Longitudinal Early-onset Alzheimer's Disease Study Protocol
Conditions: Early Onset Alzheimer Disease, Alzheimer Disease, Mild Cognitive Impairment
Sponsor: Indiana University

 
 
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Longitudinal Early-onset Alzheimer’s Disease Study (LEADS) Protocol 
 
Protocol Short Title: LEADS 
 
Protocol Number:  ATRI-003 
 
PRINCIPAL INVESTIGATORS 
Liana Apostolova, M.D., M.Sc. 
Brad Dickerson, M.D. 
Gil Rabinovici, M.D. 
Maria Carrillo, Ph.D. 
PROJECT DIRECTOR 
CLINICAL CORE - LEAD 
ADMINISTRATIVE CORE - LEAD 
ADMINISTRATIVE CORE 
Liana Apostolova, M.D., M.Sc. 
Indiana University 
Lapostol@iu.edu  
Liana Apostolova, M.D., M.Sc. 
Brad Dickerson, M.D. 
Gil Rabinovici, M.D. 
Maria Carrillo, Ph.D. 
 
CLINICAL COORDINATION CENTER 
GENETICS & BIOREPOSITORY CORE 
Paul Aisen, M.D. 
University of Southern California  
paisen@usc.edu 
Tatiana Foroud, Ph.D. 
Indiana University 
tforoud@iu.edu 
BIOSTATISTICS CORE 
INFORMATICS CORE 
 
 
Ani Eloyan, Ph.D. 
Brown University 
ani_eloyan@brown.edu 
 
Arthur Toga, Ph.D. 
University of Southern California 
toga@usc.edu 
 
MAGNETIC RESONANCE IMAGING 
CORE 
POSITRON EMISSION TOMORGRAPHY 
CORE 
Brad Dickerson, M.D. 
Massachusetts General Hospital/Harvard 
University 
brad.dickerson@mgh.harvard.edu 
Gil D. Rabinovici, M.D. 
University of California San Francisco 
Gil.rabinovici@ucsf.edu 
NEUROPATHOLOGY CORE 
 
Bernardino Ghetti, M.D. 
Indiana University 
bghetti@iupui.edu 
 
Kathy Newell, M.D. 
Indiana University 
klnewell@iu.edu  
 
Melissa Murray 
Mayo Clinic 
Murray.Melissa@mayo.edu 
 
Lea Grinberg 
University of California San Francisco 
Lea.Grinberg@ucsf.edu 

 
 
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Table of Contents 
LIST OF ABBREVIATIONS............................................................................................................. 5 
PROTOCOL SYNOPSIS.................................................................................................................... 7 
1.0 
BACKGROUND AND SIGNIFICANCE ............................................................................. 8 
2.0 
STUDY RATIONALE ........................................................................................................... 9 
3.0 
SCIENTIFIC AIMS .............................................................................................................. 10 
3.1 Aim 1 ..................................................................................................................................................... 10 
3.2 Aim 2 ..................................................................................................................................................... 10 
3.3 Aim 3 ..................................................................................................................................................... 11 
3.4 Exploratory Aim 4............................................................................................................................ 12 
3.5 Aim 5: ................................................................................................................................................... 12 
3.6 Aim 6: ................................................................................................................................................... 13 
4.0 
STUDY DESIGN AND INVESTIGATIONAL PLAN ..................................................... 14 
4.1 LEADS Consortium Structure ...................................................................................................... 14 
4.1.1 Administrative Core ..................................................................................................................................... 14 
4.1.2 Clinical Core ..................................................................................................................................................... 14 
4.1.3 MRI Core ............................................................................................................................................................ 14 
4.1.4 PET Core ............................................................................................................................................................ 14 
4.1.5 Genetics and Biorepository Core ............................................................................................................ 15 
4.1.6 Biostatistics Core ........................................................................................................................................... 15 
4.1.7 Informatics Core ............................................................................................................................................ 15 
4.1.8 Neuropathology Core................................................................................................................................... 16 
4.2 End of Study Definition .................................................................................................................. 16 
5.0 
STUDY POPULATION ...................................................................................................... 16 
5.1 Inclusion Criteria ............................................................................................................................. 16 
5.2 Exclusion Criteria ............................................................................................................................ 17 
6.0 
RECRUITMENT ................................................................................................................. 19 
7.0 
STUDY PROCEDURES ..................................................................................................... 19 
7.1 Description of Study Visits and Procedures .......................................................................... 19 
7.1.1 Prescreen phase (not an actual visit) ................................................................................................... 19 
7.1.2 Screening ........................................................................................................................................................... 19 
7.1.3 Active Study Phase (Baseline to Endpoint Assessments) ............................................................ 20 
7.1.4 Wellness Check ............................................................................................................................................... 20 
7.1.5 PET Scan Results Disclosure..................................................................................................................... 20 
7.1.6 Genetic Counseling Sessions and Genetic Testing Disclosure ................................................... 20 
7.1.7 Neuropathology ............................................................................................................................................. 21 
7.1.8 Study Participation Report........................................................................................................................ 22 
7.1.9 Participant Travel ......................................................................................................................................... 22 
7.2 Clinical Assessments and Procedures ...................................................................................... 22 
7.3 Cognitive Testing ............................................................................................................................. 26 
PROTOCOL VERSION 
 
 
VERSION DATE 
 
10.0 
May 23, 2024 

 
 
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7.3.1 NACC Uniform Data Set (UDS) and Frontotemporal Lobar Degeneration (FTLD) 
Neuropsychological Batteries .................................................................................................................. 26 
Montreal Cognitive Assessment (MoCA ............................................................................................ 26 
7.3.2 Additional Cognitive Tests: ....................................................................................................................... 28 
7.3.3 Additional Cognitive Tests to be Used at Select International Sites: ...................................... 28 
7.3.4 Audio Recording and Transcription ...................................................................................................... 29 
7.4 Imaging ................................................................................................................................................ 29 
7.4.1 Magnetic Resonance Imaging (MRI) ..................................................................................................... 29 
7.4.2 PET scanning. Amyloid, Tau, and FDG PET Imaging ...................................................................... 29 
7.5 Fluid Biomarker Collection .......................................................................................................... 34 
7.5.1 Peripheral Blood Collection for Fluid Biomarker Analyses ........................................................ 34 
7.5.2 Peripheral Blood Collection for Genetic Testing ............................................................................. 34 
7.5.3 Lumbar Puncture and CSF (optional) ................................................................................................... 35 
7.6 Safety Assessments ......................................................................................................................... 35 
7.6.1 Concomitant Medication Review ............................................................................................................ 35 
7.6.2 Safety Laboratory Assessments .............................................................................................................. 35 
7.6.3 Urine Pregnancy Test .................................................................................................................................. 36 
7.6.4 Brain Imaging .................................................................................................................................................. 36 
7.7 Biofluid Sample Processing ......................................................................................................... 36 
7.7.1 Site processing: .............................................................................................................................................. 36 
7.7.2 National Centralized Repository for Alzheimer’s Disease and Related Dementias 
(NCRAD) Sample Processing..................................................................................................................... 37 
8.0 
CRITERIA FOR REPEAT ASSESSMENTS, INCOMPLETE VISIT PROCEDURES, 
RESCREENING, EARLY TERMINATION, DISCONTINUATION, REMOTE 
PROCEDURES, AND RETURNING PARTICIPANTS. ............................................................. 37 
8.1 Re-screens .......................................................................................................................................... 37 
8.2 Repeat Assessments ....................................................................................................................... 37 
8.3 Incomplete Visit Procedures and Protocol Deviations ...................................................... 37 
8.4 Early Termination Visit ................................................................................................................. 38 
8.5 Discontinuation ................................................................................................................................ 38 
8.6 Participant Re-Contact after Study Withdraw ...................................................................... 38 
8.7 Remote Procedures......................................................................................................................... 39 
8.8 LEADS Participants Returning After Therapeutic Trial (Returning Participants 
(RPs)) 39 
9.0 
STUDY COMPOUNDS....................................................................................................... 39 
9.1 Florbetaben ........................................................................................................................................ 39 
9.2 C-Pittsburgh Compound B (11C-PiB) (for International sites only) ............................. 39 
9.3 [18F]NAV-4694 (for international sites only) ...................................................................... 40 
9.4 Flutemetamol (for international sites only).......................................................................... 40 
9.5 Flortaucipir ........................................................................................................................................ 40 
9.6 FDG ........................................................................................................................................................ 41 
10.0 SIDE EFFECTS .................................................................................................................... 41 
10.1 Lumbar Puncture .......................................................................................................................... 41 
10.2 PET Imaging .................................................................................................................................... 41 
10.2.1. Radiation Exposure................................................................................................................................... 41 
10.2.2 Other Side Effects Associated with Amyloid Tracers .................................................................. 42 
10.2.3 Other Side Effects Associated with Flortaucipir ........................................................................... 42 
10.3 Psychological Risks from Genetic Testing ........................................................................... 42 
10.4 Psychological Risks from PET Results ................................................................................... 42 
10.5 Loss of Privacy ................................................................................................................................ 43 

 
 
