish the performance characteristics of these assays 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
 
To study drug response, including drug effects and the processes of drug 
absorption and disposition 
 
4.5.9.2 
Future Research 
Within 15 years after the trial is completed, the specimens in the biological sample 
repositories that are collected with the participants’ informed consent will be made 
available for objectives described in Section 4.5.9.1.  The implementation and use of 
the repository specimens is governed by a biological sample oversight committee 
(composed of trial leadership) in accordance with policies and procedures to ensure the 
appropriate use of the specimens.  Sample and data sharing will be prioritized on the 
basis of scientific considerations and in relationship to the volume of samples available.  
Samples may be shared with researchers and laboratories working with Roche, Banner 
Alzheimer’s Institute, and the University of Antioquia.   
4.5.9.3 
Sample Collection 
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers to pursue the objectives described above in Section 4.5.9.1: 
 
Plasma and serum 
 
Whole blood for RNA extraction  
 
CSF 
 
The following samples will be collected for identification of genetic (inherited) 
biomarkers to pursue the objectives described above in in Section 4.5.9.1: 
 
Whole blood for DNA extraction 
 
Leftover blood, serum, plasma, and CSF samples and any derivatives thereof 
(e.g., DNA, RNA, proteins, peptides) will be collected to pursue the objectives described 
above in Section 4.5.9.1. 
Biological sample repository specimens will be stored for 15 years after the final study 
report. 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 6.10.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   

 
Crenezumab—F. Hoffmann-La Roche Ltd 
86/Protocol GN28352, Version 11 
4.5.9.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche and NCRAD have implemented 
additional processes to ensure participant confidentiality for genetic specimens and 
associated data.  Each specimen is "double-coded" by replacing the participant 
identification number with a new independent number.  Data generated from the use of 
these specimens and all clinical data transferred from the clinical database and 
considered relevant are also labeled with this same independent number.  
A "linking key" between the participant identification number and this new independent 
number is stored in a secure database system.  Access to the linking key is restricted to 
authorized individuals and is monitored by audit trail.   
Data generated from RCR and NCRAD specimens must be available for inspection 
upon request by representatives of national and local health authorities, and Roche 
monitors, representatives, and collaborators, as appropriate. 
Participant medical information associated with RCR and NCRAD specimens is 
confidential and may only be disclosed to third parties as permitted by the 
Informed Consent Form (or separate authorization for use and disclosure of personal 
health information) signed by the participant, unless permitted or required by law. 
The aggregate results of any research conducted using repository samples will be 
available in accordance with the effective Roche policy on study data publication except 
where agreed. 
4.5.9.5 
Participation in the RCR and NCRAD 
The investigator or authorized designee will explain to each participant the objectives, 
methods, and potential hazards of contributing samples to the sample repositories.  
Participants will be told that they are free to withdraw their specimens at any time and 
for any reason during the storage period.  A separate, specific signature will be required 
to document a participant’s agreement to provide CSF specimens by signing the 
Optional CSF Substudy Informed Consent. 
In the event of an RCR and NCRAD participant's death or loss of competence, the 
participant's specimens and data will continue to be used as part of the RCR and 
NCRAD research. 
4.5.9.6 
Withdrawal from the RCR and NCRAD 
Participants have the right to withdraw their samples at any time for any reason.  
After withdrawal of consent, any remaining samples will be destroyed or will no longer 
be linked to the participant.  However, if RCR samples have been tested prior to 
withdrawal of consent, results from those tests will remain as part of the overall 
research data.  If a participant wishes to withdraw consent to the testing of his or her 
samples, the investigator must inform the Medical Monitor in writing of the participant’s 
wishes using the Repository Subject Withdrawal Form and, if the trial is ongoing, must 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
87/Protocol GN28352, Version 11 
enter the date of withdrawal on the Repository Research Sample Withdrawal of 
Informed Consent eCRF.  The participant will be provided with instructions on how to 
withdraw consent after the trial is closed.  A participant’s withdrawal from 
Study GN28352 does not, by itself, constitute withdrawal of specimens from the 
repositories.  Likewise, a participant’s withdrawal from the repositories does not 
constitute withdrawal from Study GN28352. 
4.5.9.7 
Monitoring and Oversight 
Repository samples will be tracked in a manner consistent with GCP by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Study monitors and auditors will have direct access to 
appropriate parts of records relating to individual participation in the repositories for the 
purposes of verifying the data provided.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the repository samples. 
4.6 
PARTICIPANT DISCONTINUATION 
Participants may withdraw consent or be withdrawn from the study at any time 
(see criteria below).  Every effort should be made to obtain information on participants 
who discontinue early or are withdrawn from the study (see Section 4.5.6).  If a 
participant withdraws for reasons related to an serious adverse event, every effort will 
be made to follow the participant until resolution or stabilization of the event.  
The reason for withdrawal or early discontinuation should be recorded on the 
appropriate eCRF page.  
Reasons for withdrawal from the study may include, but are not limited to, the following:  
 
Participant withdrawal of consent at any time  
 
Any medical condition that the investigator determines may jeopardize the 
participant’s safety if he or she continues in the study  
 
Investigator determines it is in the best interest of the participant  
 
Participant becomes pregnant  
 
See the Study Flowchart provided in Appendix 1, Appendix 2, Appendix 3, Appendix 4, 
Appendix 5, and Appendix 6 for assessments that are to be performed for participants 
who prematurely withdraw from Study Period A (Appendix 1 to Appendix 4) or 
Study Period B (Appendix 5 and Appendix 6). 
Participants who discontinue from the study will not be allowed to re-enter the study. 
The investigator has the right to discontinue a participant from the study for any medical 
condition that the investigator determines may jeopardize the participant’s safety if he or 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
88/Protocol GN28352, Version 11 
she continues in the study; for reasons of noncompliance (e.g., missed doses, visits); if 
the participant becomes pregnant; or if the investigator determines it is in the best 
interest of the participant. 
4.7 
STUDY DISCONTINUATION 
Roche and Banner Alzheimer’s Institute have the right to terminate this study at any 
time.  Reasons for terminating the study may include, but are not limited to, the 
following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants 
 
Participant enrollment is unsatisfactory 
 
Data recording is inaccurate or incomplete 
 
4.8 
POST-TRIAL ACCESS TO STUDY DRUG 
The Sponsor will offer post-trial access to the study drug (crenezumab) free of charge 
to eligible participants in accordance with the Roche Global Policy on Continued Access 
to Investigational Medicinal Product, as outlined below. 
A participant will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
 
The participant has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the participant 
 
The participant and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
A participant will not be eligible to receive study drug after completing the study if any of 
the following conditions are met: 
 
The study drug is commercially marketed in the participant’s country and is 
reasonably accessible to the participant (e.g., is covered by the participant's 
insurance or wouldn't otherwise create a financial hardship for the participant) 
 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for ADAD 
 
The Sponsor has reasonable safety concerns regarding the study drug as 
treatment for AD or ADAD 
 
Provision of study drug is not permitted under the laws and regulations of the 
participant's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
https://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
89/Protocol GN28352, Version 11 
 
Roche does not have a specific plan to provide crenezumab or other study interventions 
to participants who withdraw from the study early (prior to completion of 
Study Period A).  Participation in, or completion of, Study Period B is not required. 
4.9 
ASSAY METHODS  
 
Total serum levels of crenezumab will be measured using a validated ELISA 
 
ADAs in serum will be measured using a validated bridging ELISA 
 
Total plasma levels of A140 and A142 will be measured using qualified assays 
 
Levels of A142, ptau-181, and total tau will be measured in CSF using qualified 
assays 
 
4.10 
STATISTICAL METHODS 
Analyses planned for Study Period A include the following: 
 
An interim analysis of the cohort of carriers may occur at the Sponsor’s discretion 
 
A primary analysis will occur after all participants have completed the Week 260 
assessment 
 
During Study Period B, safety analyses from Study Period A will be refreshed and 
reported in the final Clinical Study Report (CSR); no other analyses 
(e.g., primary and secondary endpoints and PK/PD endpoints) will be refreshed 
 
If the Sponsor decides to terminate the study based on the primary analysis results 
from Study Period A, all the data and analyses from Study Period B will be considered 
as exploratory in nature; a final CSR will be written, including these extra data.  
A planned data snapshot will occur 2 years after the last efficacy visit in 
Study Period A.  
Sections 4.10.14.10.9 focuses on the analyses for Study Period A. 
4.10.1 
Analysis of the Conduct of the Study 
The number of participants who enroll, discontinue from treatment, discontinue from 
study, and complete the study will be tabulated by treatment group.  Reasons for early 
discontinuation of treatment or ET from the study will be listed and summarized by 
treatment group.  Any eligibility criteria and other major protocol deviations will also be 
summarized by treatment group.  
4.10.2 
Analysis of Treatment Group Comparability 
Demographic and baseline characteristics such as age, sex, race, APOE4 status, and 
baseline cognitive scores will be summarized for all randomized participants by 
treatment group using descriptive statistics. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
90/Protocol GN28352, Version 11 
4.10.3 
Efficacy Analyses 
Primary efficacy analysis for the primary endpoint family in Study Period A will be based 
on a mITT population.  The mITT population is defined as participants who are mutation 
carriers treated with any amount of study drug.  Participants in the efficacy analysis 
population will be grouped based on treatment assigned at randomization. 
Efficacy data from Study Period B will contribute to delayed start analyses and 
time-to-event analyses. 
4.10.3.1 
Primary Efficacy Endpoints 
The primary efficacy analysis will be performed on the mITT population.  The primary 
endpoint family, 1) annualized rate of change on the API ADAD Composite Cognitive 
Test Battery total score and 2) annualized rate of change on the FCSRT Cueing Index, 
will be assessed using a mixed effects (ME) model.  The model will be used to test the 
treatment effect on annualized rate of change adjusting for selected baseline 
characteristics and randomization factors.  Statistical tests for the primary endpoints will 
be two-sided and performed at an overall 0.05 level:    04 for testing the treatment 
effect on the annualized rate of change on the API ADAD Composite Cognitive Test 
Battery total score;   0.01 for testing the treatment effect on the annualized rate of 
change on the FCSRT Cueing Index.  Estimated treatment effects and CIs will also be 
provided as an aid to interpretation of study results. 
In order to maximize the power, data beyond each participant's Week 260 assessment 
through the unblinding of the study will be included in the primary analysis or its 
sensitivity analysis. 
All details of the prespecified statistical analyses for the primary efficacy endpoints will 
be provided in the SAP.  
4.10.3.2 
Secondary Efficacy Endpoints 
The final selection of secondary efficacy endpoints will be on the basis of baseline data 
from the study population, ongoing clinical trials, and other external data that will 
emerge prior to database unblinding.  The selected secondary endpoints will be 
provided in the SAP to be submitted prior to database unblinding.  Secondary endpoints 
will be selected from the following: 
Clinical 
 
Time to progression to MCI due to AD (Albert et al. 2011) or dementia due to AD 
(McKhann et al. 2011) (see Section 4.5.1 for criteria) 
 
Time to progression to non-zero in the CDR global score (Morris 1993) 
 
Annualized rate of change in CDR-SOB (Morris 1993) 
 
Annualized rate of change in a measure of overall neurocognitive functioning:  
RBANS (Randolph 1998) 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
91/Protocol GN28352, Version 11 
Imaging Biomarkers 
 
Annualized rate of change in mean cerebral fibrillar amyloid accumulation using 
florbetapir PET 
 