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11.0 ADVERSE EVENTS/UNANTICIPATED PROBLEMS ................................................ 43 
12.0 SERIOUS ADVERSE EVENTS (SAE) ............................................................................. 44 
12.1 Reporting of SAEs .......................................................................................................................... 45 
13.0 SITE QUALIFICATIONS ................................................................................................... 45 
13.1 Study Personnel ............................................................................................................................. 45 
13.2 MRI Instrument .............................................................................................................................. 45 
13.3 PET Instrument .............................................................................................................................. 45 
14.0 DATA COLLECTION ......................................................................................................... 46 
14.1 Data Summary ................................................................................................................................ 46 
14.2 Case Report Form .......................................................................................................................... 46 
15.0 DATA ENTRY AND STORAGE ....................................................................................... 47 
15.1 Clinical Data Storage and Sharing ........................................................................................... 47 
15.1.1 National Alzheimer’s Disease Coordinating Center (NACC) Database ................................ 47 
15.1.2 Unique LEADS data .................................................................................................................................... 47 
15.2 MRI and PET Imaging Data Storage ........................................................................................ 48 
15.3 Biospecimen Storage – NCRAD and NIH databases .......................................................... 48 
15.4 Audio Recording Transcription and Storage ...................................................................... 49 
15.5 Global Unique Identifiers (GUIDs) .......................................................................................... 49 
16.0 DATA SHARING ................................................................................................................ 49 
17.0 REQUESTS FOR LEADS DATA ...................................................................................... 50 
17.1 Biospecimen Data Requests ...................................................................................................... 50 
17.2 Terms & Obligations of Data Usage ........................................................................................ 51 
18.0 DATA AND SAFETY MONITORING BOARD (DSMB) ............................................. 51 
19.0 STUDY MONITORING ..................................................................................................... 52 
20.0 ETHICS AND REGULATORY CONSIDERATIONS ..................................................... 52 
20.1 Good Clinical Practice .................................................................................................................. 52 
20.2 Informed Consent.......................................................................................................................... 52 
20.3 Confidentiality and HIPAA/GDPR Compliance................................................................... 53 
20.4 Certificate of Confidentiality ..................................................................................................... 54 
21.0 STATISTICAL CONSIDERATIONS ................................................................................ 54 
21.1 Analysis Goals and Strategies ................................................................................................... 54 
21.1.2 Statistical analysis ...................................................................................................................................... 54 
21.1.3 Missing Data .................................................................................................................................................. 56 
21.1.4 Sample Size .................................................................................................................................................... 56 
22.0 REFERENCES ..................................................................................................................... 57 
APPENDIX 1  SCHEDULE OF EVENTS ..................................................................................... 61 
All (EOAD, EOnonAD, and CN) Participants– Screening and Baseline ................................. 61 
EOAD Participants – Longitudinal Visits ........................................................................................ 64 
EOnonAD Participants – Longitudinal Visits ................................................................................ 66 
Cognitively Normal Participants – Longitudinal Visits ............................................................. 68 
 
 
 

 
 
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LIST OF ABBREVIATIONS  
 
Aβ 
Beta Amyloid 
AD 
Alzheimer’s Disease 
ADAD 
Autosomal Dominant Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale – Cognitive  
ADI 
Area Deprivation Index 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
ADRC 
Alzheimer’s Disease Research Center 
ADSP 
Alzheimer Disease Sequencing Project 
AE 
Adverse Event 
APOE/APOE4 
Apolipoprotein E (APOE) epsilon 4 (APOE4) 
APP 
Amyloid Precursor Protein gene 
ASL 
Arterial Spin Labeling  
ATRI 
Alzheimer’s Therapeutic Research Institute 
C9ORF72 
Chromosome 9 open reading frame 72 
CDR 
Clinical Dementia Rating 
CLIA 
Clinical Laboratory Improvement Amendments 
CN 
Cognitively normal 
CSF 
Cerebrospinal Fluid 
CT 
Computerized Tomography  
DIAN 
Dominantly Inherited Alzheimer’s Network 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition  
DTI 
Diffusion Tensor Imaging  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture System 
EOAD 
Early-onset Alzheimer’s Disease 
EOnonAD 
Early-onset non-Alzheimer’s Disease  
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FLAIR 
Fluid Attenuation Inversion Recovery 
FTD 
Frontotemporal Dementia 
fMRI 
Functional Magnetic Resonance Imaging  
GAAIN 
Global Alzheimer’s Association Interactive Network  
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GRN 
Progranulin 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed consent form 

 
 
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ICH 
International Conference on Harmonization 
IDA 
Image Data Archive at LONI 
INR 
International Normalized Ratio 
iPSCs 
Induced pluripotent stem cells  
IRB 
Institutional Review Board 
LAR 
Legally Authorized Representative 
LOAD 
Late-onset Alzheimer’s Disease 
LONI 
Laboratory of Neuroimaging at USC  
LP 
Lumbar Puncture 
lvPPA 
Logopenic variant primary progressive aphasia 
MAPT 
Microtubule-associated protein tau  
MCI 
Mild Cognitive Impairment  
MINT 
Multi-lingual Naming Test  
MMSE 
Mini-Mental State Examination 
MoCA 
Montreal Cognitive Assessment  
MPRAGE 
Magnetization Prepared Rapid Gradient Echo 
MR/MRI 
Magnetic Resonance / Magnetic Resonance Imaging 
MTA 
Material Transfer Agreement 
MTL 
Medial temporal lobe 
NCRAD 
National Centralized Repository for AD and Related Dementia 
NIA 
National Institute on Aging, under the NIH 
NIA-AA 
National Institute on Aging – Alzheimer Association 
NIAGADS 
National Institute on Aging Genetics of Alzheimer's Disease Data 
Storage Site 
NIH 
National Institutes of Health 
NPI 
Neuropsychiatric Inventory 
OTC 
Over-the-Counter 
PBMC 
Peripheral Blood Mononuclear Cell 
PCA 
Posterior cortical atrophy 
PET 
Positron-Emission Tomography 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PiB 
Pittsburgh Compound B 
PLPH 
Post lumbar puncture headache 
PSEN1 
Presenilin 1 gene 
PSEN2 
Presenilin 2 gene 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QA / QC 
Quality Assurance / Quality Control 
RDRC 
Radioactive Drug Research Committee 
REB 
Research Ethics Board 
RNA 
Ribonucleic Acid  

 
 
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SAE 
Serious Adverse Event 
T 
Tesla 
TIV 
Total intracranial volume 
vMRI 
Volumetric Magnetic Resonance Imaging 
 
PROTOCOL SYNOPSIS 
 
PROTOCOL TITLE 
Longitudinal Early-onset Alzheimer’s Disease Study 
(LEADS)  
PROJECT 
DIRECTOR/PRINCIPAL 
INVESTIGATOR 
Liana Apostolova, M.D., M.Sc. 
STUDY DESIGN 
Non-randomized, natural history, non-treatment study 
STUDY COMPOUNDS 
Florbetaben 
Flortaucipir  
Fluorodeoxyglucose (FDG) 
Pittsburgh Compound B (PiB) (for International sites only) 
NAV-4694 (Flutafuranol) (for International sites only) 
Flutemetamol (for International sites only) 
RECRUITMENT 
GOALS AND 
DURATION OF STUDY  
Up to 850 cognitively impaired participants (in the US) = 3+ 
Years in duration 
• Approximately 650 EOAD participants 
• Approximately 200 EOnonAD participants 
100 CN participants = 2+ Years in duration 
40 cognitively impaired participants (across international sites) 
= 3 + Years in duration 
10 CN participants (across international sites) = 2+ Years in 
duration  
Screening period = < 60 days (including baseline assessments) 
SUMMARY OF KEY 
ELIGIBILITY 
CRITERIA  
Cognitively Impaired Cohorts:  
• Diagnosis of NIA-AA criteria of MCI or dementia due 
to probable AD  
• CDR score ≤ 1.0  
Cognitively Normal Cohort:  

 
 
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• Meets criteria for cognitively normal, based on an 
absence of significant impairment in cognitive 
functions and activities of daily living 
• Mini-Mental State Exam score between 26-30  
• CDR score = 0  
Both Cohorts:  
• 40-64 (inclusive) years of age at the time of consent 
• Willing and able to undergo study procedures as 
outlined in the Schedule of Events 
• Must have study partner (informant) who spends a 
minimum average of 10 hours per week with the 
participant. 
PRIMARY 
OBJECTIVES  
• Collect longitudinal assessments and biomarker data 
for 650 EOAD, and 200 EOnonAD, and 100 CN 
participants in the US, and an additional 40 CI and 10 
CN particpiants internationally.  
• Compare baseline and longitudinal cognitive and 
functional characteristics, between EOAD and CN, and 
EOAD and Late Onset Alzheimer’s Diseases (LOAD) 
from the Alzheimer’s Disease Neuroimaging Initiative 
(ADNI) 
• Study the associations of longitudinal clinical and 
cognitive assessments with multimodal imaging and 
biofluid markers that capture different elements of the 
AD pathophysiological cascade 
OUTCOME MEASURES 
/ STUDY PROCEDURES 
Rate of decline on cognitive, global, and functional tests; rates 
of change on imaging and fluid biomarkers; Longitudinal 
extent and rate of brain atrophy, amyloid and tau deposition; 
Discovery of new AD genetic risk variants 
 
1.0 BACKGROUND AND SIGNIFICANCE 
While the risk of AD increases with advancing age, approximately 5% of AD patients 
develop symptoms before age 65 (~280,000 Americans). Patients with early-onset 
Alzheimer’s disease (EOAD), occurring before the age of 65, are an understudied segment 
of the patient population with Alzheimer’s Disease (AD). Many treatment studies exclude 
these younger individuals.  
 
Of the two major North American consortia, ADNI includes only a few EOAD cases all 
with a “typical” amnestic presentation and the Dominantly Inherited Alzheimer Network 
(DIAN) focuses solely on autosomal dominant AD (ADAD). Clinical and neuroimaging 
measures that emphasize episodic memory and medial temporal neurodegeneration in 

 
 
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LOAD are insensitive to the baseline deficits and the disease progression in EOAD, which 
predominantly involve non-memory cognitive domains and posterior cortical 
neurodegeneration. The overarching aim of this Longitudinal Early-Onset AD Study 
(LEADS) is to fill this gap in AD research by conducting a clinical and biomarker study in 
the EOAD population.  
 
LEADS includes key AD research sites across the U.S. and will leverage existing 
infrastructure and processes applied in ADNI. The over-arching goals are to advance our 
knowledge about disease mechanisms and develop sensitive composite clinical and 
biomarker tools that capture disease progression in this unique cohort for implementation in 
clinical trials. Our secondary goals include: (1) collection of DNA from EOAD participants 
for exploratory studies applying next generation sequencing; (2) collection and banking of 
clinical, biofluid and imaging measures for future research and sharing with the larger 
research community; and (3) establishing a network of EOAD sites that will enable future 
planning and implementation of clinical trials in EOAD. While the research is focused on 
EOAD, LEADS will also follow individuals who meet clinical criteria for MCI or dementia 
due to probable AD but have a negative amyloid PET scan (EOnonAD) with the goal to 
generate important scientific knowledge about this patient population.  
 
Data collected in this study will address several significant gaps in AD research. In addition 
to affording this highly motivated population the chance to contribute to AD research, 
EOAD patients offer the opportunity to study a more “pure” form of AD with fewer age-
related brain co-pathologies[1, 2].  
 
The study will also leverage existing data. We plan to compare our EOAD individuals to 
ADNI LOAD participants. ADNI is a non-randomized, natural history, non-treatment study 
with up to 2000 longitudinal LOAD participants with clinical, cognitive, MRI, amyloid and 
tau PET, CSF and peripheral blood data collected across approximately 59 sites in the 
United States and Canada. ADNI data is freely shared with other researchers. 
 
In addition, all of our sites who are federally funded Alzheimer’s Disease Research Centers 
under the auspices of the National Alzheimer Coordinating Center (NACC) will be 
encouraged to enroll all subjects in their longitudinal observational clinical cohorts. We will 
leverage the ADRCs as they are well positioned to follow their research participants 
indefinitely (until death) and are also funded to perform post mortem examinations of the 
brain tissue. This partnership will greatly benefit the LEADS program as it will secure a 
mechanism for longitudinal follow-up. A portion of the standardized NACC assessment will 
be adopted into the LEADS study. 
2.0 STUDY RATIONALE  
In contrast to the predominant amnestic phenotype of LOAD, 30-64% of EOAD manifest 
with non-amnestic presentations, including focal cortical syndromes such as posterior 
cortical atrophy (PCA) and logopenic variant primary progressive aphasia (lvPPA), which 
can lead to missed or delayed diagnosis. Despite being highly motivated and having fewer 
age-related comorbidities compared to LOAD, EOAD patients are commonly excluded from 
clinical research and therapeutic trials due to their young age or non-amnestic deficits, 
which is increasingly viewed as being marginalizing and unethical [3]. Fewer than 10% of 
EOAD patients carry a known mutation in APP or PSEN1/2, and <50% carry the APOE4+ 

 
 
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risk allele. Still studies suggest high heritability in EOAD in the absence of known 
mutations or APOE4+, signifying that this population may be enriched for novel genetic risk 
factors [4]. 
 
3.0 SCIENTIFIC AIMS 
3.1 Aim 1  
To compare the baseline and longitudinal cognitive and functional characteristics of 
EOAD compared to LOAD and identify optimal outcome measures for clinical trials.  
 
H1a: Controlling for performance on episodic memory tests, EOAD will show greater 
impairment in executive, language and visuospatial function compared to ADNI LOAD.  
 
H1b: EOAD will show more rapid decline on MMSE, ADAS-Cog and CDR-SB compared 
to ADNI LOAD.  
H1c: A data-driven analysis of functional ratings and psychometric test scores will identify 
measures more sensitive to change over time in the full spectrum of EOAD (amnestic and 
non-amnestic subtypes) than existing composite measures (ADAS-Cog and CDR-SB), 
leading to a new EOAD composite outcome measure for use in future clinical trials and 
observational studies. 
 
Rationale for Aim 1: Multiple small studies have demonstrated greater impairment in non-
memory compared to memory performance[5-7] and more rapid cognitive decline in EOAD 
than in LOAD[8, 9]. Among these studies the study sample composition (e.g. inclusion of 
autosomal dominant or focal variants like lvPPA/PCA), assessment and outcome measures 
vary. Whether clinical trial outcomes employed in LOAD trials (emphasizing episodic 
memory) should be applied to EOAD or be modified to account for the predominant non-
amnestic deficits remains a critical, unanswered question. In this aim we will test both 
traditional and novel cognitive and functional outcome measures in the full EOAD spectrum 
defined by current NIA-AA criteria. Our ultimate goal is to empirically reduce our broader 
battery into a short battery of measures that are especially sensitive in EOAD and feasible 
for clinical trials. 
 
3.2 Aim 2  
To compare baseline and longitudinal MRI, amyloid PET, tau PET and CSF and plasma 
ATN measures between EOAD and LOAD and identify optimal outcome measures for 
clinical trials. 
 
H2a: EOAD will show greater baseline and longitudinal changes in cortical gray matter 
atrophy and tau burden than matched ADNI LOAD participants, but no differences in 
baseline or longitudinal amyloid PET, plasma or CSF measures.  
H2b: Baseline and longitudinal change in cortical tau, gray matter atrophy, CSF and plasma 
measures will correlate with baseline and longitudinal measures of cognitive function.  

 
 
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H2c: Through a data-driven approach we will identify composite biomarker measures that 
optimally capture change over time, leading to EOAD composite imaging outcomes for use 
in future clinical trials and observational studies.  
 
Rationale for Aim 2: Neuroimaging outcomes have become critical for subject selection and 
for gauging target engagement and disease modification in clinical trials. The advent of tau 
PET ligands such as AV1451 [10] represent a major advance in the field, as they offer both 
molecular specificity for AD pathophysiology (in contrast with MRI) and temporal 
correlations with clinical outcomes (in contrast with Aβ PET). While MTL 
neurodegeneration is considered the imaging hallmark of LOAD, multiple studies have 
shown more prominent cortical atrophy and hypometabolism and relative sparing of the 
MTL in EOAD compared to LOAD[11-13]. Early-stage neurodegeneration of  
the posterior temporo-parietal cortical regions represents a common denominator across all 
clinical variants of EOAD (amnestic, dysexecutive, lvPPA and PCA)[14-17]. 
Clinicopathological studies have demonstrated that “hippocampal- sparing AD” is strongly 
associated with early onset[15]. Current methods do not take into account the spatial 
topography differences between LOAD and EOAD. Therefore, neurodegenerative 
biomarkers commonly used to track disease progression and monitor for drug effects will 
not directly generalize from LOAD to EOAD. The goals in Aim 2 are to characterize the 
MRI and PET signature of EOAD in comparison to CN, to compare PET, CSF and plasma 
measures of Aβ and tau with LOAD, to link imaging measures to cognitive outcomes, and to 
use a data-driven approach to develop summary imaging measures uniquely sensitive to 
disease progression in EOAD for application in future therapeutic trials. 
 
3.3 Aim 3  
To investigate the influence of APOE genotype on baseline and longitudinal imaging 
biomarkers and clinical phenotype in EOAD.  
 
H3a: Atypical subtypes of EOAD (PPA, PCA) will show a lower APOE4+ carrier rate than 
memory predominant EOAD.  
H3b: Relative to non-carriers, APOE4+ carries will demonstrate greater baseline and 
longitudinal change in medial temporal atrophy and tau PET signal. 
H3c: EOnonAD will show a significantly lower APOE4 carrier rate than EOAD.  
 
Rationale for Aim 3: APOE4+, the most significant genetic risk factor for sporadic AD [18], 
exerts its maximal effects between ages 65-75[19, 20]. The prevalence of APOE4+ is 
substantially lower in EOAD than in LOAD[21]. Furthermore, APOE4 seems to moderate 
the phenotype of AD by predisposing to MTL vulnerability[15, 22-29]. Greater memory 
impairment and MTL atrophy in APOE4+ AD, and greater non- amnestic presentations and 
cortical atrophy in APOE4- subjects has been reported by some [23, 26-28, 30-33] but not 
others[34, 35]. Yet since most of these clinical studies lack pathologic or biomarker 
confirmation of AD pathology, the perceived differences might be driven by increased rates 
of non-AD pathology in APOE4- individuals, necessitating a more definitive study. 
Furthermore, APOE genotype is emerging as a major pharmacogenomic consideration for 
AD trials. It is therefore critical to stratify EOAD and EOnonAD participants and determine 

 
 
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how rates and patterns of atrophy, Aβ and tau accumulation may differ on the basis of APOE 
genotype. 
 
3.4 Exploratory Aim 4 
To characterize genetic contributions to EOAD and obtain annually an array of 
uniformly collected biospecimens for future biomarker development.  
 
H4a: A subset of EOAD will have mutations in genes known to contribute to AD.  
H4b: A subset of EOnonAD will have mutations in genes known to contribute to FTLD .  
H4c: Next generation sequencing will identify novel genes in EOAD involved in Aβ, tau, 
inflammation and lipid processing pathways. 
 
Rationale for Aim 4: Pedigree analyses suggest that apparently “sporadic” EOAD is a highly 
heritable condition, recognized pathogenic mutations in APP, PSEN1 and PSEN2 are rarely 
identified in these subjects, and much of the measured heritability of EOAD remains 
unexplained even after accounting for APOE4 [36, 37]. Few studies have amassed a large 
enough sample of sporadic EOAD to be sufficiently powered to identify new genes 
contributing to disease risk. Next generation sequencing has rarely been applied to this 
population, yet is well suited to identify rare genes with large effects, recessive or de novo 
mutations and other more complex heritability patterns. This study’s cohort (400 deeply 
phenotyped sporadic EOAD without a known genetic etiology) will be the focus of this 
exploratory aim to initiate new gene discovery, which may lead to insights into novel 
disease mechanisms and pathways. We propose to apply innovative genetic approaches (i.e., 
whole genome sequencing and epigenetic analyses) to study vulnerability in EOAD. In 
addition, we will investigate the influence of APOE genotype on cognitive, imaging and 
biofluid biomarkers, which is critical to help plan pharmacogenomic approaches in AD 
clinical trials. 
 
3.5 Aim 5:  
To characterize demographic, clinical, neuroimaging, and fluid biomarker measures in 
EOnonAD cases to explore the possible etiologies of cognitive impairment.  
 
H5a: EOnonAD participants will show MRI and/or FDG PET patterns that are either 
supportive of a nonAD neurodegenerative disease or suggestive of non-neurodegenerative 
etiology.  
 