Annualized rate of change in regional CMRgl using FDG-PET 
 
Annualized rate of change in volumetric measurements using MRI 
 
CSF Biomarkers 
 
Annualized rate of change in a tau-based CSF biomarkers 
 
Imaging biomarkers, CSF biomarkers, and CDR-SOB will be analyzed using 
ME models in the same manner as the primary efficacy outcome measure.  The time to 
progression outcome measures (time to MCI progression and time to non-zero in the 
CDR global score) will be analyzed using survival analysis methods. 
Estimated treatment effects, CIs and p-values will be provided for all selected 
secondary endpoints.  Details of prespecified statistical analyses of the secondary 
efficacy endpoints will be provided in the SAP. 
4.10.4 
Safety Analysis 
The safety analysis population in Study Period A will consist of all carrier participants 
with at least one dose of study medication.  The participants in this population will be 
grouped according to treatment received. 
If the Sponsor decides to initiate an OLE study, safety data from Study Period B will 
also be used to contribute to the safety analysis in the OLE study.  In this case, the 
safety analysis population in Study Period B will be grouped according to the treatment 
received in Study Period B. Safety assessments will be on the basis of adverse event 
reports, the results of vital signs, physical examinations, MRI evaluations, 
immunogenicity as measured by ADAs, and clinical laboratory tests.  
Observed toxicities and adverse events will be coded and tabulated using the MedDRA; 
the frequencies of participants who receive active medication and those who receive 
placebo will be compared using descriptive statistics and reviewed for potential clinical 
significance and importance.  Treatment-emergent adverse event tabulations will be 
provided overall, by severity, for serious adverse events, and further subcategorized by 
relationship to study drug. 
4.10.4.1 
Adverse Events 
Adverse events will be recorded from the time informed consent is given until 16 weeks 
following the last administration of any investigational product, or a participant 
completes the study or discontinues prematurely, whichever occurs last 
(see Section 5.2.1 for details).  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
92/Protocol GN28352, Version 11 
As the study participants are considered treatment-exposed during the 16-week 
(approximately 5 half-lives) follow-up period, adverse events reported within 16 weeks 
after the last dose of study drug administered in Study Period A will be included in 
the safety analyses from Study Period A.  During Study Period B, safety data from 
Study Period A will be refreshed and reported in the final CSR.  Verbatim descriptions 
of adverse events will be coded and analyzed using appropriate thesaurus terms.  
A treatment-emergent adverse event is defined as any adverse event reported on or 
after the first dose of study drug.  
Adverse events occurring during Study Period B, up through 16 weeks after the last 
dose, will be summarized in the final CSR. 
4.10.4.2 
Clinical Laboratory Evaluations  
Clinical laboratory data (serum chemistry, hematology evaluations, including complete 
blood count with differential and platelet counts, and urinalysis values) and ECG data 
will be summarized over time by descriptive statistics by treatment group.  
4.10.4.3 
MRI Evaluations  
Neuroradiologic evaluation with respect to the occurrence of cerebral VE, superficial 
siderosis of the CNS, and cerebral micro- or macrohemorrhages will be performed 
during the treatment period and will be summarized by treatment group using 
descriptive statistics.  
4.10.4.4 
Vital Signs 
Vital signs (pulse rate, blood pressure, body temperature, and respiratory rate) and 
changes from baseline will be summarized by treatment group. 
4.10.4.5 
Electrocardiogram 
Electrocardiogram data and changes from baseline for relevant ECG intervals will be 
summarized by treatment group. 
4.10.4.6 
Anti-Drug Antibodies 
The number and percentage of participants with confirmed positive ADAs will be 
reported for each treatment group. 
4.10.5 
Pharmacokinetic and Pharmacodynamic Analyses 
Mean serum and CSF crenezumab concentration versus time data will be tabulated and 
plotted.  In serum, Ctrough, ss will be tabulated and summarized (e.g., mean, standard 
deviation, minimum, and maximum).  Additional PK analyses may be conducted as 
appropriate. 
Mean plasma total A140 and A142 concentrations versus time will be tabulated 
and plotted.  The relationship between crenezumab and total A140 and A142 
concentrations will be tabulated and plotted to explore the peripheral PK/PD 
relationship.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
93/Protocol GN28352, Version 11 
The schedule for PK and PD analyses will be independent of the safety and efficacy 
endpoints.  
4.10.6 
Exploratory Analyses 
The exploratory efficacy outcome measures (see Section 3.3.5) will be analyzed in a 
similar manner to the secondary efficacy outcome measures.  Details of prespecified 
statistical analyses of the exploratory endpoints will be provided in the SAP. 
4.10.7 
Handling of Missing Data 
All efforts will be made to minimize missing data.  Missing values will not be imputed 
since ME models are robustly capable of handling missing data when data are missing 
at random.  Various sensitivity analyses to support the primary analysis will use 
alternative methods of handling missing values.  Details will be provided in the SAP.  
4.10.8 
Determination of Sample Size 
This study will enroll up to 300 participants:  up to 200 participants will be enrolled in the 
carrier cohort and up to 100 participants will be enrolled in the non-carrier cohort. 
Participants in the carrier cohort will be randomized in a 1:1 randomization ratio of 
active to placebo participants.  The study was originally powered to compare the mean 
change from baseline over 260 weeks in the API ADAD Composite Cognitive Test total 
score between the crenezumab group and the placebo.  Assuming a 25% dropout rate, 
two-sided testing at an overall 0.05 level, a placebo group CV of 65% for the Week 260 
change scores ( 100%  standard deviation of placebo participant change 
scores/mean of placebo participant change scores) and 100 participants per arm, the 
study will have at least 80% power to detect a true effect of 30% reduction of the mean 
decline in the placebo group. 
Participants in the non-carrier cohort will all receive placebo and will be included in the 
study in order to maintain the genotype blind. 
The study was originally powered based on the API ADAD Composite Cognitive Test 
Battery total score.  However, due to concerns about learning effects and general lack 
of sensitivity to change in a cognitively normal population, before study unblinding, the 
Sponsor performed a blinded power analysis on the original primary endpoint 
API ADAD Composite Cognitive Test Battery Total Score and the secondary clinical 
endpoints.  The Sponsor decided to promote the FCSRT Cueing Index from a 
secondary endpoint to part of a primary endpoint family (along with the API ADAD 
Composite) due to its favorable statistical properties and clinical relevance as a 
sensitive measure of episodic memory dysfunctionthe hallmark of emerging 
symptomatic AD and the most commonly observed, early, and consistent 
neuropsychological marker of AD (Tounsi et al. 1999; Bateman et al. 2012; 
Caselli et al. 2020)  In the SAP, the Sponsor will provide details of the blinded power 
analysis along with the evidence of type I error control. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
94/Protocol GN28352, Version 11 
4.10.9 
Interim Analysis 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one or more interim analyses.  Sites are to be informed prior to 
an interim analysis.  Below are the specifications to ensure the study continues to meet 
the highest standards of integrity when an optional interim analysis is executed. 
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim 
analysis will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the 
iDMC Charter.  
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP.  
The iDMC Charter will be updated to document potential recommendations the iDMC 
can make to the Sponsor as a result of the analysis (e.g., stop the study for positive 
efficacy, stop the study for futility), and the iDMC Charter will also be made available to 
relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate of the primary analysis will be controlled to ensure 
statistical validity is maintained.  If the study continues beyond the interim analysis, the 
critical value at the final analysis would be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology. 
4.10.10 
Analyses for Study Period B 
All efficacy analyses will include data from Study Period A and Study Period B.  
The analysis population will be based on mITT population.  The delayed-start efficacy 
analyses and rank-preserving structural failure time analyses will be triggered 2 years 
after the last efficacy visit in Study Period A.  
All the safety analyses described in Section 4.10.4 will be reported.  
Summaries of conduct of study and summaries of treatment group 
comparability/demographics and baseline characteristics will also be presented.  
The population is based on the Study Period B ITT population.  The analyses are 
similar to what are specified for Study Period A and are specified in the SAP. 
Pharmacokinetic and PD analyses will be handled in a similar fashion to 
Study Period A. 
4.11 
DATA QUALITY ASSURANCE 
The data will be collected via Electronic Data Capture (EDC) using eCRFs.  The site will 
be responsible for data entry into the EDC system.  In the event of discrepant data, the 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
95/Protocol GN28352, Version 11 
Sponsor or the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system.   
Banner and Roche will perform oversight of the data management of this trial.  
Roche will produce an EDC Study Specification document that describes the quality 
checking to be performed on the data.  Data from the central laboratory and central 
imaging reader will be sent directly to Roche, using Roche’s standard procedures to 
handle and process the electronic transfer of these data.   
The eCRFs and correction documentation will be maintained in the EDC system’s audit 
trail.  System backups for data stored at Roche and records retention for the study data 
will be consistent with the Roche’s standard procedures.  
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, serious 
adverse events, and adverse events of special interest; measurement of 
protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-specified tests that 
are deemed critical to the safety evaluation of the study drug(s). 
Roche or its designee is responsible for reporting relevant serious adverse events to 
the Competent Authority, other applicable regulatory authorities, and participating 
investigators, in accordance with ICH guidelines, FDA regulations, European Clinical 
Trials Directive (Directive 2001/20/EC), and/or local regulatory requirements. 
Roche or its designee is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the study drug to the regulatory agencies and 
competent authorities by telephone or fax within 7 calendar days after being notified of 
the event.  Roche or its designee will report other relevant serious adverse events 
associated with the use of the study medication to the appropriate competent 
authorities (according to local guidelines), investigators, and central IRBs/ECs 
(except in the United States where investigators are responsible for reporting to their 
IRBs per local requirements) by a written safety report within 15 calendar days of 
notification.   
5.1.1 
Adverse Events 
An adverse event is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational product or other 
protocol-imposed intervention, regardless of attribution.  For this protocol, all products 
not approved for marketing in Colombia will be considered an investigational product.  
This includes PET tracers. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
96/Protocol GN28352, Version 11 
This includes the following: 
 
Adverse events not previously observed in the participant that emerge during the 
protocol-specified adverse event reporting period 
 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies) 
 
Adverse events that occur prior to assignment of the first study investigational 
product (study drug and/or PET ligand) that are related to a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, medication washout, or no 
treatment run-in).  See Section 5.2.1 for reporting requirements for these adverse 
events.  
 
Preexisting medical conditions, other than AD, judged by the investigator to have 
worsened in severity or frequency or changed in character during the 
protocol-specified adverse events reporting period 
 
Unchanged, chronic conditions that are present at baseline are NOT adverse events 
and should not be recorded on the Adverse Event eCRF.  An exacerbation or 
worsening of a chronic condition should be recorded as an adverse event.  
A preexisting condition should be recorded on the General Medical History and 
Baseline Conditions eCRF. 
5.1.2 
Serious Adverse Event 
A serious adverse event is any adverse event that meets any of the following: 
 
Fatal (i.e., the adverse event actually causes or leads to death) 
 
Life-threatening (i.e., the adverse event, in the view of the investigator, places the 
participant at immediate risk of death) 
 
Requires or prolongs inpatient hospitalization 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the participant’s ability to conduct normal life 
functions) 
 
A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product(s) 
 
Considered a significant medical event by the investigator (e.g., may jeopardize the 
participant or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity 
of an adverse event (as in mild, moderate, or severe pain); the event itself may be of 
relatively minor medical significance (such as severe headache).  “Serious” is a 
regulatory definition and is on the basis of participant or event outcome or action criteria 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
97/Protocol GN28352, Version 11 
usually associated with events that pose a threat to a participant’s life or vital functions.  
Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations. 
Severity and seriousness should be independently assessed when recording adverse 
events and serious adverse events on the eCRF. 
5.1.3 
Protocol-Defined Events of Special Interest/Non-Serious 
Expedited Adverse Events  
The following events are events of special interest and will need to be reported to the 
Sponsor expeditiously (i.e., no more than 24 hours after learning of the event; 
see Section 5.4 for reporting instructions), irrespective of regulatory seriousness 
criteria: 
 
ARIA-E (cerebral VE or sulcal effusion) (see Section 3.5.2) 
 
ARIA-H 
– 
Superficial siderosis of the CNS (see Section 3.5.2) 
– 
Cerebral microhemorrhages (see Section 3.5.2)  
 
Macrohemorrhages (see Section 3.5.2) 
 
Occurrence of pneumonia verified by imaging (e.g., chest X-ray) 
(see Section 3.5.3) 
 
The finding of an elevated ALT or AST  3  ULN in combination with either an 
elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis 
or other causes of hyperbilirubinemia is considered to be an indicator of severe 
liver injury.  Therefore, investigators must report as an adverse event cases of 
potential drug-induced liver injury that include the occurrence of either of the 
following: 
– 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
– 
Treatment-emergent ALT or AST  3  ULN in combination with clinical 
jaundice 
 
Suspected transmission of an infectious agent by the investigational product, as 
defined below 
– 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product.  This term applies 
only when a contamination of the study drug is suspected. 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
98/Protocol GN28352, Version 11 
5.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events and serious adverse 
events (as defined in Section 5.1) are recorded on the eCRF and reported to the 
Sponsor in accordance with protocol instructions.  
5.2.1 
Adverse Event Reporting Period 
After informed consent, but prior to the first administration of any of the investigational 
products (study drug and/or PET ligand), only serious adverse events caused by a 
protocol-mandated intervention will be collected (e.g., serious adverse events related to 
invasive procedures such as biopsies, medication washout, or no treatment run-in).  
During this period, non-serious adverse events are not collected.  If a non-serious 
adverse event occurs during this period and continues to Day 1, the event can then be 
recorded as a baseline condition.  
After initiation of the first investigational product (study drug and/or PET ligand), 
all adverse events and serious adverse events, regardless of attribution, will be 
collected until 16 weeks following the last administration of any investigational product 
(study drug and/or PET ligand) or study discontinuation/termination, whichever is later.  
After this 16-week follow-up period, investigators should report only serious adverse 
events that are considered to be related to a previously administered investigational 
product (see Section 5.6).  
5.2.2 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting adverse events at all 
participant evaluation time points should be adopted.  Examples of non-directive 
questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.2.3 
Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on adverse events and serious adverse events at 
each participant contact.  All adverse events and serious adverse events, whether 
reported by the participant or noted by authorized study personnel, will be recorded in 
the participant’s medical record and on the Adverse Event eCRF. 
For each adverse event and serious adverse event recorded on the applicable eCRF, 
the investigator will make an assessment of seriousness (see Section 5.1.2 for 
seriousness criteria), severity and causality.   
Table 1 provides guidance for grading adverse event severity, and Table 2 provides 
guidance for assessing the causal relationship to the investigational product(s).   

 
Crenezumab—F. Hoffmann-La Roche Ltd 
99/Protocol GN28352, Version 11 
The adverse event grading (severity) scale found in the NCI CTCAE v4.0 will be used 
for assessing adverse event severity.  
Table 1 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI CTCAE grading criteria) 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
2 
Moderate (apply event-specific  
NCI CTCAE grading criteria) 
Minimal, local, or non-invasive intervention 
indicated; limiting age-appropriate instrumental 
ADL b 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Severe or medically significant but 
not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; 
disabling; limiting self-care ADL c 
4 
Very severe, life threatening,  
or disabling (apply event-specific 
NCI CTCAE grading criteria) 
Life-threatening consequences; 
urgent intervention indicated 
5 
Death related to AE 
 
ADL  activities of daily living; AE  adverse event; NCI CTCAE  National Cancer Institute 
Common Terminology Criteria for Adverse Events. 
The NCI CTCAE (Version 4.0) can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc. 
Note:  Regardless of severity, some events may also meet regulatory seriousness criteria.  
See the definition of a serious AE (see Section 5.1.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI CTCAE listing. 
b Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
100/Protocol GN28352, Version 11 
To ensure consistency of causality assessments, investigators should apply the general 
guidelines in Table 2. 
Table 2 
Causal Attribution Guidance 
Is the AE/SAE suspected to be caused by the investigational product on the basis of 
facts, evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the AE and 
administration of the investigational product, and the AE cannot be readily explained 
by the participant’s clinical state, intercurrent illness, or concomitant therapies; and/or 
the AE follows a known pattern of response to the investigational product; and/or the 
AE abates or resolves upon discontinuation of the investigational product or dose 
reduction and, if applicable, reappears upon re-challenge. 
Investigators should apply facts, evidence, or rationales on the basis of scientific 
principles and clinical judgment to support a causal/contributory association with an 
investigational product. 
NO 
AEs will be considered related, unless they fulfill the criteria as specified below. 
Evidence exists that the AE has an etiology other than the investigational product 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the AE has no plausible temporal relationship to 
administration of the investigational product (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
Note:  The investigator’s assessment of causality for individual AE reports is part of 
the study documentation process.  Regardless of the “Yes” or “No” causality 
assessment for individual AE reports, the Sponsor will promptly evaluate all reported 
SAEs against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators and applicable regulatory 
authorities.  Attribution of SAEs will be reviewed on an ongoing basis, and may be 
changed as additional clinical data emerges (e.g., reversibility of AE, new clinical 
findings in participant with AE, effects of retreatment, AEs in other participants). 
AE  adverse event; SAE  serious adverse event. 
 