H5b: Frontotemporal atrophy and hypometabolism and elevated plasma neurofilament light 
(NfL) will predict transition to an FTD spectrum diagnosis over time.  
 
H5c: Data-driven analyses of EOnonAD clinical and biomarker assessments will identify 
clusters suggestive of potential etiologies, which will be confirmed at autopsy.  
 
Rationale for Aim 5: To date, no studies have systematically investigated EOnonAD 
subjects. Amyloid-negative (A-) tau-negative (T-) late onset amnestic cases show focal 
medial temporal and posterior cingulate FDG PET hypometabolism relative to their amyloid 

 
 
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positive counterparts. In ADNI 36% A- MCI individuals show neurodegenerative changes 
on both FDG PET and MRI, 41% on MRI only, and 23% on FDG only. 
Essentially all studies of A- LO MCI to date have shown higher conversion rates ranging 
between 18-56% in A- neurodegeneration-positive (N+) compared to subjects without 
neurodegeneration but with brain amyloidosis (A+N+) and to biomarker-negative (A-N-) 
subjects. Whether the same holds true for early onset subjects remains unknown.  
Some researchers have argued that A-N+ subjects might be a neurodegeneration-first AD 
variant. There is some evidence to suggest that this could be the case for some of these 
subjects. Mormino et al. showed that these cases are more likely to have subthreshold mean 
amyloid PET SUVR compared to biomarker-negative controls. The rates of conversion of 
A-N+ to A+N+ in the literature are variable. Caroli et al. reported that 64% of A-N+ cases 
converted to A+N+ in their series, yet the rate reported by Gordon et al. for the WashU 
cohort was only 14-17% at 3 years.  
 
 
3.6 Aim 6:  
To follow all patients to autopsy and perform neuropathologic analyses of postmortem brain 
tissue to identify the pathophysiologic substrate and comorbid pathologies in EOAD and 
EOnonAD cases.  
 
H6a: Neuroimaging and fluid biomarkers collected during life in EOAD/EOnonAD cases will 
correlate with postmortem neuropathologic changes, which will be the basis for prediction 
models. 
 
Rationale for Aim 6: EOAD and LOAD share a comparable neuropathologic substrate, 
however, there are notable differences in their clinical and biological phenotypes. 
Neuropathologically, EOAD is reported to have a more severe pathology (particularly 
neurofibrillary tangles) than LOAD; however, at this time, there is no standardized 
neuropathology research protocol for analyzing brains of non-autosomal dominant EOAD 
individuals. A major goal of the NPC will be to correlate clinical and imaging data with the 
presence of neuropathologic lesions in different brain areas. Histologic examination is also 
the ultimate confirmation of AD diagnosis and it is fundamental to determine the presence 
of comorbidities co-occurring with AD. Although new diagnostic biomarkers hold promise 
for increasing the clinical diagnostic accuracy for AD, it is expected that there will continue 
to be overlap in these measures between AD subjects, subjects with non-AD dementias and 
cognitively intact individuals. Importantly, enabling correlations between antemortem 
biomarkers and neuropathology and creating a tissue repository for in-depth state-of-the-art 
neuropathological and biological/omic studies of LEADS cases (EOAD, EOnonAD and 
controls) will be invaluable. The neuropathologic examination of well-characterized brain 
tissue from non-autosomal dominant EOAD individuals may lead to the identification of 
novel AD phenotypes. Novel technology may be applicable to interrogate the tissue in order 
to determine the stages in the evolution of the biochemical, molecular and, possibly, 
structural changes that take place in the trajectory of formation of neuropathologic lesions. 
By expanding our knowledge of the structural and genetic properties associated with 
pathologic CNS tissue of LEADS subjects, each brain we study will become an invaluable 
resource for the AD research community at-large.  
 

 
 
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4.0 STUDY DESIGN AND INVESTIGATIONAL PLAN 
The LEADS design builds on the success of two major natural history/biomarker initiatives 
in AD: ADNI and DIAN. Like those initiatives, the LEADS approach links longitudinal 
clinical and cognitive assessments with multiple imaging and biofluid markers that capture 
different elements of the AD pathophysiological cascade. Its alignment to ADNI will allow 
us to use ADNI LOAD participants as a disease comparison group. 
 
LEADS is a non-randomized, natural history, non-treatment study. Approximately 850 
cognitively impaired (EOAD and EOnonAD) participants and 100 CN participants will be 
enrolled at approximately 20 sites in the United States. Approximately 40 CI participants 
and 10 CN participants will be enrolled in sites outside of the U.S. as a part of iLEADS, the 
international expansion of LEADS. Clinical/cognitive, imaging, biomarker, and genetic 
characteristics will be assessed across the three cohorts: EOAD,  EOnonAD, and CN.  
4.1 LEADS Consortium Structure 
LEADS is modeled after ADNI and many ADNI leaders are involved in the LEADS study.  
4.1.1 Administrative Core The Administrative Core, with headquarters at Indiana University 
(IU), has the overall responsibility for the entire project. The core will oversee the activities 
of all sites and cores and facilitate collaboration with ADNI, DIAN, and other relevant 
projects. This core will be responsible for approving the protocol and any amendments, 
reviewing and approving study budgets, reviewing interim data and amending the 
methodology as appropriate, reviewing and approving significant changes to study 
timelines, overseeing publication planning and reviewing and approving joint publications.  
4.1.2 Clinical Core The Clinical Core at IU and the Clinical Coordinating Center (ATRI at 
USC) will be responsible for managing the day-to-day clinical operations. ATRI is the 
Coordinating Center for ADNI. The Clinical Core/Coordinating Center will be responsible 
for oversight of clinical activities, contracting with all sites, performance oversight, data 
management, tracking and quality control, recruitment and retention of participants, and 
regulatory oversight. Clinical Monitors, under the supervision of the ATRI, will regularly 
visit all LEADS sites to ensure compliance with regulatory requirements and protocol 
procedures, and accurate data entry. As leader of the Clinical Core, Dr. Apostolova will 
have final responsibility for all aspects of data acquisition.  
4.1.3 MRI Core The LEADS MRI Core Components at Massachusetts General Hospital 
(MGH)/Harvard and Mayo Clinic Rochester will perform standardization of data acquisition 
and quality control, including creation and distribution of protocols to each site, qualifying 
each scanner and re-qualifying after every upgrade, performing quality control assessments 
of every exam. It will also perform quantitative MR measurements for each MR modality. 
ADNI Imaging protocols will be used to ensure our ability to conduct combined analyses of 
LEADS and ADNI MRI data. Collaborations with other ADNI-affiliated and non-affiliated 
investigators will be developed to perform data analyses. The core will work with the 
Administrative Core to assure that all regulatory compliance is in place and with the 
Laboratory of Neuroimaging (LONI) to ensure the protocols and procedures for data 
uploading are in place. As leader of the MRI Core, Dr. Dickerson will have final 
responsibility for all aspects of MRI data acquisition.  
4.1.4 PET Core The PET Core at the University of California San Francisco (UCSF) and 
University of Michigan will implement the standardized procedures for multisite 

 
 
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florbetaben, PiB, NAV-4694, flutemetamol, flortaucipir, and FDG PET imaging. The PET 
Core will be responsible for oversight of site qualification, quality control, standardization, 
pre-processing and analysis of florbetaben, PiB, NAV-4694, flutemetamol, flortaucipir, and 
FDG PET images acquired in the study. The PET Core will work with the Administrative 
Core to assure that all regulatory compliance is in place and with LONI to ensure the 
protocols and procedures for data uploading are in place. As leader of the PET Core, Dr. 
Rabinovici will have final responsibility for all aspects of PET data acquisition.  
4.1.5 Genetics and Biorepository Core This core will be led by Dr. Foroud who is the PI of 
National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD). 
NCRAD is a national resource funded by the National Institute on Aging (NIA) where 
clinical information and biological material (such as DNA, plasma, serum, RNA, CSF, cell 
lines, and brain tissue) from individuals with AD, related dementias and normal controls can 
be stored and requested. The Core will prepare all protocols and materials to be used with 
participants when discussing the decision to receive information about pathogenic mutations 
in ADAD genes, if identified. The Core will coordinate confirmatory CLIA laboratory 
genetic testing of pathogenic mutations, ensure that confirmed pathogenic mutations are 
communicated to the site where the participant was seen, and if needed, assist sites in 
providing genetic counseling. This core will be responsible for receiving, processing and 
banking genetic, peripheral blood and CSF material. As Genetics & Biorepository Core Co-
Leader, Dr. Dage will oversee all fluid biomarkers analyses. Dr. Foroud will ensure that 
genetics and related data is comprehensively analyzed and reported using state-of-the-art 
approach including candidate pathway and genome-wide analyses. As leader of the Genetics 
and Biorepository Core, Dr. Foroud will have final responsibility for all aspects of genetic 
and fluid biomarker processing, banking and analyses.   
4.1.6 Biostatistics Core The Biostatistics Core at Brown University will have the overall 
responsibility for meeting the analytic goals of this project and will provide expertise in 
longitudinal modeling of clinical and biomarker data, in modeling multivariate trajectories, 
statistical applications in consideration for future clinical trial design, as well as exploratory 
and discovery studies. The core will also provide design and analysis support for validation 
and calibration studies as necessary. New strategies will be considered. As leader of the 
Biostatistics Core, Dr. Eloyan will have final responsibility for all aspects of the statistical 
analyses.  
4.1.7 Informatics Core The Informatics Core located at LONI at USC will also follow 
ADNI’s model. The Core will provide a secure and reliable environment for storing and 
sharing neuroimaging and related data and a supportive, responsive team dedicated to 
meeting the evolving needs of the community. As it has done for ADNI and many other 
studies, the Informatics Core will provide a reliable, long-term repository for imaging, 
clinical and related data storage and distribution. To date, ADNI Informatics Core has stored 
more than 87,000 ADNI MRI and PET images with more than 21 million images 
downloaded by approved ADNI data users. Additionally, the clinical and genetic data have 
been provided to thousands of users. Finally, subsystems for image quarantine and release, 
data management, and data user application and review have been implemented and the 
same set of operations will be provided for LEADS. The Informatics Core will work closely 
with ATRI and NACC to assure that all clinical and cognitive data is safely transferred and 
stored in LONI and is accessible as appropriate to approved investigators. The Informatics 
Core will provide support to sites uploading MRI and PET scans. 