5.3 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
5.3.1 
Recording Adverse Events on the eCRF 
Investigators should use correct medical terminology/concepts when recording adverse 
events or serious adverse events on the eCRF.  Avoid colloquialisms and 
abbreviations. 
There is 1 eCRF page for recording adverse events or serious adverse events. 
Only 1 medical concept should be recorded in the event field on the Adverse Event 
eCRF. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
101/Protocol GN28352, Version 11 
5.3.1.1 
Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an adverse event or serious adverse event 
on the eCRF.  If a diagnosis is subsequently established, it should be reported as 
follow-up information. 
Diagnoses for ARIA-E, ARIA-H, and cerebral macrohemorrhage will be made on the 
basis of MRI by the central reader. 
5.3.1.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events 
or clinical sequelae) should be identified by their primary cause.  For example, if severe 
diarrhea is known to have resulted in dehydration, it is sufficient to record only diarrhea 
as an adverse event or serious adverse event on the eCRF.  
However, medically significant adverse events occurring secondary to an initiating 
event that are separated in time should be recorded as independent events on the 
eCRF.  For example, if a severe gastrointestinal hemorrhage leads to renal failure, both 
events should be recorded separately on the eCRF. 
5.3.1.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution between 
participant evaluation timepoints.  Such events should only be recorded once in the 
eCRF unless their severity increases.  If a persistent adverse event becomes more 
severe, it should be recorded again on the Adverse Event eCRF.  The initial 
(less severe) adverse event report should be updated to indicate that the event 
resolved on the date just prior to the day the event became more severe.  If a persistent 
adverse event becomes serious, it should then be recorded as a separate event on the 
Adverse Event eCRF and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.3 for reporting 
instructions).  The initial (non-serious) adverse event report should be updated to 
indicate that the event resolved on the date just prior to the day the event became 
serious).  If the severity of the previously reported serious adverse event changes, it 
should be reported as follow-up to the previous serious adverse event, not as a new 
event. 
A recurrent adverse event is one that occurs and resolves between participant 
evaluation time points and subsequently recurs.  All recurrent adverse events should be 
recorded on the Adverse Event eCRF. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
102/Protocol GN28352, Version 11 
5.3.1.4 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will 
be recorded as adverse events or serious adverse events on the eCRF 
(e.g., abnormalities that require investigational product dose modification, 
discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  the ULN associated with cholecystitis), only 
the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an adverse event or serious adverse event 
on the eCRF.  If the laboratory abnormality can be characterized by a precise clinical 
term, the clinical term should be recorded as the adverse event or serious adverse 
event.  For example, an elevated serum potassium level of 7.0 mEq/L should be 
recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as adverse events or serious adverse events on the 
eCRF, unless their severity, seriousness, or etiology changes.  
5.3.1.5 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.2.1), regardless of attribution, will be recorded on an eCRF and 
expeditiously reported to the Sponsor.  This includes death attributed to progression of 
AD. 
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF.  If the cause 
of death is unknown and cannot be ascertained at the time of reporting, record 
“Unexplained Death” on the eCRF. 
If the death is attributed to progression of AD, record Alzheimer’s disease Progression” 
as the serious adverse event term on the eCRF.   
5.3.1.6 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  
Such conditions should be recorded on the Medical and Surgical History eCRF. 
A preexisting medical condition should be recorded as an adverse event or serious 
adverse event only if the frequency, severity, or character of the condition worsens 
during the study.  When recording such events on an Adverse Event eCRF, it is 
important to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
103/Protocol GN28352, Version 11 
5.3.1.7 
Development or Worsening of Alzheimer’s Disease 
Emergence of cognitive symptoms and/or functional impairment during the study or 
other events that are clearly consistent with the expected pattern of progression of AD 
should not be recorded as an adverse event.  These data will be captured as efficacy 
assessment data only.  In most cases, the expected pattern of progression will be on 
the basis of established criteria for MCI (Albert et al. 2011) or dementia 
(McKhann et al. 2011).  If there is any uncertainty as to whether an event is due to 
disease progression, or if the progression is unexpected or thought to be treatment 
related, it should be reported as an adverse event. 
5.3.1.8 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.   
There are some hospitalization scenarios that do not require reporting as a serious 
adverse event when there is no occurrence of an adverse event.  These scenarios 
include a planned hospitalization or prolonged hospitalization to: 
 
Perform an efficacy measurement for the study 
 
Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed 
 
Receive scheduled therapy for the target disease of the study 
 
5.3.1.9 
Pregnancy 
If a female participant becomes pregnant while receiving investigational therapy or 
within 16 weeks after the last dose of investigational product (crenezumab/placebo or 
florbetapir), a Pregnancy Report eCRF should be completed within 24 hours of learning 
of the pregnancy.  A pregnancy report will automatically be generated and sent to 
Roche Drug Safety by the EDC system.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  In the event the EDC system is unavailable, a paper Pregnancy 
Report form and Pregnancy Fax Coversheet should be completed and faxed to Roche’s 
Drug Safety Department, or its designee, at the fax numbers listed in Section 5.4.3. 
5.3.1.10 
Pregnancies in Female Partners of Male Participants 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant after the first dose of either 
crenezumab/placebo or florbetapir has been administered or within 8 weeks after the 
last dose of crenezumab/placebo or florbetapir has been administered.  A Pregnancy 
Report eCRF should be completed by the investigator immediately (i.e., no more than 
24 hours after learning of the pregnancy) and submitted via the EDC system.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to investigational product.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
104/Protocol GN28352, Version 11 
Pregnancy Health Information to allow for follow-up on her pregnancy.  Once the 
authorization has been signed, the investigator will update the Pregnancy Report eCRF 
with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male participant or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician.  In the event that the EDC system is unavailable, follow reporting 
instructions provided in Section 5.3.1.9. 
5.3.1.11 
Congenital Anomalies/Birth Defects  
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
study drug or the female partner of a male participant exposed to study drug should be 
classified as an serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.3). 
5.3.1.12 
Abortions 
A spontaneous abortion should be classified as an serious adverse event (as the 
Sponsor considers abortions to be medically significant), recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.3). 
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as an serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.3).  
A therapeutic or elective abortion performed for reasons other than an underlying 
maternal or embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS (AND PROTOCOL-DEFINED EVENTS OF 
SPECIAL INTEREST) 
5.4.1 
Reporting Requirements for Fatal/Life-Threatening Serious 
Adverse Events Related to Investigational Product 
Any life-threatening (i.e., imminent risk of death) or fatal adverse event that is attributed 
by the investigator to the investigational product will be telephoned to the 
Medical Monitor immediately, followed by submission of written case details on the 
serious adverse event reporting form within 24 hours as described in Section 5.4.3. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
105/Protocol GN28352, Version 11 
5.4.2 
Emergency Medical Contacts 
PRA Medical Monitor Contact No.:   
 
 
 1 (866) 326-5053 (24 hours) 
Alternative Medical Monitor: 
, M.D., M.A.S. 
Mobile Telephone No.: 
Fax Telephone No.: 
 
To ensure the safety of study participants, an Emergency Medical Call Center Help 
Desk will access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 
24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as 
Medical Monitor and Medical Responsible contact information, will be distributed to all 
investigators.  
5.4.3 
Reporting Requirements for All Serious Adverse Events and 
Protocol-Defined Events of Special Interest 
Investigators will submit reports of all serious adverse events and the Protocol-Defined 
Events of Special Interest/Non-Serious Expedited Adverse Events (see Section 5.1.3), 
regardless of attribution, to Roche within 24 hours of learning of the events.  For initial 
serious adverse events and protocol-defined events of special interest reports, 
investigators should record all case details that can be gathered within 24 hours on an 
eCRF and submit the report via the EDC system.  A report will be generated and sent to 
Roche’s Drug Safety by the EDC system. 
In the event the EDC system is unavailable, a completed Serious/Non-Serious 
Expedited Adverse Event paper reporting form and fax coversheet should be faxed 
immediately upon completion to Roche’s Drug Safety Department, or its designee, at 
the fax numbers indicated below.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system.  
Fax No.: 
 1 (888) 772-6919 
 
Relevant follow-up information should be submitted to Roche’s Drug Safety Department 
or its designee as soon as it becomes available and/or upon request. 
5.5 
TYPE AND DURATION OF FOLLOW-UP OF PARTICIPANTS 
AFTER ADVERSE EVENTS 
The investigator should follow all unresolved adverse events and serious adverse 
events until the events are resolved or stabilized, the participant is lost to follow-up, or it 
has been determined that the investigational product or participation is not the cause of 
the adverse event/serious adverse event.  Resolution of adverse events and serious 
adverse events (with dates) should be documented on the Adverse Event eCRF and in 
the participant’s medical record to facilitate source data verification (SDV). 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
106/Protocol GN28352, Version 11 
For some serious adverse events, the Sponsor or its designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details 
deemed necessary to appropriately evaluate the serious adverse event report 
(e.g., hospital discharge summary, consultant report, or autopsy report). 
5.6 
POST-STUDY ADVERSE EVENTS 
At the last scheduled visit, the investigator should instruct each participant to report to 
the investigator any subsequent serious adverse event that the participant’s personal 
physician believes could be related to prior investigational product treatment.  
The investigator should notify the study Sponsor of any death or other serious adverse 
event occurring at any time after a participant has discontinued or terminated study 
participation if considered to be related to prior investigational product treatment.  
The Sponsor should also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived 
offspring of a participant that participated in this study.  The investigator should report 
these events to Roche’s Drug Safety on the study eCRF.  
If the study eCRF is no longer available, the investigator should report the event directly 
to the Roche Colombian Affiliate via phone at 57 4178860. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Crenezumab 
Crenezumab Investigator's Brochure  
Florbetapir 
Florbetapir Investigator's Brochure 
GTP1 
GTP1 Investigator's Brochure  
GTP1  [18F]-Genentech Tau Probe 1. 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
107/Protocol GN28352, Version 11 
6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with Roche or a Roche representative: 
 
FDA Form 1572 for each site (for all studies conducted under U.S. Investigational 
New Drug [IND] regulations), signed by the Principal Investigator 
– 
The names of any subinvestigators must appear on this form.  
Investigators must also complete all regulatory documentation as required by 
local and national regulations. 
 
Current curricula vitae and evidence of licensure of the Principal Investigator and 
all subinvestigators 
 
Complete financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572  
 
Federalwide Assurance number or IRB statement of compliance 
 
Written documentation of IRB/EC approval of the protocol (identified by protocol 
number or title and date of approval) and Informed Consent Form (identified by 
protocol number or title and date of approval) 
 
A copy of the IRB/EC-approved Informed Consent Form 
– 
Roche or its designee must review any proposed deviations from the sample 
Informed Consent Form 
 
Current laboratory certification of the laboratory performing the analysis 
(if other than a Roche-approved central laboratory), as well as current references 
ranges for all laboratory tests 
 
A Clinical Research Agreement signed and dated by the study site 
 
Investigator Brochure Receipt signed and dated by the Principal Investigator 
 
Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the participant (when applicable), IRB/EC approval 
letters, and pertinent correspondence 
 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
 
6.2 
STUDY COMPLETION 
The following data and materials are required by Roche before a study can be 
considered complete or terminated: 
 
Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period 
 
All laboratory certifications for laboratories performing the analysis (is other than 
Roche-approved central laboratory), as well as current normal laboratory ranges 
for all laboratory tests 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
108/Protocol GN28352, Version 11 
 
eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator 
 
Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log) 
 
Copies of protocol amendments and IRB/EC approval/notification, if appropriate 
 
A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable) 
 
All essential documents (e.g., curriculum vitae for each Principal Investigator and 
subinvestigator, FDA Form 1572 for each site) 
 
A signed and dated Protocol Amendment Acceptance Form(s) (if applicable) 
 
Updated financial disclosure forms for the Principal Investigator and all 
subinvestigators listed on the FDA Form 1572 (applicable for 1 year after the last 
participant has completed the study) 
 
6.3 
INFORMED CONSENT FORM 
Roche’s Sample Informed Consent Form will be provided to each site.  Roche or its 
designee must review and approve any proposed deviations from the Sample Informed 
Consent Form or any alternate consent forms proposed by the site (collectively, the 
“Consent Forms”) before IRB/EC submission.  Participants must be re-consented to the 
most current version of the Consent Forms during their participation in the study.  
The final IRB/EC-approved Consent Forms must be provided to Roche for regulatory 
purposes. 
The Consent Forms must be signed by the participant before his or her participation in 
the study.  The case history for each participant shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study.  The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes 
available that may affect the willingness of the individual to participate.  For any 
updated or revised Consent Forms, the case history for each participant shall document 
the informed consent process and that written informed consent was obtained for the 
updated/revised Consent Form from the participant or his/her representative for 
continued participation in the study.   
If, during the course of the trial, a participant develops dementia and loses his/her 
capacity to consent, the most recently signed consent form prior to loss of capacity will 
remain active.  Any revisions to the consent form will require re-consent by the 
participant’s representative (legally authorized representative when available, else 
temporary representative) as well as assent from the participant as per site standard 
operating procedure TR-Pr-058. 
All signed and dated Consent Forms, and documentation of verbal consent, if 
applicable, must remain in each participant’s study file and must be available for 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
109/Protocol GN28352, Version 11 
verification by study monitors at any time.  A copy of each signed Consent Form must 
be provided to the participant or the participant’s legally authorized representative.  
If applicable, it will be provided in a certified translation of the local language. 
If the site utilizes a separate Authorization Form for participant authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) regulations, the review, approval, and other processes 
outlined above apply except that IRB/EC review and approval may not be required per 
study site policies. 
6.4 
COMMUNICATION WITH THE INSTITUTIONAL REVIEW 
BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the 
participant and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator for review and approval before the study is initiated.  In addition, 
any participant recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol changes or 
amendments and of any unanticipated problems involving risk to human participants 
or others. 
In addition to the requirements to report protocol-defined adverse events to the 
Sponsor, investigators are required to promptly report to their respective IRB/EC all 
unanticipated problems involving risk to human participants.  Some IRBs/ECs may want 
prompt notification of all serious adverse events, whereas others require notification 
only about events that are serious, assessed to be related to study treatment, and are 
unexpected.  Investigators may receive written IND safety reports or other 
safety-related communications from Roche.  Investigators are responsible for ensuring 
that such reports are reviewed and processed in accordance with regulatory 
requirements and with the policies and procedures established by their IRB/EC and 
archived in the site’s Study File.  
6.5 
STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized Roche representative to inspect study 
data, participants’ medical records, and eCRFs.  The Principal Investigator will permit 
Roche monitors/representatives and collaborators, the FDA, other regulatory agencies, 
IRBs, and the respective national or local health authorities to inspect facilities and 
records relevant to this study. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
110/Protocol GN28352, Version 11 
6.6 
ELECTRONIC CASE REPORT FORMS 
Electronic Case Report Forms are to be completed using the Medidata RAVE EDC 
system.  Sites will receive training and a manual for appropriate eCRF completion.  
Electronic Case Report Forms will be submitted electronically to Roche and should be 
handled in accordance with instructions from Roche. 
All eCRFs should be completed by designated, trained examining personnel or the 
study coordinator as appropriate.  The eCRF should be reviewed and electronically 
signed and dated by the investigator. 
In addition, at the end of the study, the investigator will receive participant data for his or 
her site in a readable format on a compact disc that must be kept with the study 
records. 
6.7 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing SDV to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents are where participant data are recorded and documented for the first 
time.  They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, participant diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, participant files, and 
records kept at the pharmacy, laboratories, and medico-technical departments involved 
in a clinical trial. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct 
access to applicable source documents and reports for trial-related monitoring, Sponsor 
audits, and IRB/EC review.  The investigational site must also allow inspection by 
applicable regulatory authorities. 
6.8 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), 
the electronic record can serve as the source document if the system has been 
validated in accordance with FDA requirements pertaining to computerized systems 
used in clinical research.  An acceptable computerized data collection system 
(for clinical research purposes) would be one that (1) allows data entry only by 
authorized individuals; (2) prevents the deletion or alteration of previously entered data 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
111/Protocol GN28352, Version 11 
and provides an audit trail for such data changes (e.g., modification of file); (3) protects 
the database from tampering; and (4) ensures data preservation. 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified. 
6.9 
STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be provided by Roche.  
The recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will 
be replaced. 
Accurate records of all study drug received at, dispensed from, returned to and 
disposed of by the study site should be recorded by using the Drug Inventory Log. 
Study drug will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to Roche with the appropriate 
documentation, as determined by the study site.  If the study site chooses to destroy 
study drug, the method of destruction must be documented. 
Roche must evaluate and approve the study site’s drug destruction standard operating 
procedure prior to the initiation of drug destruction by the study site. 
6.10 
DISCLOSURE OF DATA 
Participant medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the participant 
or unless permitted or required by law. 
Data and samples arising from assessments prior to the treatment period may be 
shared prior to the end of the study subject to appropriate authorization to use such 
data and subject to appropriate provisions to maintain confidentiality, including that of 
mutation carrier status. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare for treatment 
purposes. 
Genetic status will be made available for those participants who desire this information 
after Study Period A is complete and results are available.  Genetic counseling and 
disclosure of PSEN1 mutation results will be provided by an independent 
group specializing in genetic testing and counseling.  

 
Crenezumab—F. Hoffmann-La Roche Ltd 
112/Protocol GN28352, Version 11 
If a participant learns that he/she is not a PSEN1 mutation carrier during 
Study Period B, he/she will be withdrawn from treatment since placebo will not be 
administered to known non-carriers.   
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Roche monitors/representatives and collaborators, and the IRB/EC for each 
study site, if appropriate. 
6.11 
RETENTION OF RECORDS 
The FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP 
(see Section 4.9 of the guideline) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including eCRFs, 
consent forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for 2 years after the last marketing application 
approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product.  All state and local 
laws for retention of records also apply.  
No records should be disposed of without the written approval of Roche.  
Written notification should be provided to Roche for transfer of any records to another 
party or moving them to another location. 
For studies conducted outside the United States under a U.S. IND, the 
Principal Investigator must comply with the record retention requirements set forth in 
the FDA IND regulations and the relevant national and local health authorities, 
whichever is longer. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
113/Protocol GN28352, Version 11 
7. 
REFERENCES 
Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, et al. Pre-dementia clinical 
stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a 
retrospective cohort study. Lancet Neurol 2011;10:21320. 
Adolfsson O, Pihlgren M, Toni N, et al. An effector-reduced anti-amyloid (A) 
antibody with unique aβ binding properties promotes neuroprotection and glial 
engulfment of A. J Neurosci 2012;32:967789. 
Aguirre-Acevedo DC, Gómez RD, Moreno S, et al. Validity and reliability of the 
CERAD-Col neuropsychological battery. Rev Neurol 2007;45:65560. 
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment 
due to Alzheimer's disease: recommendations from the National Institute on 
AgingAlzheimer's Association workgroups on diagnostic guidelines for 
Alzheimer’s disease. Alzheimers Dement 2011;7:2709. 
Armitage SG. An analysis of certain psychological tests used for the evaluation of brain 
injury. Psychological Monographs 1946;60:i48. 
Ayutyanont N, Langbaum JB, Hendrix SB, et al. The Alzheimer’s Prevention Initiative 
composite cognitive test score: sample size estimates for the evaluation of 
preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation 
carriers. J Clin Psychiatry 2014;75:652–60. 
Barkhof F, Daams M, Scheltens P, et al. An MRI rating scale for amyloid-related 
imaging abnormalities with edema or effusion. AJNR Am J Neuroradiol 
2013;34:15505. 
Bateman RJ, Aisen PS, De Strooper B, et al. Autosomal-dominant Alzheimer's disease: 
a review and proposal for the prevention of Alzheimer's disease. Alzheimers Res 
Ther 2011;3:1. 
Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in 
dominantly inherited Alzheimer’s disease. N Engl J Med 2012;367:795804. 
Brookmeyer R, Gray S, Kawas C, et al. Projections of Alzheimer's disease in the 
United States and the public health impact of delaying disease onset. Am J Public 
Health 1998;88:133742. 
Caselli RJ, Langlais BT, Dueck AC, et al. Neuropsychological decline up to 20 years 
before incident mild cognitive impairment. Alzheimers Dement 2020;16:51223. 
Chong CP, Street PR. Pneumonia in the elderly: a review of the epidemiology, 
pathogenesis, microbiology, and clinical features. Southern Med J 
2008;101:11415. 
Corrada MM, Brookmeyer R, Paganini-Hill A, et al. Dementia incidence continues to 
increase with age in the oldest old: the 90  study. Ann Neurol 2010;67:11421. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
114/Protocol GN28352, Version 11 
Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia 
patients. Neurology 1997;48:S106. 
Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive 
assessment of psychopathology in dementia. Neurology 1994;44:230814. 
Deng R, Iyer S, Theil FP, et al. Projecting human pharmacokinetics of therapeutic 
antibodies from nonclinical data: what have we learned? MAbs 2011;3:616. 
Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal 
antibodies. Clin Pharmacokinet 2010;49:63359. 
Donohue MC, Sperling RA, Salmon DP, et al. The preclinical Alzheimer cognitive 
composite: measuring amyloid-related decline. JAMA Neurol 2014 71:96170. 
Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a 
community population of older persons. Higher than previously reported. 
JAMA 1989;262:25516. 
Fleisher AS, Chen K, Quiroz YT, et al. Florbetapir PET analysis of amyloid- deposition 
in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a 
cross-sectional study. Lancet Neurol 2012;11:105765. 
Fleisher AS, Chen K, Quiroz YT, et al. Associations between biomarkers and age in the 
presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a 
cross-sectional study. JAMA Neurol 2015;72:31624. 
Fuller JP, Stavenhagen JB, Teeling JL. New roles for Fc receptors in 
neurodegenerationthe impact on immunotherapy for Alzheimer's disease. 
Front Neurosci 2014;8:235. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res 
1975;12:18998. 
Gollan TH, Weissberger GH, Runnqvist E, et al. Self-ratings of spoken language 
dominance: a multi-lingual naming test (MINT) and preliminary norms for young 
and aging Spanish-English bilinguals. Biling (Camb Engl) 2012;15:594615. 
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and 
problems on the road to therapeutics. Science 2002;297:3536. 
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. 
Lancet Neurol 2015;14:388405.  
Koffie RM, Meyer-Luehmann M, Hashimoto T, et al. Oligomeric amyloid beta associates 
with postsynaptic densities and correlates with excitatory synapse loss near 
senile plaques. Proc Natl Sci USA 2009;106:40127. 
Kramp VP, Herrling P. List of drugs in development for neurodegenerative diseases: 
update June 2010. Neurodegener Dis 2011;8:4494. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
115/Protocol GN28352, Version 11 
Langbaum JB, Hendrix SB, Ayutyanont N, et al. An empirically derived composite 
cognitive test score with improved power to track and evaluate treatments for 
preclinical Alzheimer's disease. Alzheimers Dement 2014;10:66674. 
Liu P, Reed MN, Kotilinek LA, et al. Quaternary structure defines a large class of 
amyloid- oligomers neutralized by sequestration. Cell Rep 2015;11:176071. 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging and 
the Alzheimer's Association workgroup. Alzheimers Dement 2011;7:2639. 
Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for 
use in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease 
Assessment Scale that broaden its scope. The Alzheimer’s Disease Cooperative 
Study. Alzheimer Dis Assoc Disord 1997;11:S1321. 
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology 1993;43:24124. 
Morris JC, Heyman A, Mohs RC, et al. The Consortium to Establish a Registry for 
Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological 
assessment of Alzheimer's disease. Neurology 1989;39:115965. 
Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal 
antibodiesmechanistic modeling applied to drug development. Curr Opin Drug 
Discov Devel 2007;10:8496. 
Oddo S, Billings L, Kesslak JP, et al. Abeta immunotherapy leads to clearance of early, 
but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 
2004;43:32132. 
Ostrowitzki S, Dentula D, Thurfjell L, et al. Mechanism of amyloid removal in patients 
with Alzheimer disease treated with gantenerumab. Arch Neurol 
2012:69:198207. 
Quinn B, Dauer Z, Pandit-Taskar N, et al. Radiation dosimetry of 18F-FDG PET/CT: 
incorporating exam-specific parameters in dose estimates. BMC Med Imaging 
2016;16:41. 
Randolph C. Repeatable Battery for the Assessment of Neuropsychological Status. 
San Antonio, TX: The Psychological Coporation, 1998. 
Raven JC. Revised Manual for Raven's Progressive Matrices and Vocabulary Scale. 
New York: The Psychological Corporation, Harcourt Brace Jovanovich, Inc., 
1976. 
Reiman EM, Langbaum JBS. Brain imaging in the evaluation of putative Alzheimer's 
disease slowing, risk-reducing and prevention therapies. In: Jagust WJ, 
D'Esposito M (editors). Imaging the aging brain. New York: Oxford University 
Press, 2009;31950. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
116/Protocol GN28352, Version 11 
Reiman EM, Langbaum JB, Tariot PN. Alzheimer's Prevention Initiative: a proposal to 
evaluate presymptomatic treatments as quickly as possible. Biomark Med 
2010;4:314. 
Reiman EM, Sink KM, Hu N, et al. P4-209: A public resource of baseline data from 
the API autosomal dominant Alzheimer’s disease COLOMBIA trial. 
Alzheimer’s & Dement 2018;14:P1521. 
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J 
Psychiatry 1984;141:135664. 
Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of 
bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 
73:206170. 
Sclan SG, Reisberg B. Functional assessment staging (FAST) in Alzheimer's disease:  
reliability, validity, and ordinality. Int Psychogeriatr 1992;4:5569. 
Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and 
behavior. Behav Brain Res 2008;192:10613. 
Sevigny J, Chiao P, Williams L, et al. Randomized, double-blind, placebo-controlled, 
Phase 1b study of aducanumab (BIIB037), an anti-A monoclonal antibody, in 
patients with prodromal or mild Alzheimer’s disease: Interim results by disease 
stage and ApoE14 status [poster].  [Resource available on the Internet]. 
April 2015 [cited: June 2016]. Available from: 
https://www.biogenconferences.com/AAN2015/BART/BART_Sevigny_PhIB_subg
p_IA2.pdf. 
Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontologist: J Aging Mental Health 
1986;5:16573. 
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of 
Alzheimer's disease: recommendations from the National Institute on Aging and 
the Alzheimer's Association workgroup. Alzheimers Dement 2011b;7:28092. 
Sperling RA, Jack CR Jr, Black SE, et al. Amyloid-related imaging abnormalities in 
amyloid-modifying therapeutic trials: recommendations from the Alzheimer's 
Association Research Roundtable Workgroup. Alzheimers Dement 
2011a;7:36785. 
Tounsi H, Deweer B, Ergis AM, et al.  Sensitivity to semantic cuing: an index of episodic 
memory dysfunction in early Alzheimer disease. Alzheimer Dis Assoc Disord 
1999;13:3846. 
Ultsch M, Li B, Maurer T, et al. Structure of crenezumab complex with A shows loss of 
-hairpin. Sci Rep 2016. [Resource available on the Internet]. Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171940/pdf/srep39374.pdf. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
117/Protocol GN28352, Version 11 
Wilcock DM, Alamed J, Gottschall PE, et al. Deglycosylated anti-amyloid-beta 
antibodies eliminate cognitive deficits and reduce parenchymal amyloid with 
minimal vascular consequences in aged amyloid precursor protein transgenic 
mice. J Neurosci 2006;26:5340–6. 
Xing B, Bachstetter AD, Van Eldik LJ. Microglial p38 MAPK is critical for LPS-induced 
neuron degeneration, through a mechanism involving TNF. Mol Neurodegener 
2011;6:84. 

Appendix 1 
(SC Dosing) Study Flowchart (Screening–Week 104) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
121/Protocol GN28352, Version 11 
PSEN1  presenilin-1 (gene); Q2W  every 2 weeks; Screen  screening; SMC  Subjective Memory Checklist; SPCQ  Study Partner Characterization 
Questionnaire; W  week. 
Note:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted.  
a Obtain informed consent prior to conducting any assessments.  Informed Consent Forms must be signed by the participant and study partner. 
b Review study criteria to ensure that the participant still qualifies to participate in the study.  All baseline assessments must be completed before first study drug 
administration (Day 1). 
c At screening, obtain participant screening number assignment through IxRS.  On Day 1, obtain participant randomization number and kit assignment number 
through IxRS. 
d Height should be obtained only at screening.  Weight should be obtained at screening and all other indicated visits noted in the study flowchart. 
e Cognitive and selected other assessments (GDS, SMC, CDR, and suicidality assessment) should not be administered to the participant immediately after dosing 
or any potentially stressful procedures (e.g., blood draws, LPs, imaging).  Also, participants should not perform these assessments while fasting.  For each 
participant, best efforts should be exerted to perform subsequent assessments at the same time of day as the baseline assessments.   
f In rare instances, these assessments permitted by phone or video technology (see Section 4.5.4). 
g The SPCQ, CDR (study partner portion), FAST, SMC, and NPI should be administered to the same study partner throughout the study.  The study partner must 
be present at the clinic for these assessments at screening and baseline, and best efforts should be exerted in order for the study partner to be present for all 
other visits requiring study partner assessments.  In rare instances, for which the study partner cannot be present in person, these assessments may be 
administered by telephone.  See Appendix 7 for additional details regarding study partner considerations. 
h The Screening Battery should be administered in the following order:  MMSE, Word List:  Memory, GDS, Word List:  Recall, Word List:  Recognition. 
Note: the GDS is not part of the Screening Battery but is inserted as a distracter and to create a delay for Word List:  Recall. 
i The API ADAD Composite Cognitive Test Battery should be administered in the following order:  MMSE, Multilingual Naming Test, Word List:  Memory, CERAD 
Constructional Praxis, Word List:  Recall, Word List:  Recognition, Raven’s Progressive Matrices–Set A. 
j The Extended Cognitive Battery should be administered after the API ADAD Composite Cognitive Test Battery. 
k Completed prior to the administration of all other study partner assessments at each visit. 
l Study partner portion of the CDR must be administered prior to the participant portion of the CDR. 
m  Includes pH, protein, glucose, ketones, bilirubin, blood, specific gravity, leukocyte esterase, urobilinogen, and nitrite, as well as microscopic analysis on the basis 
of dipstick results. 
n Includes sodium, potassium, BUN, bicarbonate, estimated glomerular filtration rate, calcium, AST, ALT, -glutamyl transpeptidase, total and direct bilirubin, 
alkaline phosphatase, lactate dehydrogenase, total protein, albumin, glucose, cholesterol, triglycerides, uric acid, creatine phosphokinase, and glycosylated 
hemoglobin.  At screening, this sample will also include vitamin B12, ultrasensitive thyroid-stimulating hormone, and thyroxine.  Participants will be fasting 
(water only) for blood tests only at screening; fasting is not required at all visits. 
o Includes hematocrit, hemoglobin, RBC count, WBC count with differential and platelets.  Participants will be fasting (water only) for blood tests only at screening; 
fasting is not required at all visits. 
p Includes aPTT and INR.  Participants will be fasting (water only) for blood tests only at screening; fasting is not required at all timepoints. 