 
 
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4.1.8 Neuropathology Core 
The LEADS Neuropathology Core comprises three hub sites that will oversee organization 
of participating clinical sites. The three hub sites are located at Indiana University, 
University of California, San Francisco, and Mayo Clinic Jacksonville. The three hub sites 
coordinate autopsies at participating sites and perform clinicopathologic analyses on EOAD 
and EOnonAD brain tissue. The Neuropathology Core leaders will support the clinical sites, 
collaborate with LEADS investigators, organize and participate in consensus-building 
activities, and lead tissue-sharing efforts. The Neuropathology Core will fulfill the following 
goals: 1) Facilitate and secure brain procurement at the time of death from all LEADS 
participants; 2) Conduct thorough, uniform postmortem neuropathologic examinations and 
assign all appropriate diagnoses for each case and contribute neuropathologic data to the 
NACC database (including diagnoses, accurate staging, and semiquantitative assessments of 
distribution and density of neuropathologic lesions); 3) Maintain a resource of formalin-
fixed brain tissue blocks for LEADS investigators and outside investigators with an updated 
database of frozen tissue location and availability; and, 4) Review tissue requests by 
committee and provide samples and data to qualified investigators. 
4.2 End of Study Definition  
Given the overarching goal of the study to advance our knowledge and facilitate 
implementation in clinical trials with this unique cohort, there is no specific end point. Study 
activities are anticipated to continue until funding is no longer available.  
5.0 STUDY POPULATION 
5.1 Inclusion Criteria 
 
Cognitively impaired (EOAD and EOnonAD) Cohorts Only:  
1. Meets NIA-AA criteria for MCI due to AD or probable AD dementia 
2. Have a global CDR score ≤ 1.0  
3. Have capacity to provide informed consent (IC) or has a legal authorized 
representative or guardian who provides IC  
4. Age between 40-64 years (inclusive) at the time of consent 
5. Must have a study partner (informant) who spends a minimum average of 10 hours 
per week with the participant (e.g., family member, significant other, friend, 
caregiver) who is generally aware of the participants’ daily activities and can provide 
information about the participant’s cognitive and functional performance. If the 
participant does not have a study partner who spends at least 10 face-to-face hours 
per week, other arrangements for identifying a viable study partner will be granted 
on a case-by-case basis by the Site PI 
6. Willing and able to complete longitudinal study procedures aside from LP which is 
an optional procedure 
7. Not pregnant or lactating. Women must be two years post-menopausal, be surgically 
sterile, or have a negative pregnancy test prior to each PET scan 
8. Fluent in English or Spanish if enrolled in the U.S. 
9. Fluent in English, Spanish, Dutch or Swedish for sites outside the U.S., according to 
site’s spoken language(s).  
 
Cognitively Normal (CN) Cohort Only:  

 
 
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1. Meets criteria for cognitively normal, based on an absence of significant impairment 
in cognitive functions or activities of daily living 
2. Have a global CDR score = 0  
3. Have capacity to provide informed consent 
4. Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be 
made for participant with less than 8 years of education at the discretion of the Site 
PI 
5. Age between 40-64 years (inclusive) at the time of consent 
6. Must have a study partner (informant) who spends a minimum average of 10 hours 
per week with the participant (e.g., family member, significant other, friend, 
caregiver) who is generally aware of the participants’ daily activities and can provide 
information about the participant’s cognitive and functional performance. If the 
participant does not have a study partner who spends 10 face-to-face hours per week, 
other arrangements for identifying a viable study partner will be granted on a case-
by-case basis by the Site PI 
7. Willing and able to complete longitudinal study procedures aside from LP which is 
an optional procedure 
8. Not pregnant or lactating. Women must be two years post-menopausal, be surgically 
sterile, or have a negative pregnancy test prior to each PET scan 
9. Fluent in English or Spanish if enrolled in the U.S. 
10. Fluent in English, Spanish, Dutch or Swedish for sites outside the U.S., according to 
site’s spoken language(s). 
 
Returning Participant (RP) Cohort Only:  
1. Must be a previous participant of LEADS that met initial eligibility criteria and 
completed a baseline visit 
2. Have capacity to provide informed consent (IC) or has a legal authorized 
representative or guardian who provides IC  
3. Must have a study partner (informant) who spends a minimum average of 10 hours 
per week with the participant (e.g., family member, significant other, friend, 
caregiver) who is generally aware of the participants’ daily activities and can provide 
information about the participant’s cognitive and functional performance. If the 
participant does not have a study partner who spends at least 10 face-to-face hours 
per week, other arrangements for identifying a viable study partner will be granted 
on a case-by-case basis by the Site PI  
 
See section 8.8 for description of Returning Participants.  
5.2 Exclusion Criteria 
EOAD, EOnonAD and CN Cohorts:  
 
1. Meets core clinical criteria for non-AD dementia 
2. Two or more first degree relatives with a history of early-onset dementia suggestive 
of autosomal dominant transmission, unless known pathogenic mutations in APP, 
PSEN1, PSEN2, MAPT, GRN and C9ORF72 have been excluded 
3. Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other 
autosomal dominant genes associated with other neurodegenerative disorders (MAPT, 
GRN, C9ORF72) 

 
 
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4. Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip, 
artificial heart valve, select ear implants, select stents incompatible with 3T MRI, 
metal fragments or foreign objects in the eyes, skin or body, etc.)  
5. Lifetime medical history of a brain disorder other than the disorder causing dementia 
except for headache (exceptions are allowed at the discretion of the Site PI - e.g., 
seizure disorder thought to be due to EOAD).  
6. MRI scan with evidence of infection or focal lesions, cortical strokes, multiple 
lacunes (single lacune is allowable unless it meets criteria for strategic lacune 
affecting cognition)  
7. Any significant systemic illness or unstable medical condition, which could lead to 
difficulty complying with the protocol (at the discretion of the Site PI) 
8. Research radiation exposure will be assessed by the study physician. If the candidate 
participant has had more than one nuclear medicine study in the prior 12 months for 
research-related purposes, study inclusion will require approval from the PET Core 
9. Investigational agents are prohibited 30 days prior to entry  
10. Previous enrollment in a therapeutic trial targeting amyloid or tau. 
11. Participation in other clinical studies with neuropsychological measures, with the 
exception of participants who are co-enrolled in the NACC Uniform Data Set (UDS) 
protocol (Note: This criterion is intended to reduce repeat measures effects during 
neuropsychological testing. Exceptions are allowed at the discretion of the Site PI) 
12. Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria) 
13. Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar 
disorder with or without psychotic features 
14. Current history (in previous 6 months) of moderate or severe substance abuse 
(nicotine or caffeine is allowed)  
15. Suicidal behaviors in the past 12 months or active suicidal ideations 
16. Residing in a 24-hour care skilled nursing facility (at the time of screening) 
17. (For optional lumbar puncture procedure only):  
a. Clinical laboratory values must be within normal limits or, if abnormal, must 
be judged to be not clinically significant by the Site PI 
i. Platelet count <100,000/ml 
ii. INR>1.2  
iii. Abnormal PT or PTT at screening 
b. Contraindications to the procedure, including but not limited to severe 
degenerative joint disease, deformity of the spine, history of a bleeding 
disorder 
c. Suspected elevated intracranial pressure, Arnold Chiari malformation or mass 
lesion 
d. Use of the anticoagulant medications such as but not limited to warfarin, 
rivaroxaban, dabigatran  
18. Deemed ineligible by the Site PI for any other reason 
 
RP Cohort: 
1. Investigational agents are prohibited for five half-lives prior to study re-entry.  
 
NOTE: Deviations from the inclusion/exclusion criteria will be considered with prior review 
and approval by the Site PI, the Clinical Core, and the IRB. Contact the ATRI Coordinating 
Center to request a review.  

 
 
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6.0 RECRUITMENT 
Participants will be recruited from the diagnostic and treatment clinics or longitudinal 
research cohorts at each study site, most of which are Clinical Cores of the federally funded 
Alzheimer’s Disease Research Centers (ADRCs). Study-wide recruitment efforts will be 
overseen by a recruitment team at the Alzheimer’s Association. The Alzheimer’s 
Association (AA) has developed a coordinated recruitment plan to ensure enrollment occurs 
in a timely fashion. The overall goals of the plan are to raise awareness of the trial among 
the targeted population and to ensure adequate enrollment. The AA’s recruitment and 
retention team developed materials specific to the LEADS for use by sites and will provide 
ongoing assistance and support.  
 
In addition, the AA will work both through its local field offices and through the TrialMatch 
database to help identify EO cognitively impaired participants and connect them with the 
enrolling sites. The AA will reach out directly to individuals who may be eligible for the 
LEADS study and who live near study sites to inform them of the study and how they can 
participate.  
 
7.0 STUDY PROCEDURES 
See Schedule of Events (Appendix 1). 
 
All assessments will be completed by study personnel trained to administer the instruments 
and will be based on interviews with and examination or testing of the participant, 
interviews with the study informant, and/or questionnaires completed by the participant and 
the informant.  
 
LEADS participants that are co-enrolled in other AD research (e.g., local NACC protocols) 
may have their data shared between the studies.  
 
International sites may share pre-existing data with LEADS from their standard clinical 
assessments to reduce repeat measure effects and participant burden. Data collected within 6 
months of the LEADS consent or visit date may be used to fulfill the required assessments 
within the Schedule of Events. See relevant study manual for further details.  
 
7.1 Description of Study Visits and Procedures 
7.1.1 Prescreen phase (not an actual visit) 
During the prescreen phase, sites will assess existing (i.e., outpatient clinics, other 
observational studies) and referred potential participants for eligibility criteria, such as age, 
disease history, comorbidities and ability to tolerate procedures.  
7.1.2 Screening  
The purpose of the Screening Visit is to further determine eligibility and to complete the 
informed consent process. The screening procedures will be conducted as outlined in the 
Schedule of Events (Appendix 1).  
 

 
 
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If previous NACC data exists within 6 months of consent date, it may be used to assess 
eligibility at Screening. If participant is consented, this previous existing NACC data, within 
6 months of consent date, can be used to fulfill the NACC UDS/FTLD modules and 
neuropsychological battery required at Screening or Baseline. See Schedule of Events 
Appendix 1.  
 
The participant’s capacity to consent will be assessed whenever consent is collected. 
Guidelines for assessing capacity to consent will be left at the local level to adhere to 
institutional-specific standard operating procedures (SOPs). Clinical monitors will review 
that capacity to consent was assessed during their interim monitoring visits against the local 
SOPs. The relying sites’ plan for assessing participants’ capacity to consent is to be provided 
to the reviewing IRB through completion of a relying site form. If the local process for 
assessing capacity to consent changes at the relying site during the study, the relying site 
must submit an amendment with an updated site form to the reviewing IRB along with the 
corresponding SOP, as applicable. 
7.1.3 Active Study Phase (Baseline to Endpoint Assessments)  
The baseline visit will occur within 60 days of screening. The remaining study procedures 
will be conducted as outlined in Appendix 1.  
7.1.4 Wellness Check  
Telephone calls will be made to participants within 48 hours post lumbar puncture procedure 
to ascertain if adverse events occurred post procedure. Additional telephone calls will be 
made to follow up on any adverse events reported that are not already resolved.  Additional 
calls may be conducted at the discretion of the Site PI. 
 
Additionally, a telephone call will be made to cognitively impaired participants within two 
weeks post amyloid results disclosure to assess the impact of having amyloid PET status 
results disclosed. If applicable, the impact of having tau PET and FDG disclosure may also 
be discussed during the telephone call. If there are any concerns about the impact of results 
disclosure on the participant or family, a follow-up plan will be developed.  
7.1.5 PET Scan Results Disclosure   
Cognitively impaired individuals will meet with the study clinician to discuss the results of 
the amyloid, tau, and FDG PET scans. Amyloid PET results must be disclosed within the 60 
day visit window. Tau and/or FDG PET results may be disclosed outside of the 60 day visit 
window.  
7.1.6 Genetic Counseling Sessions and Genetic Testing Disclosure 
Cognitively impaired participants will be asked if they wish to receive results if a known 
pathogenic mutation in an ADAD or other neurodegenerative disease gene (APP, PSEN1, 
PSEN2, C9ORF72, MAPT and GRN) is identified. If a known pathogenic mutation is found 
in one of these genes and confirmed in a CLIA laboratory and the participant has opted to 
receive pathogenic mutation results, the participant will be referred to the site’s genetic 
counselor for result disclosure and appropriate counseling. At international sites only, the 
Site PI or clinical investigator with acceptable credentials may disclose results, if a genetic 
counselor is not available. Acceptable credentials for a clinical investigator are those who 
have clinical training in genetic counseling and have experience disclosing diagnostic 
genetic testing results. Unless required by local site-specific practice, when a positive 

 
 
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mutation is identified, these results may be discussed and the CLIA report may be placed in 
their medical record if the participant or his or her surrogate decision-maker chooses.  
 
Cognitively impaired participants who have opted to receive pathogenic mutation results, 
but a known pathogenic mutation is not found, will also be informed of the results. Negative 
results (when no pathogenic mutation is found) will not be confirmed in the CLIA 
laboratory. Participants should be instructed that these results are from research screening 
only and not verified in a CLIA laboratory.  
 
See section 7.2 for more detail. 
7.1.7 Neuropathology 
A member of the study team will discuss autopsy brain donation with each participant at 
every visit unless the participant has indicated refusal. For those participants who agree to 
participate in autopsy brain donation, consent will be collected for LEADS even if there is 
already an existing autopsy brain donation consent for the site’s local ADRC. There are 3 
objectives of the discussion: 1) to convey information about the value of brain autopsy in 
confirming the clinical diagnosis and advancing knowledge regarding EOAD; 2) to initiate 
consideration of the individual’s wishes concerning an autopsy; and 3) to answer questions, 
misconceptions, or concerns about autopsy. This repeated dialogue will be offered at every 
visit, even after the participant has agreed/consented to autopsy brain donation, unless the 
participant has clearly refused autopsy. Ongoing discussions can be helpful to ensure that 
the study participant conveys their wishes to their family.  
 
This decision is voluntary and designed not to involve pressure; participants are encouraged 
to involve family members, clergy, physicians, or any other appropriate persons in their 
decision-making. Participants are assured that refusing autopsy in no way jeopardizes their 
research participation or any other patient rights. It is important to note that the autopsy will 
not interfere with funerary arrangements (e.g., an open-casket funeral is acceptable as there 
will be no visual disfigurement) nor will it be a financial burden to the participant's family. 
As a supplement to this discussion, the LEADS Neuropathology Core will develop an 
Autopsy Brochure to dispel some of the common myths and concerns regarding the autopsy 
procedure and a Brain Donation letter, which will explain the importance of autopsy and 
brain donation for research in layperson language. We will encourage the study team to use 
these tools when discussing autopsy with participants. 
 
Regular contact (e.g., at each in-clinic visit, phone calls) with individuals and their family 
who have provisionally consented, can help ensure that autopsy arrangements are made in 
advance, which aids successful brain donation. This includes annual phone checks after 
completion of the LEADS study and after all LEADS study visits have been completed, 
until the death of the participant. Periodically revisiting the procedure to follow at the time 
of death and reiterating the participant’s wish for donation to family members strengthens 
the likelihood of a completed brain donation at time of death.  
 
Participation in the autopsy component of the study is optional for international sites. 
Therefore, international sites may refrain from approaching their participants for autopsy 
brain donation. If international sites choose to take part, they may leverage existing brain 
banks in order to store the brain tissue locally and share tissue and/or data with LEADS as 
regulations allow.  

 
 
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After Obtaining Provisional Consent 
When voluntary autopsy consent is granted, more detailed information should be provided to 
the participant about procedures to follow at time of death, including telephone numbers to 
call and other guidelines. The LEADS Neuropathology Core has developed autopsy 
notification materials such as wallet cards that list contact information for the person to be 
notified at the time of death and letters to primary care physicians that communicate the 
participant’s wishes regarding autopsy. Participants are strongly encouraged to share this 
information with the next-of-kin, legally authorized representatives (e.g., Durable Power of 
Attorney (DPOA)), and private physicians. In many states, final legal authorization by the 
DPOA or next-of-kin must be obtained at the time of death. LEADS is a multi-center study; 
sites must follow state and local laws regarding autopsy consent procedures. 
At the Time of Expiration  
Sites will follow standard autopsy procedures as outlined in the LEADS Neuropathology 
Manual upon notification of the death of a LEADS participant.  
7.1.8 Study Participation Report  
Study participants can be optionally provided a report of study procedure results. The report 
will summarize key results from relevant procedures (cognitive testing, diagnosis, and MRI 
results) and be used to aid in study retention. Amyloid and tau PET scan results will be 
provided to cognitively impaired participants only. FDG PET scan results will be provided 
to EOnonAD participants only. 
 
Clinically significant results will be relayed in a timely manner by the Site clinician. 
Appropriate follow-up with a treating physician will be arranged as indicated.  
7.1.9 Participant Travel 
In certain situations (e.g., imaging machine is down at home site, tracer is unavailable, etc.) 
it is permissible for participants participating at one clinical site to complete some 
procedures at another clinical site. Contact the Coordinating Center for prior approval and 
guidance.  
 
7.2 Clinical Assessments and Procedures 
Demographics 
Participants and study informants will provide basic demographic information 
throughout the study.  
Family History  
Detailed family history will be collected from all participants. Participants with two 
or more first degree family members with EOAD (defined as AD with onset < 64 
years) will be ineligible for LEADS, unless known pathogenic mutations in APP, 
PSEN1, PSEN2, MAPT, GRN and C9ORF72 have been excluded. 
Early Developmental History Questionnaire 
Studies have shown that neurodevelopmental differences (non-right-handedness, 
learning disabilities, etc.) may be overrepresented in atypical early-onset 
neurodegenerative diseases. [38, 39] Preliminary data suggests that 
neurodevelopmental differences might contribute towards disease susceptibility. A 

 
 
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brief questionnaire will be used to assess handedness and previous 
neurodevelopmental disorders in the research participant or participant’s family. In 
symptomatic participants, the questionnaire should be completed by the study 
informant on behalf of or together with the participant. In asymptomatic participants, 
the questionnaire can be completed independently. This questionnaire may be 
administered by study staff if need be. 
Autoimmune History Questionnaire 
Studies have shown that non-thyroid autoimmune disorders may be overrepresented 
in atypical early-onset neurodegenerative diseases – including conditions due to 
underlying Alzheimer’s disease. [40, 41] Preliminary data suggests that select 
autoimmune diseases might contribute individually towards disease susceptibility. 
Brief autoimmune history will be collected for the research participant and 
participant’s family. In symptomatic participants, the questionnaire should be 
completed by the study informant on behalf of or together with the participant. In 
asymptomatic participants, the questionnaire can be completed independently. This 
questionnaire may be administered by study staff if need be. 
 