Appendix 1 
(SC Dosing) Study Flowchart (Screening–Week 104) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
122/Protocol GN28352, Version 11 
q Sample should be taken immediately after consent and assignment of a screening number to ensure adequate time for testing and reporting of results. 
r Routine ECGs will be calculated and read locally; the exception is the optional ECG substudy at Weeks 16–17, for which the additional ECG data will only be 
processed centrally.  Baseline ECGs for the optional ECG substudy participants will be read locally and also processed centrally.  Single ECGs at baseline, 
Week 4, and Week 12 should be submitted to the vendor for all participants. 
s At Week 16, and 7 days ( 3 days) following the Week 16 study drug administration, a subset of participants will undergo an additional ECG assessment.  
Each ECG assessment in this ECG substudy will be accompanied by additional PK, PD, and exploratory plasma, serum, and RNA blood samples as well as vital 
signs (BP, HR, RR) after the ECG assessment (order of assessments:  ECG, vital signs, blood draws, and study drug administration).  Triplicate ECGs are 
required only for ECG substudy participants, and only at baseline, Week 16, and 7 days ( 3 days) following the Week 16 study drug administration. 
t 
Collect PK, PD, and exploratory serum, plasma, and RNA samples prior to study drug administration. 
u Participants who experience serious or severe hypersensitivity reactions (e.g., hypotension, mucosal involvement) should not receive additional study drug.  
In addition, in any case of anaphylaxis, anaphylactoid reaction, serious or severe hypersensitivity reaction, ADA and concurrent PK samples should be collected 
as close as possible to the event, and then at the 4-week ET visit and at the 16-week safety follow-up visit after the final dose (see schedules of assessments for 
further details). 
v Includes amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opioids. 
w Serum pregnancy test must be administered and have a negative result prior to enrollment into the study.  Urine pregnancy test must be administered and have 
a negative result prior to any study drug administration.  If the participant has discontinued study drug but is continuing with study assessments, the urine 
pregnancy test may be deferred except for visits during which FDG-PET or florbetapir PET scans are administered.  Serum and urine pregnancy testing will 
apply to all women unless documented (by medical records or physician’s note) to be surgically sterile or postmenopausal as defined in Section 3.5.5. 
x Vital signs will include measurements of temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure while the participant has been supine 
for  3 minutes.  On study drug administration days, record vital signs prior to the injection. 
y Although visit windowing for dosing days allows for 5 days around any expected visit day, the interval between study drug administrations from 1 biweekly visit 
to the following biweekly visit must be between 8 and 20 days. 
z Participants will be observed for a minimum of 30 minutes for the first four dose administrations and 15 minutes for subsequent dose administrations, following 
injection of study drug. 
aa During the treatment period:  Participants who develop  8 amyloid-related imaging abnormalitieshemosiderin deposition cumulatively will receive a lower dose 
of the study drug.  Participants who develop  10 amyloid-related imaging abnormalitieshemosiderin deposition cumulatively will be permanently discontinued 
from the study drug.  Cumulative is the sum of amyloid-related imaging abnormalitieshemosiderin deposition at baseline and newly detected amyloid-related 
imaging abnormalitieshemosiderin deposition during the study.  
bb If MRI and FDG-PET scans are performed on the same day, the FDG-PET scan should be performed first.  A urine pregnancy test must be administered and 
have a negative result prior to any PET scan.  It is recommended, but not required, to use effective contraception during sexual intercourse occurring within 
24 hours following a male or female participant receiving a PET scan.   
cc Screening MRI is to occur 10 days prior to randomization to ensure adequate time for MRI interpretation prior to randomization, and also before the optional LP, 
with sufficient time to allow review for possible contraindications to LP. 

Appendix 1 
(SC Dosing) Study Flowchart (Screening–Week 104) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
123/Protocol GN28352, Version 11 
dd ET FDG-PET and fibrillar amyloid PET scans should only be performed if the investigator has determined that the total radiation exposure from the ET FDG-PET 
and fibrillar amyloid PET scans does not exceed local safety guidelines. 
ee FDG-PET and fibrillar amyloid PET should be performed after the participant is deemed eligible on the basis of all other screening assessments.  Although part 
of the screening period, eligibility is not dependent upon FDG-PET and fibrillar amyloid PET results. 
ff Participant must be fasting (water only) for a minimum of 4 hours prior to the scan.  Fluorodeoxyglucose-PET should be performed a minimum of 12 hours and a 
maximum of 7 days apart from the accompanying fibrillar amyloid PET scan.  For each participant, best efforts should be exerted to perform subsequent 
FDG-PET scans at the same time of day as the baseline scan. 
gg It is strongly preferred that the LP be performed in the morning.  Participants will be required to stay in the clinic or hospital for approximately 1 hour after the LP 
for safety follow-up.  For each participant, best efforts should be exerted to perform subsequent LPs at the same time of day as the baseline LP.  
See Section 4.5.1.10 for additional details regarding LP.   
hh If the participant agrees to undergo optional LP, CSF sample should be drawn a) after the participant is deemed eligible on the basis of all other screening 
assessments, b) after the participant is deemed eligible on the basis of MRI, and c) at least 72 hours prior to the first study drug administration. 
ii This sample may be collected during a subsequent visit if it cannot be collected at baseline. 
 

Appendix 2 
(SC Dosing) (Week 106–End of Study Period A) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
129/Protocol GN28352, Version 11 
AD  Alzheimer’s disease; ADA  anti-drug antibody; ADAD  autosomal-dominant Alzheimer’s disease; API  Alzheimer’s Prevention Initiative; CDR  Clinical Dementia 
Rating; CERAD  Consortium to Establish a Registry for Alzheimer’s Disease; Comp  completion; CSF  cerebrospinal fluid; d  day; ET  early termination; 
FAST  Functional Assessment Staging of Alzheimer’s Disease; FDG  fluorodeoxyglucose; GDS  Geriatric Depression Scale; LP  lumbar puncture; MCI  mild cognitive 
impairment; MMSE  Mini-Mental State Examination; MRI  magnetic resonance imaging; NPI  Neuropsychiatric Inventory; PD  pharmacodynamic; PET  positron 
emission tomography; PK  pharmacokinetic; Q2W  every 2 weeks; SMC  Subjective Memory Checklist; SPCQ  Study Partner Characterization Questionnaire; 
W  week. 
Note:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted. 
a Participants who discontinue from study drug treatment (early discontinuation) will not receive further doses of study drug, but should be asked to stay in the study for 
subsequent safety, cognitive, and biomarker assessments at complex visits, including at Weeks 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, 260, and every 
2428 weeks thereafter until the study ends.  In addition, the suicidality assessment, review of concomitant medications and adverse events should be collected at 
Weeks 12, 64, 92, 116, 144, 168, 196, 220, 248, and every 2428 weeks until the study ends; these assessments may be completed by telephone (but it is preferred they 
be completed in person).  If a phone visit it completed during these weeks, vital signs assessments may be omitted. 
b If a participant discontinues from the study (ET) or discontinues from study drug treatment and elects to no longer stay in the study, ET Visit A should be completed if the 
last visit occurred more than 12 weeks after functional, behavioral and cognitive assessments were performed; 
c If a participant discontinues from the study (ET) or discontinues from study drug treatment and elects to no longer stay in the study, ET Visit B should be performed if the 
last visit occurred within 12 weeks of functional, behavioral, and cognitive assessments.  
d Safety follow-up at 16 weeks is only applicable for those participants that do not consent to the continued access study. 
e Weight should be obtained at all weeks marked on the study flowchart.  
f 
Cognitive and selected other assessments (GDS, SMC, CDR, and suicidality assessment) should not be administered to the participant immediately after dosing or any 
potentially stressful procedures (e.g., blood draws, LP, imaging).  Also, participants should not perform these assessments while fasting.  For each participant, best efforts 
should be exerted to perform subsequent assessments at the same time of day as the baseline assessments. 
g In rare instances, these assessments permitted by phone or video technology (see Section 4.5.4). 
h The SPCQ, CDR (study partner portion), FAST, SMC, and NPI should be administered to the same study partner throughout the study.  Best efforts should be exerted in 
order for the study partner to be present for all other visits requiring study partner assessments.  In rare instances, for which the study partner cannot be present in person, 
these assessments may be administered by telephone.  See Appendix 7 for additional details regarding study partner considerations. 
i 
The API ADAD Composite Cognitive Test Battery should be administered in the following order:  MMSE, Multilingual Naming Test, Word List:  Memory, CERAD 
Constructional Praxis, Word List:  Recall, Word List:  Recognition, Raven’s Progressive Matrices–Set A. 
j 
The Extended Cognitive Battery should be administered after the API ADAD Composite Cognitive Test Battery. 
k Completed prior to the administration of all other study partner assessments at each visit. 
l 
Study partner portion of the CDR must be administered prior to the participant portion of the CDR.

Appendix 2 
(SC Dosing) (Week 106–End of Study Period A) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
130/Protocol GN28352, Version 11 
m Includes pH, protein, glucose, ketones, bilirubin, blood, specific gravity, leukocyte esterase, urobilinogen, and nitrite, as well as microscopic analysis on the basis of 
dipstick results. 
n Includes sodium, potassium, BUN, bicarbonate, estimated glomerular filtration rate, calcium, AST, ALT, -glutamyl transpeptidase, total and direct bilirubin, alkaline 
phosphatase, lactate dehydrogenase, total protein, albumin, glucose, cholesterol, triglycerides, uric acid, creatine phosphokinase, and glycosylated hemoglobin.  
At screening, this sample will also include vitamin B12, ultrasensitive thyroid-stimulating hormone, and thyroxine.  Participants will be fasting (water only) for blood tests 
only at screening; fasting is not required at all visits. 
o Includes hematocrit, hemoglobin, RBC count, WBC count with differential and platelets.  Participants will be fasting (water only) for blood tests only at screening; fasting is 
not required at all visits. 
p Includes aPTT and INR.  Participants will be fasting (water only) for blood tests only at screening; fasting is not required at all timepoints. 
q Routine ECGs will be calculated and read locally. 
r 
Collect PK, PD, and exploratory serum, plasma, and RNA samples prior to study drug administration. 
s Participants who experience serious or severe hypersensitivity reactions (e.g., hypotension, mucosal involvement) should not receive additional study drug.  In addition, in 
any case of anaphylaxis, anaphylactoid reaction, serious or severe hypersensitivity reaction, ADA, and concurrent PK samples should be collected as close as possible to 
the event, and then at 4 and 16 weeks postdose (see schedules of assessments for further details). 
t 
Includes amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opioids. 
u Urine pregnancy test must be administered and have a negative result prior to any study drug administration.  If the participant has discontinued study drug but is 
continuing with study assessments, the urine pregnancy test may be deferred except for visits during which FDG-PET or florbetapir PET are administered.  Serum and 
urine pregnancy testing will apply to all women unless documented (by medical records or physician’s note) to be surgically sterile or postmenopausal as defined in 
Section 3.5.5. 
v Vital signs will include measurements of temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure while the participant has been supine for 
 3 minutes.  On study drug administration days, record vital signs prior to study drug administration. 
w Although visit windowing for dosing days allows for  5 days around any expected visit day, the interval between study drug administrations from 1 biweekly visit to the 
following biweekly visit must be between 8 and 20 days. 
x During the treatment period:  Participants who develop  8 amyloid-related imaging abnormalities hemosiderin deposition cumulatively will receive a lower dose of study 
drug.  Participants who develop  10 amyloid-related imaging abnormalitieshemosiderin deposition cumulatively will be permanently discontinued from study drug.  
Cumulative is the sum of amyloid-related imaging abnormalities hemosiderin deposition at baseline and newly detected amyloid-related imaging 
abnormalitieshemosiderin deposition during the study. 
y Participants will be observed for a minimum of 15 minutes following SC crenezumab injections. 
z If MRI and FDG-PET scans are performed on the same day, the FDG-PET scan should be performed first. 
aa If a participant transitions from SC to IV (higher dose) administration, participants should receive an MRI scan after 3 and 6 months of initiation of SC treatment.  
Thereafter MRI should be scheduled every 2428 weeks until end of study or ET. 
bb Urine pregnancy test must be administered and have a negative result prior to a PET scan.  It is recommended, but not required, to use effective contraception during 
sexual intercourse occurring within 24 hours following a male or female participant receiving a florbetapir PET or FDG-PET scan.   

Appendix 2 
(SC Dosing) (Week 106–End of Study Period A) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
131/Protocol GN28352, Version 11 
cc Participant must be fasting (water only) for a minimum of 4 hours prior to the scan.  FDG-PET should be performed a minimum of 12 hours and a maximum of 7 days 
apart from the accompanying fibrillar amyloid PET scan.  For each participant, best efforts should be exerted to perform subsequent FDG-PET scans at the same time of 
day as the baseline scan. 
dd The LP for CSF, FDG-PET, and amyloid PET scans is not required at ET (A or B) if they have been done within 24 weeks of ET. 
ee It is strongly preferred that the LP be performed in the morning.  Participants will be required to stay in the clinic or hospital for approximately 1 hour after the LP for safety 
follow-up.  For each participant, best efforts should be exerted to perform subsequent LPs at the same time of day as the baseline LP.  See Section 4.5.1.10 for additional 
details regarding LP.   
ff FDG-PET and fibrillar amyloid PET scans should be performed only if the investigator has determined that the total radiation exposure from the ET FDG-PET and fibrillar 
amyloid PET scans does not exceed local safety guidelines.   
 

Appendix 4 
(IV Dosing) Study Flowchart (Week 108–End of Study Period A) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
134/Protocol GN28352, Version 11 
AD  Alzheimer’s disease; ADA  anti-drug antibody; ADAD  autosomal-dominant Alzheimer’s disease; API  Alzheimer’s Prevention Initiative; CDR  Clinical Dementia 
Rating; CERAD  Consortium to Establish a Registry for Alzheimer’s Disease; CSF  cerebrospinal fluid; d  day; ET early termination; FAST Functional Assessment 
Staging of Alzheimer’s Disease; FDG  fluorodeoxyglucose; GDS  Geriatric Depression Scale; LP  lumbar puncture; MCI  mild cognitive impairment; MMSE  Mini-Mental 
State Examination; MRI  magnetic resonance imaging; NPI  Neuropsychiatric Inventory; PD  pharmacodynamic; PET  positron emission tomography; 
PK  pharmacokinetic; Q4Wevery 4 weeks; SMC  Subjective Memory Checklist; SPCQ  Study Partner Characterization Questionnaire; W  week. 
Note:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted.  
a Weight should be obtained at all weeks as marked on the study flowchart. 
b Cognitive and selected other assessments (GDS, SMC, CDR, and suicidality assessment) should not be administered to the participant immediately after dosing or any 
potentially stressful procedures (e.g., blood draws, LP, imaging).  Also, participants should not perform these assessments while fasting.  For each participant, best efforts 
should be exerted to perform subsequent assessments at the same time of day as the baseline assessments. 
c In rare instances, these assessments permitted by phone or video technology (see Section 4.5.4). 
d The API ADAD Composite Cognitive Test Battery should be administered in the following order:  MMSE, Multilingual Naming Test, Word List:  Memory, CERAD 
Constructional Praxis, Word List:  Recall, Word List:  Recognition, Raven’s Progressive Matrices–Set A. 
e The Extended Cognitive Battery should be administered after the API ADAD Composite Cognitive Test Battery. 
f Study partner portion of the CDR must be administered prior to the participant portion of the CDR. 
g Completed prior to the administration of all other study partner assessments at each visit. 
h The SPCQ, CDR (study partner portion), FAST, SMC, and NPI should be administered to the same study partner throughout the study.  Best efforts should be exerted in 
order for the study partner to be present for all other visits requiring study partner assessments.  In rare instances, for which the study partner cannot be present in person, 
these assessments may be administered by telephone.  See Appendix 7 for additional details regarding study partner considerations. 
i Includes pH, protein, glucose, ketones, bilirubin, blood, specific gravity, leukocyte esterase, urobilinogen, and nitrite, as well as microscopic analysis on the basis of 
dipstick results. 
j Includes sodium, potassium, BUN, bicarbonate, estimated glomerular filtration rate, calcium, AST, ALT, -glutamyl transpeptidase, total and direct bilirubin, alkaline 
phosphatase, lactate dehydrogenase, total protein, albumin, glucose, cholesterol, triglycerides, uric acid, creatine phosphokinase, and glycosylated hemoglobin.  
At screening, this sample will also include vitamin B12, ultrasensitive thyroid-stimulating hormone, and thyroxine.  Participants will be fasting (water only) for blood tests 
only at screening; fasting is not required at all visits. 
k Includes hematocrit, hemoglobin, RBC count, WBC count with differential and platelets.  Participants will be fasting (water only) for blood tests only at screening; fasting is 
not required at all visits. 
l Includes aPTT and INR.  Participants will be fasting (water only) for blood tests only at screening; fasting is not required at all timepoints. 
m Routine ECGs will be calculated and read locally. 
n Collect PK, PD, and exploratory serum, plasma, and RNA samples prior to study drug administration. 
o Participants who experience serious or severe hypersensitivity reactions (e.g., hypotension, mucosal involvement) should not receive additional study drug. In addition, in 
any case of anaphylaxis, anaphylactoid reaction, serious or severe hypersensitivity reaction, ADA and concurrent PK samples should be collected as close as possible to 
the event, and then at 4 and 16 weeks postdose (see Appendix 4 for further details). 

Appendix 4 
(IV Dosing) Study Flowchart (Week 108–End of Study Period A) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
135/Protocol GN28352, Version 11 
p Includes amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opioids. 
q Urine pregnancy test must be administered and have a negative result prior to any study drug administration.  If the participant has discontinued study drug but is 
continuing with study assessments, the urine pregnancy test may be deferred except for visits during which FDG-PET or florbetapir PET are administered.  Serum and 
urine pregnancy testing will apply to all women unless documented (by medical records or physician’s note) to be surgically sterile or postmenopausal as defined in 
Section 3.5.5. 
r Vital signs will include measurements of temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure while the participant has been supine for 
3 minutes.  On study drug administration days, record vital signs just prior to IV infusion, at the end of IV infusion, and  60 minutes after the end of the IV infusion. 
s Participants will be observed for a minimum of 60 minutes following administration of study drug by IV infusion. 
t 
Although visit windowing for dosing days allows for  5 days around any expected visit day, the interval between study drug administrations from 1 monthly visit to the 
following monthly visit must be between 21 and 35 days. 
u During the treatment period:  Participants who develop  8 amyloid-related imaging abnormalities hemosiderin deposition cumulatively will receive a lower dose of the 
study drug.  Participants who develop  10 amyloid-related imaging abnormalities-hemosiderin deposition cumulatively will be permanently discontinued from the study 
drug.  Cumulative is the sum of amyloid-related imaging abnormalities hemosiderin deposition at baseline and newly detected amyloid-related imaging abnormalities-
hemosiderin deposition during the study. 
v Following transition from SC to IV (higher dose) administration, participants should receive an MRI scan after 3 and 6 months of initiation of IV treatment.  Thereafter, MRI 
should be scheduled every 2428 weeks until the end of the study or ET. 
w Urine pregnancy test must be administered and have a negative result prior to a PET scan. It is recommended, but not required, to use effective contraception during 
sexual intercourse occurring within 24 hours following a male or female participant receiving a florbetapir PET or FDG-PET scan 
x FDG-PET and fibrillar amyloid PET scans should be performed only if the investigator has determined that the total radiation exposure from the ET FDG-PET and fibrillar 
amyloid PET scans does not exceed local safety guidelines. 
y If MRI and FDG-PET scans are performed on the same day, the FDG-PET scan should be performed first. 
z Participant must be fasting (water only) for a minimum of 4 hours prior to the scan.  Fluorodeoxyglucose-PET should be performed a minimum of 12 hours and a 
maximum of 7 days apart from the accompanying fibrillar amyloid PET scan.  For each participant, best efforts should be exerted to perform subsequent FDG-PET scans 
at the same time of day as the baseline scan. 
aa It is strongly preferred that the LP be performed in the morning.  Participants will be required to stay in the clinic or hospital for approximately 1 hour after the LP for safety 
follow-up.  For each participant, best efforts should be exerted to perform subsequent LPs at the same time of day as the baseline LP.  See protocol (Section 4.5.1.10) for 
additional details regarding LP. 

Appendix 4 
(IV Dosing) Study Flowchart (Week 108–End of Study Period A) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
139/Protocol GN28352, Version 11 
Note:  On treatment days, all assessments should be performed prior to dosing unless otherwise noted. 
a Participants who discontinue from study drug treatment (early discontinuation) will not receive further doses of study drug, but should be asked to stay in the study for 
subsequent safety, cognitive, and biomarker assessments at complex visits, including at Weeks 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, 260, and every 2428 weeks 
thereafter until the study ends.  In addition, the suicidality assessment, review of concomitant medications and adverse events should be collected at Weeks 12, 64, 92, 
116, 144, 168, 196, 220, 248, and every 2428 weeks until the study ends; these assessments may be completed by telephone (but it is preferred they be completed in 
person). If a phone visit it completed during these weeks, vital signs assessments may be omitted. 
b If a participant discontinues from the study (ET) or discontinues from study drug treatment and elects to no longer stay in the study, ET Visit A should be completed if the 
last visit occurred more than 12 weeks after functional, behavioral and cognitive assessments were performed. 
c If a participant discontinues from the study (ET) or discontinues from study drug treatment and elects to no longer stay in the study, ET Visit B should be performed if the 
last visit occurred within 12 weeks of functional, behavioral, and cognitive assessments.  
d Safety follow-up 16 weeks after last dose is only applicable to participants that do not consent to participate in the continued access study. 
e Weight should be obtained at all weeks marked on the study flowchart. 
f Cognitive and selected other assessments (GDS, SMC, CDR, and suicidality assessment) should not be administered to the participant immediately after dosing or any 
potentially stressful procedures (e.g., blood draws, LPs, imaging).  Also, participants should not perform these assessments while fasting.  For each participant, best 
efforts should be exerted to perform subsequent assessments at the same time of day as the baseline assessments. 
g In rare instances, these assessments permitted by phone or video technology (see Section 4.5.4). 
h The SPCQ, CDR (study partner portion), FAST, SMC, and NPI should be administered to the same study partner throughout the study.  Best efforts should be exerted in 
order for the study partner to be present for all other visits requiring study partner assessments.  In rare instances, for which the study partner cannot be present in person, 
these assessments may be administered by telephone.  See Appendix 7 for additional details regarding study partner considerations. 
i The API ADAD Composite Cognitive Test Battery should be administered in the following order:  MMSE, Multilingual Naming Test, Word List:  Memory, CERAD 
Constructional Praxis, Word List:  Recall, Word List:  Recognition, Raven’s Progressive Matrices–Set A. 
j The Extended Cognitive Battery should be administered after the API ADAD Composite Cognitive Test Battery. 
k Study partner portion of the CDR must be administered prior to the participant portion of the CDR. 
l Completed prior to the administration of all other study partner assessments at each visit. 
m Includes pH, protein, glucose, ketones, bilirubin, blood, specific gravity, leukocyte esterase, urobilinogen, and nitrite, as well as microscopic analysis on the basis of 
dipstick results. 
n Includes sodium, potassium, BUN, bicarbonate, estimated glomerular filtration rate, calcium, AST, ALT, -glutamyl transpeptidase, total and direct bilirubin, alkaline 
phosphatase, lactate dehydrogenase, total protein, albumin, glucose, cholesterol, triglycerides, uric acid, creatine phosphokinase, and glycosylated hemoglobin.  
At screening, this sample will also include vitamin B12, ultrasensitive thyroid-stimulating hormone, and thyroxine.  Participants will be fasting (water only) for blood tests 
only at screening; fasting is not required at all visits. 
o Includes hematocrit, hemoglobin, RBC count, WBC count with differential and platelets.  Participants will be fasting (water only) for blood tests only at screening; fasting is 
not required at all visits. 
p Includes aPTT and INR.  Participants will be fasting (water only) for blood tests only at screening; fasting is not required at all timepoints. 

Appendix 4 
(IV Dosing) Study Flowchart (Week 108–End of Study Period A) (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
140/Protocol GN28352, Version 11 
q Routine ECGs will be calculated and read locally. 
r Collect PK, PD, and exploratory serum, plasma, and RNA samples prior to study drug administration. 
s Participants who experience serious or severe hypersensitivity reactions (e.g., hypotension, mucosal involvement) should not receive additional study drug.  In addition, in 
any case of anaphylaxis, anaphylactoid reaction, serious or severe hypersensitivity reaction, ADA, and concurrent PK samples should be collected as close as possible to 
the event, and then at 4 and 16 weeks postdose (see study flowchart for further details). 
t Includes amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opioids. 
u Urine pregnancy test must be administered and have a negative result prior to any study drug administration.  If the participant has discontinued study drug but is 
continuing with study assessments, the urine pregnancy test may be deferred except for visits during which FDG-PET or florbetapir PET scans are done.  Serum and 
urine pregnancy testing will apply to all women unless documented (by medical records or physician’s note) to be surgically sterile or postmenopausal as defined in 
Section 3.5.5. 
v Vital signs will include measurements of temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure while the participant has been supine for 
 3 minutes.  On study drug administration days, record vital signs just prior to the injection, at the end of IV infusion, and  60 minutes after the end of the IV infusion. 
w Although visit windowing for dosing days allows for  5 days around any expected visit day, the interval between study drug administrations from 1 monthly visit to the 
following monthly visit must be between 21 and 35 days. 
x Participants will be observed for a minimum of 60 minutes following administration of study drug by IV infusion. 
y During the treatment period:  Participants who develop  8 amyloid-related imaging abnormalities hemosiderin deposition cumulatively will receive a lower dose of the 
study drug.  Participants who develop  10 amyloid-related imaging abnormalities–hemosiderin deposition cumulatively will be permanently discontinued from the study 
drug.  Cumulative is the sum of amyloid-related imaging abnormalities hemosiderin deposition at baseline and newly detected amyloid-related imaging 
abnormalitieshemosiderin deposition during the study. 
z Following transition from SC to IV (higher dose) administration, participants should receive an MRI after 3 and 6 months of initiation of IV treatment.  Thereafter, MRI 
should be scheduled every 2428 weeks until the end of the study or ET. 
aa FDG-PET and fibrillar amyloid PET scans should be performed only if the investigator has determined that the total radiation exposure from the ET FDG-PET and fibrillar 
amyloid PET scans does not exceed local safety guidelines. 
bb Participant must be fasting (water only) for a minimum of 4 hours prior to the scan.  Fluorodeoxyglucose-PET should be performed a minimum of 12 hours and a 
maximum of 7 days apart from the accompanying fibrillar amyloid PET scan.  For each participant, best efforts should be exerted to perform subsequent FDG-PET scans 
at the same time of day as the baseline scan. 
cc If MRI and FDG-PET scans are performed on the same day, the FDG-PET scan should be performed first. 
dd It is strongly preferred that the LP be performed in the morning.  Participants will be required to stay in the clinic or hospital for approximately 1 hour after the LP for safety 
follow-up.  For each participant, best efforts should be exerted to perform subsequent LPs at the same time of day as the baseline LP.  See Section 4.5.1.10 for additional 
details regarding LP. 
ee The LP for CSF, FDG-PET, and amyloid PET scans is not required at ET (A or B) if it has been done within 24 weeks of ET 
 