Sex and Reproductive Health Questionnaire 
The Sex and Reproductive Health is a self-report questionnaire that will be 
administered to all participants. The questionnaire should be administered in-person 
but may be administered over the phone when in-person administration is not 
feasible.   
Genetic Counseling and Genetic Testing – cognitively impaired participants only 
At the Screening Visit, participants will view a video that outlines the implications of 
mutations in known ADAD loci (e.g., in APP, PSEN1, PSEN2, C9ORF72, MAPT 
and GRN) and be provided a genetics handout summarizing the information 
reviewed in the video. The video outlines the implications positive results might 
have for participants and their families. The video will describe how receipt of the 
genetic testing results and identification of pathogenic mutations will provide 
information regarding the likelihood that close relatives of the participant may also 
develop EOAD. Additionally, results of genetic testing may reveal incorrect 
assumptions in family relationships (such as learning that a child is adopted or has a 
different father). The participant will also be asked if they would like to speak with a 
genetic counselor at baseline either in person or via a telephone/video bridge to 
verify their understanding of the implications of genetic testing and answer any 
questions the participant may have. Some international sites may not have access to a 
genetic counselor. In these cases, participants will be offered a session with the site 
PI or an appropriately trained clinical investigator. Participants will be asked if they 
wish to receive results if a known pathogenic mutation is identified in an ADAD 
gene and will provide written consent. 
 
A 6 ml blood sample will be collected at the Baseline Visit from all cognitively 
impaired participants. The sample will be used for CLIA confirmation of a known 
pathogenic mutation, if one is found. The availability of this sample for all 
cognitively impaired participants will also allow a participant who initially did not 
want to learn their mutation status to change his or her mind later. This tube will be 
sent to and stored at NCRAD.  

 
 
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Research genetic screening will be performed in a research laboratory as part of the 
LEADS study and the data will be used to screen for mutations in APP, PSEN1, 
PSEN2, MAPT, C9ORF72, and GRN, and for research analyses. If a known 
pathogenic mutation is found in one of these genes and the participant has opted to 
receive pathogenic mutation results, the CLIA laboratory will utilize the stored blood 
sample to confirm the mutation identified through the research studies. If the 
participant did not request the pathogenic mutation results, NCRAD will destroy the 
stored blood sample at the time of study completion.  
 
If the mutation is confirmed in the CLIA laboratory, the participant will meet with 
the site’s genetic counselor (or Site PI/clinician for international sites) for result 
disclosure and appropriate counseling and be discontinued from the LEADS study 
and given a referral to research studies focused on familial neurodegenerative 
disorders, such as the Dominantly Inherited Alzheimer’s Network (DIAN) research 
study. Whenever feasible, results should be disclosed in person. If an in-person 
disclosure is not feasible due to geographic distance, other participant-related factors, 
or in special circumstances a videobridge genetic counseling session will be 
considered a viable substitute with approval from the Genetics Core.  
Prior neurodegenerative disease genetic testing  
Participants with previous negative genetic testing results for mutations in APP, 
PSEN1, PSEN2, MAPT, C9ORF72 and GRN performed in a CLIA laboratory may 
not require research testing. Participants enrolled at international sites may have 
previous genetic testing that was performed in a non-CLIA laboratory, but with 
similar standards. All previous genetic testing reports must be submitted to the 
Genetics Core to determine if research testing under the LEADS protocol is required. 
Submitted reports must be: 1) de-identified and labeled with the participant study ID, 
2) in English or translated into English, 3) include the genes tested and the result in 
standard protein or DNA nomenclature, 4) include the date of testing, 5) include the 
name of the laboratory or laboratory director and any certifications of quality 
assurance, 6) include description of methodology. If after review, the previous 
testing meets the requirements of the LEADS study, genetic screening for mutations 
in the six genes will not be performed and participants will not be required to view 
the video, receive the genetics handout, complete the separate genetic testing 
consent, provide a 6 ml blood sample, or meet with the genetic counselor.  
Physical and Neurological Examination 
A medically qualified professional will perform a physical examination of the major 
body systems. Neurological examination will include an assessment of cranial 
nerves, motor function, coordination, reflexes, sensation and gait. 
Medical History 
The participant’s lifetime medical history will be collected as listed in Appendix 1. 
Medical history includes previous and current diseases, psychiatric history, and 
substance use history.  
Medication List 
The participant’s current medications will be collected at each visit as indicated in 
Appendix 1.  

 
 
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Vital Signs 
Vital signs will include height, weight, systolic and diastolic blood pressure, and 
pulse. 
Clinical Dementia Rating (CDR) 
The CDR is a semi-structured interview of the informant and participant that 
assesses for impairment in 8 areas of functioning  - memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, personal care, behavior, 
personality, and language [42]. 
Functional Assessment Questionnaire (FAQ) 
Based on an interview with the informant, a participant is rated on his/her ability to 
carry out ten complex activities of daily living [43]. 
Amsterdam Instrumental Activity of Daily Living Questionnaire  
The Amsterdam IADL Questionnaire (A-IADL-Q) is a questionnaire designed to 
assess impairments in instrumental activities of daily living (IADL) in (early) 
dementia. The questionnaire is completed by a caregiver, such as a spouse, relative 
or friend. The A-IADL-Q covers a broad range of IADL, including household 
activities, household appliances, finances, work, computer, and leisure activities. It 
was demonstrated to be a reliable and valid instrument in the evaluation of dementia 
[64, 65], with good diagnostic value [64] and sensitivity to change over time [66].  
Neuropsychiatric Inventory (NPI-Q) 
The NPI-Q is a well-validated, reliable, multi-item instrument to assess the 
neuropsychiatric features in AD based on an interview with the informant [44]. It 
evaluates severity of delusions, hallucinations, dysphoria, anxiety, 
agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant 
motor behavior. 
Geriatric Depression Scale (GDS) Short Form 
The GDS Short Form is a self-report scale designed to screen for symptoms of 
depression in the elderly. [45]. 
Social Norms Questionnaire 
The intent of the questionnaire is to determine how well participants can understand 
and identify social boundaries that are part of mainstream culture in the United States 
[46]. The participant is asked to check the most accurate response to “Is it socially 
acceptable to” questions. Example: Is it socially acceptable to eat pasta with your 
fingers? 
Social Behavior Observer Checklist 
The intent of this checklist is to aid clinicians with the recognition of distinct patterns 
of social behaviors such as self-consciousness, anxiety, embarrassment, failure to 
adapt, etc.  
Clinical Symptom Assessment 
A clinical determination of the participant’s current symptomatology and onset of 
symptoms will be collected by a trained clinician. Information will be obtained 
through the participant, study partner, medical records, and/or observations.  

 
 
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Clinical Diagnosis 
At each site, a formal consensus panel will assess the participant’s diagnosis within 
30 days of each study visit.  
Area Deprivation Index (ADI) 
The ADI is a composite measure of socioeconomic disadvantage for the United 
States. Using United States Census indicators of poverty, education, housing, and 
employment, neighborhood socioeconomic status is ranked by disadvantage at the 
state and national level. Each census block/neighborhood is split into state deciles 
and national percentiles, with lower percentile scores indicating less socioeconomic 
disadvantage [67, 68]. This measure will only be collected for U.S. sites.  
 
 
7.3 Cognitive Testing 
7.3.1 NACC Uniform Data Set (UDS) and Frontotemporal Lobar Degeneration (FTLD) 
Neuropsychological Batteries 
Montreal Cognitive Assessment (MoCA)  
The MoCA is a rapid screening instrument designed to help health professionals 
detect cognitive dysfunction. It assesses numerous cognitive domains: attention and 
concentration, executive function, memory, language, visuospatial skills, conceptual 
thinking, calculations and orientation[47].  
 
Note: The MoCA cannot be administered on the same day as the MMSE. MMSE 
should be done at the screening visit. MoCA should be administered at a subsequent 
visit. 
Craft Stories 
This test assesses one’s ability to recall a short story[48]. Hearing acuity must be 
established prior to the test. The participant is read a short story and asked to recall 
it. The participant is asked to repeat the test again after 20 minutes to assess delayed 
recall (episodic memory).  
Benson Complex Figure Copy and Recall 
The purpose of this test is to assess a participant’s visuospatial skills and visual 
memory. It is a simplified version of the Rey-Osterrieth Complex Figure[49, 50]. 
The participant is asked to first copy and after 10-15 minutes to draw the figure again 
from memory. 
Number Span Forward and Backward 
This is a test of working memory, and it taps two different constructs. The first, 
Forward Number Span, measures the capacity for briefly holding information and 
repeating it exactly. The second, Backward Number Span, measures the ability not 
only to hold the information but also to manipulate the numbers by reversing the 
sequence. Sequences of 2 to 9 numbers (two trials at each sequence length) are 
presented for both Forward and Backward Number Span[48].  

 
 
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Category Fluency 
This is a widely used measure of verbal fluency. The participant is asked to name 
different exemplars of a given semantic category (e.g., animals), and the number of 
unique exemplars named is scored[51].  
Trail Making Tests (A and B) 
These are tests of processing speed and executive function. Both Parts A and B 
depend on visuomotor and perceptual-scanning skills. Part B also requires cognitive 
flexibility in shifting from number to letter sets under time pressure. The 
participant’s performance is judged in terms of time[52].  
The Multilingual Naming Test (MINT)  
The MINT is a language test that examines one’s ability for visual object naming 
[48, 69]. Line drawings are presented to the participant with the instruction to say the 
name of the object.  
Phonemic Fluency  
This is a widely used measure of word generation that may be sensitive to 
dysfunction in the dominant frontal lobe [51]. In this version, the participant is asked 
to say as many words as possible that being with the letter “F” in 60 seconds, and 
then as many words that being with the letter “L” in 60 seconds.  
Word Reading 
This is a test of word reading that includes regularly spelled and irregularly spelled 
words. The participant is asked to read out loud from the regular and irregularly spelled 
word lists. Accurate word reading is scored. 
Semantic Associates Test 
This is a test of knowledge of the meaning of objects [53]. In this test, a participant 
reviews pairs of pictures and is instructed to select those that depict related objects. 
Correct associations are scored.  
Semantic Word Picture Matching 
This test evaluates spoken word recognition and assesses for semantic errors in word 
comprehension. The stimuli consist of four-picture displays including pictures of four 
objects that are semantically related. One of the objects is named by the examiner and 
the participant is asked to point to that object. 
Northwestern Anagram 
This is a test of grammatical knowledge[54]. In this test, the participant is shown 
pictures and is then asked to assemble a sentence describing the pictures using printed 
words that are provided.  
Sentence Repetition  
This is a test of oral repetition of sentence-length utterances. A sentence is read out loud 
to the participant. The participant then repeats the sentence verbatim. Correct sentences, 
omitted words and semantic errors are recorded for scoring purposes.  
Noun and Verb Naming  
This is a test of confrontation naming of objects and actions. In this test, the participant 
is shown pictures of objects or things, as well as pictures of people doing various 
actions. The participant is then asked to name each picture as quickly and as accurately 
as possible. The primary measure of performance is the noun-to-verb ratio[55]. 