Appendix 5 
Study Flow Chart for Study Period B:  SC Dosing (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
143/Protocol GN28352, Version 11 
a Week 1 is the first dose in Study Period B and may occur on the same day as the final ET-A or ET-B visit in Study Period A after all ET 
assessments are completed and the investigator deems dosing is appropriate. 
b Early termination visit/SFU visit, occurring when someone terminates prior to the end of the Study Period B, should be done 16 weeks after the 
last dose of study drug.  Participants who continue crenezumab treatment after the end of Study Period B will not have a “last dose  16 weeks 
visit”. 
c Informed consent to continue into Study Period B must be obtained at or before the Week 1 visit in Study Period B. 
d Vital signs include measurements of pulse rate, systolic and diastolic blood pressure, respiratory rate, and body temperature.  The same arm 
should be used for all blood pressure measurements.  Participants should rest  3 minutes in a quiet room before pulse rate and blood pressure 
are measured.  On study drug administration days, vital sign assessments should be performed prior to study drug administration. 
e Urinalysis will be performed by dipstick for pH, protein, glucose, ketones, nitrites, bilirubin, blood, specific gravity, leukocyte esterase, 
urobilinogen.  Microscopic examination should be performed at the central laboratory if blood and/or protein results are positive. 
f Females of childbearing potential (including those who have had a tubal ligation) must have a pregnancy test (urine is preferred, but can be 
replaced with blood if urine sample cannot be collected) prior to each dose administration.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test at the central laboratory.  
g PK and ADA samples should be obtained prior to study drug administration on the same day of dosing.  Accurate recording of the time of study 
drug administration and pharmacokinetics is critical.  Unscheduled PK samples should be taken in the event of anaphylaxis, anaphylactoid, or 
serious or severe hypersensitivity reactions.  For any participant suspected of developing anaphylaxis, or anaphylactoid or serious or severe 
hypersensitivity reactions warranting discontinuation of dosing, ADA and concurrent PK samples as well as any clinically relevant samples 
(such as total tryptase) should be collected as close as possible to the event, and then at 4 and 8 weeks postdose. 
h PD plasma sample collection prior to study drug administration. 
i Perform after the participant has been at rest in a supine position.  Electrocardiograms for each participant should be obtained from the same 
machine whenever possible and performed prior to any other assessments (e.g., vital signs). 
j Complete physical and neurologic examinations should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Neurologic examinations should include assessment of 
mental status, level of consciousness, cranial nerve function (including fundoscopic examination), motor function, sensory function, reflexes, 
coordination, and assessment of gait.  Other examination components or systems may be assessed as clinically indicated.  Symptom-directed 
physical and neurologic examinations may be done at any other visit as needed to assess the safety of the participant. 
k Serum chemistry includes sodium, potassium, BUN, bicarbonate, estimated glomerular filtration rate, calcium, AST, ALT, -glutamyl 
transpeptidase, total and direct bilirubin, alkaline phosphatase, lactate dehydrogenase, total protein, albumin, glucose, cholesterol, triglycerides, 
uric acid, creatine phosphokinase, and glycosylated hemoglobin. 
l Hematology includes WBC count with differential, RBC count, hemoglobin, hematocrit, and platelet count  
m MRIs should be done at Week 105 or ET if ET is prior to Week 105.  However, MRI may be done at any visit if clinically indicated for new or 
unexplained neurologic symptoms. 

Appendix 5 
Study Flow Chart for Study Period B:  SC Dosing (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
144/Protocol GN28352, Version 11 
n For the optional CSF sample, only those participants that previously consented to these optional assessments in Study GN28352 have the 
option to continue to provide sample in this study.  A separate optional consent signature is required for this assessment.  
Cerebrospinal fluid samples should be collected prior to dosing on the same day of dosing or the day prior to dosing.  It is critical that the actual 
date and the time of sample collection is recorded. A follow up phone call should be made to the participant the day after the CSF collection.  
The CSF sample will also be used to determine crenezumab CSF concentration. 
o Optional tau-PET scan, only for those participants who previously consented to these optional tau PET substudy. 
p Cerebrospinal fluid and/or PET assessments to be performed at Week 105 or ET if ET is prior to Week 105.  Cerebrospinal fluid and/or PET 
assessments will not be performed at the ET visit if less than 6 months have elapsed since the previous CSF and/or PET assessment.  If needed 
because of operational constraints, CSF and/or PET assessments can be performed up to 3 months after Week 105.  Cerebrospinal fluid and 
PET assessments should not be done on the same day, but at least 24 hours apart. Amyloid PET and Tau PET assessments should not be 
done on the same day, but at least 24 hours apart.  
q Cognitive and selected other assessments (GDS, SMC, CDR, and suicidality assessment) should not be administered to the participant 
immediately after dosing or any potentially stressful procedures (e.g., blood draws, CSF sampling, imaging).  Also, participants should not 
perform these assessments while fasting.  For each participant, best efforts should be exerted to perform subsequent assessments at the same 
time of day as the baseline assessments. 
r In exceptional instances, these assessments are permitted by phone or video technology. 
s The API ADAD Composite Cognitive Test Battery includes the following assessments which should be administered in this order:  MMSE, 
Multilingual Naming Test, Word List:  Memory, CERAD Constructional Praxis, Word List:  Recall, Word List:  Recognition, Raven’s Progressive 
Matrices–Set A.  The API ADAD composite should also be administered before administering FCSRT, Trail Making Test, and RBANS. 
t The SPCQ, CDR (study partner portion), FAST, SMC, and NPI should be administered to the same study partner throughout the study.  
Best efforts should be exerted in order for the study partner to be present for all visits requiring study partner assessments.  In rare instances, for 
which the study partner cannot be present in person, these assessments may be administered by telephone. 
u Completed prior to the administration of all other study partner assessments at each visit. 
v Study drug administration should be performed only after all assessments/rating scales have been completed (unless indicated otherwise).  
Study drug will be administered to participants by injection (full details in the pharmacy manual).  Participants must be observed for a minimum of 
15 minutes after dosing. 
w Although visit windowing for dosing days allows for  7 days around any expected visit day, the interval between study drug administrations from 
one biweekly visit to the following biweekly visit must be between 8 and 20 days. 
x There should be a telephone call to the participant the day after the first infusion. 
 

Appendix 6 
Study Flow Chart for Study Period B:  IV Dosing (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
147/Protocol GN28352, Version 11 
NPI  Neuropsychiatric Inventory; PD  pharmacodynamic; PET  positron emission tomography; PK  pharmacokinetic; RBANS  Repeatable 
Battery for the Assessment of Neuropsychological Status; SFU  safety follow-up; SMC  Subjective Memory Checklist; SPCQ  Study Partner 
Characterization Questionnaire; W  week. 
a Week 1 is the first dose in Study Period B and may occur on the same day as the final ET-A or ET-B visit in Study Period A after all ET 
assessments are completed and the investigator deems dosing is appropriate. 
b Early termination visit/SFU visit, occurring when someone terminates prior to the end of the Study Period B, should be done 16 weeks after the 
last dose of study drug.  Participants who continue crenezumab treatment after the end of Study Period B will not have a “last dose  16 weeks 
visit”. 
c Informed consent to continue into Study Period B must be obtained at or before the Week 1 visit in Study Period B. 
d Vital signs include measurements of pulse rate, systolic and diastolic blood pressure, respiratory rate, and body temperature.  The same arm 
should be used for all blood pressure measurements.  Participants should rest for  3 minutes in a quiet room before pulse rate and blood 
pressure are measured. On study drug administration days, vital sign assessments should be performed just prior to the infusion, at the end of IV 
infusion, and  60 minutes after the end of the IV infusion. 
e Urinalysis will be performed by dipstick for pH, protein, glucose, ketones, nitrites, bilirubin, blood, specific gravity, leukocyte esterase, 
urobilinogen.  Microscopic examination should be performed at the central laboratory if blood and/or protein results are positive. 
f Females of childbearing potential (including those who have had a tubal ligation) must have a pregnancy test (urine is preferred, but can be 
replaced with blood if urine sample cannot be collected) prior to each dose administration.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test at the central laboratory.  
g PK and ADA samples should be obtained prior to study drug administration on the same day of dosing.  Accurate recording of the time of study 
drug administration and pharmacokinetics is critical.  Unscheduled PK samples should be taken in the event of anaphylaxis, anaphylactoid, or 
serious or severe hypersensitivity reactions.  For any participant suspected of developing anaphylaxis, or anaphylactoid or serious or severe 
hypersensitivity reactions warranting discontinuation of dosing, ADA and concurrent PK samples as well as any clinically relevant samples 
(such as total tryptase) should be collected as close as possible to the event, and then at 4 and 8 weeks postdose. 
h PD plasma sample collection prior to study drug administration. 
i Perform after the participant has been at rest in a supine position.  Electrocardiograms for each participant should be obtained from the same 
machine whenever possible and performed prior to any other assessments (e.g., vital signs). 
j Complete physical and neurologic examinations should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Neurologic examinations should include assessment of 
mental status, level of consciousness, cranial nerve function (including fundoscopic examination), motor function, sensory function, reflexes, 
coordination, and assessment of gait.  Other examination components or systems may be assessed as clinically indicated.  Symptom-directed 
physical and neurologic examinations may be done at any other visit as needed to assess the safety of the participant. 
k Serum chemistry includes sodium, potassium, BUN, bicarbonate, estimated glomerular filtration rate, calcium, AST, ALT, -glutamyl 
transpeptidase, total and direct bilirubin, alkaline phosphatase, lactate dehydrogenase, total protein, albumin, glucose, cholesterol, triglycerides, 
uric acid, creatine phosphokinase, and glycosylated hemoglobin. 

Appendix 6 
Study Flow Chart for Study Period B:  IV Dosing (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
148/Protocol GN28352, Version 11 
l Hematology includes WBC count with differential, RBC count, hemoglobin, hematocrit, and platelet count.  
m MRIs should be done at Week 105 or ET if ET is prior to Week 105.  However, MRI may be done at any visit if clinically indicated for new or 
unexplained neurologic symptoms. 
n For the optional CSF sample, only those participants that previously consented to these optional assessments in Study GN28352 have the 
option to continue to provide samples in this study.  A separate consent signature is required for each of this assessment.  Cerebrospinal fluid 
samples should be collected prior to dosing on the same day of dosing or the day prior to dosing.  It is critical that the actual date and the time of 
sample collection is recorded.  A follow-up phone call should be made to the participant the day after the CSF collection.  The CSF sample will 
also be used to determine crenezumab CSF concentration. 
o Optional tau-PET scan, only for those participants who previously consented to these optional tau PET substudy. 
p Cerebrospinal fluid and/or PET assessments to be performed at Week 105 or ET if ET is prior to Week 105.  Cerebrospinal fluid and/or PET 
assessments will not be performed at the ET visit if less than 6 months have elapsed since the previous CSF and/or PET assessment.  If needed 
because of operational constraints, CSF and/or PET assessments can be performed up to 3 months after Week 105.  Cerebrospinal fluid and 
PET assessments should not be done on the same day, but at least 24 hours apart.  Amyloid PET and Tau PET assessments should not be 
done on the same day, but at least 24 hours apart.  
q Cognitive and selected other assessments (GDS, SMC, CDR, and suicidality assessment) should not be administered to the participant 
immediately after dosing or any potentially stressful procedures (e.g., blood draws, CSF sampling, imaging).  Also, participants should not 
perform these assessments while fasting.  For each participant, best efforts should be exerted to perform subsequent assessments at the same 
time of day as the baseline assessments. 
r In exceptional instances, these assessments are permitted by phone or video technology. 
s The API ADAD Composite Cognitive Test Battery includes the following assessments which should be administered in this order:  MMSE, 
Multilingual Naming Test, Word List:  Memory, CERAD Constructional Praxis, Word List:  Recall, Word List:  Recognition, Raven’s Progressive 
Matrices–Set A.  The API ADAD composite should also be administered before administering FCSRT, Trail Making Test, and RBANS. 
t The SPCQ, CDR (study partner portion), FAST, SMC, and NPI should be administered to the same study partner throughout the study.  
Best efforts should be exerted in order for the study partner to be present for all visits requiring study partner assessments.  In rare instances, for 
which the study partner cannot be present in person, these assessments may be administered by telephone. 
u Completed prior to the administration of all other study partner assessments at each visit. 
v Study drug administration should be performed only after all assessments/rating scales have been completed (unless indicated otherwise).  
Study drug will be administered to participants by injection (full details in the pharmacy manual).  Participants must be observed for a minimum of 
60 minutes after dosing. 
w Although visit windowing for dosing days allows for  7 days around any expected visit day, the interval between study drug administrations from 
1 monthly visit to the following monthly visit must be between 21 and 35 days. 
x There should be a telephone call to the participant the day after the first infusion. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
149/Protocol GN28352, Version 11 
APPENDIX 7  
Neurocognitive and Functional Assessments 
Several cognitive, functional, and behavioral assessments will be administered during 
the course of this study.  These assessments will be given to the participant, the study 
partner, or both.  The cognitive test batteries include a Screening Battery, 
Alzheimer’s Prevention Initiative (API) autosomal-dominant Alzheimer’s Disease (ADAD) 
Composite Cognitive Test Battery, and the Extended Cognitive Battery.  
Additional functional and behavioral assessments and other self-reported questionnaires 
will also be administered.  The various assessments are described briefly below. 
SCREENING BATTERY 
The Screening Battery consists of the Mini-Mental State Examination 
(MSE, Folstein et al. 1975) and the Word List (Rosen et al. 1984; Morris et al. 1989; 
Mohs et al. 1997).  The scores obtained on these assessments will be used in 
determining trial eligibility.  Descriptions of these tests are provided below. 
MINI-MENTAL STATE EXAMINATION (MMSE) 
The MMSE (Folstein et al. 1975) is a screening instrument frequently used for 
Alzheimer’s disease drug studies (Folstein et al. 1975).  It evaluates orientation, 
memory, attention, concentration, naming, repetition, comprehension, the ability to 
create a sentence, and copy a figure.  Scores range from 0 to 30. 
WORD LIST  
Word List is a measure of delayed verbal memory that is administered per the 
Consoritum to Establish a Registry for Alzheimer’s Disease (CERAD) test protocol 
(Morris et al. 1989), comprised of four parallel word lists derived from the ADAS-Cog 
word pool (Rosen et al. 1984; Mohs et al. 1997).  Word List consists of three 
components:  Memory, Recall, and Recognition.  Scores range from 0–30 for the 
Word List:  Memory, 0–10 for Word List:  Recall, and 0–10 for Word List:  Recognition.  
Although all components of the Word List will be administered, for calculation of the 
composite cognitive endpoint, only the Word List:  Recall score will be used. 
API ADAD COMPOSITE COGNITIVE TEST BATTERY 
The tests comprising the API ADAD Composite Cognitive Test Battery were selected 
using over 10 years of neuropsychological longitudinal data collected from the Colombia 
PSEN1 E280A population and applying specific statistical techniques to extract the test 
combination that is most sensitive to cognitive decline and progression.  The API ADAD 
Composite Cognitive Test Battery was chosen for its sensitivity to measure clinical 
change in this and other at-risk populations after controlling for practice effects.  
The battery consists of the MMSE (orientation to time), Word List:  Recall, CERAD 
Constructional Praxis, Multilingual Naming Test, and Raven’s Progressive Matrices. 

Appendix 7 
Neurocognitive and Functional Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
150/Protocol GN28352, Version 11 
MINI-MENTAL STATE EXAM (MMSE) 
The MMSE (Folstein et al. 1975) is a screening instrument frequently used for 
Alzheimer’s disease (AD) drug studies (Folstein et al. 1975).  It evaluates orientation, 
memory, attention, concentration, naming, repetition, comprehension, the ability to 
create a sentence and copy a figure.  Total score ranges from 0 to 30.  For calculation of 
the API ADAD Composite Cognitive endpoint, only the Orientation to Time score from 
the MMSE, which ranges from 0 to 5, will be used. 
WORD LIST 
Word List is a measure of delayed verbal memory that is administered per the CERAD 
test protocol (Morris et al. 1989), comprised of four parallel word lists derived from the 
ADAS-Cog word pool (Rosen et al. 1984; Mohs et al. 1997).  Word List consists of three 
components:  Memory, Recall, and Recognition.  Scores range from 030 for the Word 
List: Memory, 0–10 for Word List: Recall, and 0–10 for Word List: Recognition.  
Although all components of the Word List will be administered, for calculation of the API 
ADAD Composite Cognitive endpoint, only the Word List:  Recall score will be used. 
CONSORTIUM TO ESTABLISH A REGISTRY FOR ALZHEIMER’S DISEASE 
CONSTRUCTIONAL PRAXIS – IMMEDIATE RECALL  
The CERAD (Rosen et al. 1984; Morris et al. 1989) neuropsychological test battery has 
been used widely for evaluation of the cognitive deficits associated with AD.  It has also 
been used by Dr. Lopera and colleagues in presymptomatic longitudinal research after 
being adapted to the cultural and linguistic idiosyncrasies of the Colombian culture 
(CERAD Col) (Aguirre-Acevedo et al. 2007).  The CERAD Constructional Praxis test 
consists of four line drawings of increasing complexity.  Participants are shown a figure 
and are then asked to immediately recall the figure.  Scores range from 0 to 11. 
MULTILINGUAL NAMING TEST 
The Multilingual Naming Test (Gollan et al. 2012) is a measure of visual confrontation 
naming that requires the participant to name objects depicted in outline drawings.  
The drawings are graded in difficulty, with the easiest drawings presented first.  
Difficulty of items is assigned by frequency of occurrence.  This study will be using a 
15-item subset of the 67 pictures comprising the complete test.  This subset consists of 
five drawings from each of the low, medium, and high frequency categories.  Total score 
ranges from 0–15. 
RAVEN’S PROGRESSIVE MATRICES 
This is a non-verbal, multiple-choice measure of general ability and reasoning in the 
visual modality (Raven 1976).  It was designed to be culturally nonbiased, as neither 
language nor academic skills are required to answer items successfully.  The test 
requires conceptualization of spatial design and numerical relationships with varying 

Appendix 7 
Neurocognitive and Functional Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
151/Protocol GN28352, Version 11 
levels of difficulty.  For each item a participant is asked to identify the missing 
component to complete a pattern.  For this study, only Set A, consisting of 12 items, will 
be administered.  Total scores range from 0–12. 
EXTENDED COGNITIVE BATTERY 
The Extended Cognitive Battery consists of Free and Cued Selective Reminding Task 
(FCSRT) (Grober and Buschke 1987), Trail Making Test (Armitage 1946), and 
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
(Randolph 1998).  
FREE AND CUED SELECTIVE REMINDING TASK 
The Buschke FCSRT (Grober and Buschke 1987) provides assessment of immediate 
and delayed verbal episodic memory, using Controlled Learning to optimize encoding 
specificity for more effective recall (Buschke 1984; Grober et al. 1997).  For this test, 
16 items, each from a different semantic category, is presented on cards, four to a card.  
The participant’s task is to learn the items, and attempt a free recall of the items, followed 
by a semantically cued recall of items not spontaneously produced by the participant 
during free recall.  There are a total of three learning trials, each preceded by 20 seconds 
of an interfering cognitive task (counting backwards).  For the first two trials, the 
participant will be reminded of any item not recalled in the cued recall.  The free and cued 
recall assessment occurs both immediately, after each of the three learning trials, and 
again after a delay of approximately 30 minutes.  A unique characteristic of this test is its 
use of controlled, semantic encoding by providing category cues during the learning 
(encoding) phase of the test.  This test is thought to be sensitive to conditions, such as 
AD that compromise the functioning of the hippocampus and connected networks.   
TRAIL MAKING TEST:  PARTS A AND B 
Part A consists of 25 circles, numbered 1 through 25, distributed over a white sheet of 
8 1/2"  11" paper.  The participant is instructed to connect the circles with a drawn line 
as quickly as possible in ascending numerical order.  Part B also consists of 25 circles, 
but these circles are either numbered (1 through 13) or contain letters (A through L).  
Now the participant must connect the circles while alternating between numbers and 
letters in an ascending order (e.g., 1 to A; A to 2; 2 to B; B to 3, etc.).  The participant's 
performance is judged in terms of the time (in seconds) required to complete each trail, 
the number of digits correctly connected, and by the number of errors of commission.  
The time to complete Part A (180-second maximum) and B (300-second maximum) will 
be the primary measures of interest (testing is stopped if the maximum time is reached).  
Although both Parts A and B depend on visuomotor and perceptual-scanning skills, 
Part B also requires considerable cognitive flexibility in shifting from number to letter sets 
under time pressure.  Both parts of the Trail-Making Test are available in multiple forms 
of equal difficulty for purposes of repeated evaluation (Armitage 1946). 

Appendix 7 
Neurocognitive and Functional Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
152/Protocol GN28352, Version 11 
REPEATABLE BATTERY FOR THE ASSESSMENT OF 
NEUROPSYCHOLOGICAL STATUS (RBANS)  
The RBANS (Randolph 1998) is a standardized brief, individually administered 
neurocognitive battery measuring attention, language, visuospatial/constructional 
abilities, and immediate and delayed memory.  The test, available in four parallel 
versions, consists of 12 subtests. 
OTHER ASSESSMENTS 
SUBJECTIVE MEMORY CHECKLIST (SMC)   
The SMC (Acosta-Baena et al. 2011) is an assessment developed by researchers at the 
University of Antioquia to collect subjective ratings of memory status from both a 
participant and an informant.  Participants and informants are asked to rate how often 
the given participant has difficulties relating to memory and thinking in a variety of areas.  
The scale employs a Likert-type scale, including rating options of 0 (never), 1 (rarely), 
2 (often), and 3 (always).  The SMC has a study partner portion, as well as a participant 
portion.   
SUICIDALITY ASSESSMENT 
The suicidality assessment is a tool used to assess the suicidality of a participant 
throughout the trial.  It will consist of two questions, administered to the participant, 
which assess current and previous suicidal ideation/behavior, followed by a global 
assessment of suicidality by a qualified clinician.  Questions to be included in this 
assessment are as follows: 
 
Since your last assessment (or, at the baseline visit, in the last 30 days): 
1. 
Have you thought you would be better off dead, wished you were dead, or had 
thoughts of killing yourself in any way? 
  YES  
  NO 
2. 
Have you done anything on purpose to harm yourself or tried to kill yourself? 
  YES  
  NO 
Global Assessment by qualified clinician  
3. 
Does the subject appear suicidal? 
  YES  
  NO 

Appendix 7 
Neurocognitive and Functional Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
153/Protocol GN28352, Version 11 
If the response is “YES” to Questions 1 or 2, or if the response to Question 3 reveals a 
concern about a significant level of suicidality, the subject would undergo a more 
detailed assessment by a qualified clinician who has experience in the evaluation of 
suicidal ideation and behavior, either at the site or by referral to an outside clinician.  
In either case, appropriate documentation of the clinical issues and management plan 
will be required in a narrative that would be part of the participant’s study record. 
Because of concerns about burden in such a long trial, the protocol is designed in such a 
way as to try to achieve the trial’s overarching goals while balancing feasibility and 
burden issues.  In the case of assessment of suicidality in this preclinical population, 
some suicidality assessments will be allowed to be conducted by telephone, using the 
same staff that would conduct these assessments in person and who would already 
know the participant. 
CLINICAL DEMENTIA RATING (CDR)   
The standard CDR (Morris 1993) describes five degrees of impairment in performance 
on each of six categories of cognitive functioning, including memory, orientation, 
judgment and problem solving, community affairs, home and hobbies, and personal 
care.  The ratings of degree of impairment obtained on each of the six categories of 
function are synthesized into one global rating of dementia (ranging from 0 to 3), with 
more refined measure of change available by use of the CDR Sum of Boxes 
(Berg et al. 1992).  Reliability and validity has been established, as has high inter-rater 
reliability.  This will be used as a global measure of severity of cognitive and functional 
impairment. 
GERIATRIC DEPRESSION SCALE (GDS)   
The GDS (Sheikh and Yesavage 1986) (Short Form) is a scale designed to identify 
symptoms of depression in the elderly.  The scale consists of 15 printed questions that 
the participant is asked to answer on the basis of how they felt over the past week.  
The items are presented on a single page with more benign items presented first.  
One point is given for each appropriate answer indicative of a symptom of depression, 
for a possible total of 15 points.  Total scores of 0–4 are considered normal, scores of 
58 suggest mild depression, scores of 9–11 suggest moderate depression, and scores 
of 12–15 suggest severe depression.  
STUDY PARTNER ASSESSMENTS 
The following assessments will be administered to the study partner.  As noted above, 
some of these will be performed in person at screening and baseline; it is preferable that 
they are performed in person.  They may be performed by telephone at some visits.  
The CDR has a study partner portion in addition to participant portion and should be 
performed in person, when possible. 

Appendix 7 
Neurocognitive and Functional Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
154/Protocol GN28352, Version 11 
STUDY PARTNER CHARACTERIZATION QUESTIONNAIRE (SPCQ)  
The SPCQ is a brief set of questions developed internally by Banner and designed to 
identify the study partner, assess the participant’s living arrangements (living alone 
versus with others; identification of others living with participant), and assess the study 
partner’s relationship with the participant. 
NEUROPSYCHIATRIC INVENTORY QUESTIONNAIRE (NPI)   
The NPI (Kaufer et al. 2000; Cummings et al. 1994) is a well-validated, reliable, 
multi-item instrument to assess psychopathology in AD, as well as level of distress 
experienced by the informant in response to the presence of a given feature.  
The assessment is on the basis of an interview with an informant and is relatively brief 
( 15 minutes).  These properties make it well suited for a multicenter trial.  It evaluates 
both the presence and severity and informant distress of 10 neuropsychiatric features, 
including delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, 
disinhibition, irritability, lability, apathy, and aberrant motor behavior. 
FUNCTIONAL ASSESSMENT STAGING TEST (FAST)   
The FAST (Reisberg 1988) was developed for use with AD patients to stage a patient’s 
level of disability with respect to AD.  The FAST is comprised of 7 major levels of 
functioning (from normal adult to severe AD); levels 6 and 7 are additionally divided into 
substages (11 total).  The FAST is derived from Axis V of the Brief Cognitive Rating 
Scale (BCRS) (Reisberg et al. 1983), which itself is derived from the Global Deterioration 
Scale (Reisberg et al. 1982).  The stages and substages are, thus, designed to correlate 
with the Global Deterioration Scale global level of cognition and functional capacity 
measures (Sclan and Reisberg 1992). 
CLINICAL DEMENTIA RATING (MORRIS 1993)   
See Other Assessments for description of study partner portion. 
SUBJECTIVE MEMORY CHECKLIST (SMC) (ACOSTA-BAENA ET AL. 2011) 
See Other Assessments for description. 

 
Crenezumab—F. Hoffmann-La Roche Ltd 
155/Protocol GN28352, Version 11 
REFERENCES (APPENDIX 7 ONLY) 
Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, et al. Pre-dementia clinical 
stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a 
retrospective cohort study. Lancet Neurol 2011;10:21320. 
Aguirre-Acevedo DC, Gómez RD, Moreno S, et al. Validity and reliability of the 
CERAD-Col neuropsychological battery. Rev Neurol 2007;45:65560. 
Armitage SG. An analysis of certain psychological tests used for the evaluation of brain 
injury. Psychological Monographs 1946;60:i48. 
Berg L, Miller JP, Baty J, et al. Mild senile dementia of the Alzheimer type. 4. Evaluation 
of intervention. Ann Neurol 1992;31:2429. 
Buschke H. Cued recall in amnesia. J Clin Neuropsychol 1984;6:43340. 
Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive 
assessment of psychopathology in dementia. Neurology 1994;44:230814. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res 
1975;12:18998. 
Gollan TH, Weissberger GH, Runnqvist E, et al. Self-ratings of spoken language 
dominance: a multi-lingual naming test (MINT) and preliminary norms for young 
and aging Spanish-English bilinguals. Biling (Camb Engl) 2012;15:594615. 
Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol 
1987;3:1336. 
Grober E, Merling A, Heimlich T, et al. Free and cued selective reminding and selective 
reminding in the elderly. J Clin Exp Neuropsychol 1997;19:64354. 
Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form of 
the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci 2000;12:2339. 
Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for 
use in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease 
Assessment Scale that broaden its scope. The Alzheimer’s Disease Cooperative 
Study. Alzheimer Dis Assoc Disord 1997;11:S1321. 
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology 1993;43:24124. 
Morris JC, Heyman A, Mohs RC, et al. The Consortium to Establish a Registry for 
Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment 
of Alzheimer's disease. Neurology 1989;39:115965. 
Randolph C. Repeatable Battery for the Assessment of Neuropsychological Status. 
San Antonio, TX: The Psychological Coporation, 1998.  

Appendix 7 
Neurocognitive and Functional Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
156/Protocol GN28352, Version 11 
Raven JC. Revised Manual for Raven's Progressive Matrices and Vocabulary Scale. 
New York: The Psychological Corporation, Harcourt Brace Jovanovich, Inc., 1976. 
Reisberg B. Functional assessment staging (FAST). Psychopharmacol Bull 
1988;24:6539. 
Reisberg B, Ferris SH, de Leon MJ, et al. The Global Deterioration Scale for assessment 
of primary degenerative dementia. Am J Psychiatry 1982;139:11369. 
Reisberg B, Schneck M, Ferris S, et al. The Brief Cognitive Rating Scale (BCRS): 
findings in primary degenerative dementia. Psychopharmacol Bull 1983;47:4750. 
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J 
Psychiatry 1984;141:135664. 
Sclan SG, Reisberg B. Functional assessment staging (FAST) in Alzheimer's disease:  
reliability, validity, and ordinality. Int Psychogeriatr 1992;4:5569. 
Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontologist: J Aging Mental Health 
1986;5:16573. 

Signature Page for: System identifier:RIM-CLIN-439364
Protocol - GN28352 - CRENEZUMAB - v11 - Published
Approval Task
Company Signatory
10-May-2022 14:04:10 GMT+0000