 
 
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Sentence Reading 
In this test, the participant is given a sheet of paper with five short sentences and is asked 
to read the sentences out loud. The primary measure of performance is the number of 
accurately read sentences. 
 
7.3.2 Additional Cognitive Tests: 
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog13) 
The ADAS-Cog13 [56] is an in-person examiner-administered, structured scale that 
evaluates memory, reasoning, language, orientation, ideational praxis and 
constructional praxis. Ratings of spoken language, language comprehension, word 
finding difficulty, and ability to remember test instructions are also obtained.  
Digit Symbol Substitution Test 
The Digit Symbol Substitution test [57] measures complex attention. The numbers 1-
9 are paired with different nonsense symbols. A string of these numbers is randomly 
printed directly above a row of blank squares. Following a short series of practice 
trials, the participant must use the key to fill in the blank squares with the correct 
nonsense symbol in order working from left to right across the rows. This test 
engages multiple cognitive abilities including attention, psychomotor speed, complex 
scanning, visual tracking, and immediate memory. 
Mini-Mental State Examinations (MMSE) 
The MMSE is a brief, frequently used screening instrument for Alzheimer’s disease 
drug studies [58]. The MMSE scale evaluates orientation, memory, attention, 
concentration, naming, repetition, comprehension, and ability to create a sentence 
and to copy two overlapping pentagons. The MMSE will only be administered once 
during the screening visit.  
Note: The MMSE cannot be administered on the same day as the MoCA. MMSE 
should be done at the screening visit. MoCA should be administered at a subsequent 
visit. 
Rey Auditory Verbal Learning Test (AVLT)  
The AVLT is a list-learning task, which assesses multiple cognitive parameters 
associated with learning and memory[49, 50]. 
Tablet-Based Cognitive Assessment Tools (TabCat) 
Tablet-Based Cognitive Assessment Tools (TabCat) is a tablet application that is 
composed of a growing suite of measures assessing cognitive and behavioral 
functions. Software packages can be installed on an iPad or Android-based tablet. 
The following four separate TabCat tasks will be administered: Flanker, Line 
Length, Line Orientation, and Match (Digit Symbol) [59]. 
 
7.3.3 Additional Cognitive Tests to be Used at Select International Sites:  
 
Logical Memory  
The logical memory test may be used in place of the Craft Stories in order to 
administer in different languages. The logical memory test is a measure of memory 
(declarative/episodic) in which a brief story is read to the subject, who is then asked 
to retell it from memory immediately. The primary measure of performance is the 

 
 
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number of story units recalled. Alternate paragraphs for the Logical Memory stories 
are not available, so as not to introduce more variability. The participant is asked to 
repeat the story again after 20 minutes to assess delayed recall (episodic memory) 
[69].  
 
Boston Naming Test 
The Boston Naming Test may be used in place of the MINT in order to administer in 
different languages. The Boston Naming Test is a measure of the ability to orally 
label (name) line drawings of objects. This test is sensitive to aphasia and also to 
object recognition deficits.  
 
Results from the NACC Uniform Data Set Neuropsychological Battery Crosswalk 
Study will be used to allow scores to be converted to equivalent scores on the Craft  
Stories and MINT tests, respectively [69].  
 
A summary of the neuropsychological testing may be entered in a participant’s medical 
record for clinical purposes.  
 
7.3.4 Audio Recording and Transcription 
The administration of select language and memory tests will be audio recorded for every 
participant, at every visit in the U.S..  These tests will not be audio recorded for participants 
at international sites due to language differences. This data will be collected to allow for 
additional analyses. A recording device, such as Olympus VN-722PC digital voice recorder 
or similar digital recording device, will be used. Audio recordings will be securely 
transmitted to a contracted cloud-based transcription service for automatic transcription. 
7.4 Imaging 
Use of short-to medium-acting benzodiazepines specifically for treatment of claustrophobia 
or anxiety related to imaging is allowed. The use of sedatives or hypnotics should be 
avoided for 8 hours before the administration of cognitive tests.  
7.4.1 Magnetic Resonance Imaging (MRI) 
All participants will be scanned on a 3T MR instrument with a protocol that conforms to 
FDA safety standards. The MRIs will be conducted as outlined in the Schedule of Events 
(Appendix 1). The MRI protocol includes: scout, structural T1-weighted MRI, FLAIR, T2-
weighted, diffusion tensor imaging, ASL perfusion MRI, and task free resting state 
functional MRI. The total scan time is approximately one hour but may be longer depending 
on technical factors. If the participant becomes uncomfortable they can ask to be removed 
from the scanner at any time. MRI scan findings of clinical significance, determined by the 
local neurologist or radiologist, will be shared with the participant and the participant’s local 
physician (if necessary – i.e., in the case of actionable findings).  
 
The MRI report or summary of MRI findings may be entered in participant’s medical record 
for clinical purposes.  
7.4.2 PET scanning. Amyloid, Tau, and FDG PET Imaging 
All participants will complete PET scanning on a PET instrument according to the protocol. 
The PET scans will be conducted as outlined in the Schedule of Events (Appendix 1). There 
must be at least 365 days between the first PET scan of the previous visit and the first PET 

 
 
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scan of the next yearly visit. There must also be at least 365 days from second-to-second 
PET, so that there are no more than two study-related PET scans in a year. FDG PET is not 
subject to this consideration; it can be the third study-related PET in 365 days. Consult the 
ATRI Coordinating Center for guidance on scheduling participant visits. 
 
Note: PET scans must be done on separate days and at least 12 hours apart.  
 
7.4.2.1 Amyloid PET scanning   
Cognitively impaired and CN participants will undergo an amyloid PET scan as 
outlined in Appendix 1. The study staff will evaluate each participant prior to 
administration of tracer to determine if they are still suitable to undergo the scan 
(e.g., previous research PET scan exposure in the previous 12 months). For women 
of childbearing potential, a urine pregnancy test will be obtained and negative result 
confirmed on the day of scanning. 
 
The screening scans for cognitively impaired participants only will be interpreted by 
the PET Core to assess amyloid status. The read will be based on a consensus 
between visual and quantitative assessments. Dichotomous visual interpretations of 
summed images will be performed by a qualified rater using validated criteria. 
Standardized Uptake Value Ratio (SUVR) images will be created using whole 
cerebellum as a reference region and a threshold SUVR will be used to define scan 
positivity. Scans in which visual and quantitative classifications that are incongruent 
will be arbitrated by consensus by at least two members of the PET Working Group.  
 
Screening amyloid PET results for all cognitively impaired participants and M36 
amyloid PET results, as applicable, for all EOnonAD participants, positive and 
negative, will be provided to sites. The Site PI or an affiliated study physician will be 
responsible for disclosing the results to the study participant and their family. The 
clinician should follow best practices in disclosing amyloid PET results. Whenever 
feasible, results should be disclosed in person. If an in-person disclosure is not 
feasible due to geographic distance or other factors, a telemedicine appointment 
could be considered a viable substitute. Disclosure of results by phone call only is 
discouraged but allowable at the discretion of the Site PI.  
 
Longitudinal amyloid PET scans for the EOAD and EOnonAD cohorts will not 
receive an official read, however trans-axial images may be provided to the 
participant at the discretion of the site PI. See sections 7.4.2.2-7.4.2.5 below, as not 
all participants will complete longitudinal amyloid PET scans.  
 
Amyloid PET scans from the CN cohort will not receive an official read and results 
will not be disclosed.  
 
7.4.2.2 Florbetaben (Neuraceq) 
 
Florbetaben scanning entails 8.1 mCi +/- (300MBq) 10% injection of tracer through 
an intravenous line and a 90 minute (+/- 5 minutes) uptake followed by a 20-minute 
image acquisition scan. Every effort should be made to scan at exactly 90 minutes 

 
 
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post injection. A low dose CT scan will be acquired on all PET/CT scanners for 
attenuation correction prior to beginning acquisition. The injection site will be 
observed for evidence of inflammation or damage to the surrounding tissue where 
the dose was injected and adverse events will be monitored during the imaging 
session. Participants will be asked to void completely after completion of the scan.  
 
Additional information regarding florbetaben (i.e., production, delivery, 
administration, safety) is provided in section 9.0 Study Compounds. 
 
7.4.2.3 C-Pittsburgh Compound B (11C-PiB) (for international sites only) 
Select sites may use PiB in place of Florbetaben with a prior agreement in their site’s 
contract with IU. International sites using PiB will follow Good Manufacturing 
Practice (GMP) pharmaceutical regulations.  
 
PiB scans will only be completed at screening for all subjects for cohort assignment. 
Sites that use PiB in place of florbetaben will not complete longitudinal amyloid PET 
scans.  
 
PiB scanning entails 10 mCi (370 MBq) +/- 10% injection of tracer through an 
intravenous line and a 40-minute (+/- 5 minutes) uptake followed by a 30-minute 
image acquisition scan. Every effort should be made to scan at exactly 40 minutes 
post injection. A low dose CT scan will be acquired on all PET/CT scanners for 
attenuation correction prior to beginning acquisition. The injection site will be 
observed for evidence of inflammation or damage to the surrounding tissue where 
the dose was injected and adverse events will be monitored during the imaging 
session. Participants will be asked to void completely after completion of the scan.  
 
Additional information regarding PiB (i.e., production, delivery, administration, 
safety) is provided in section 9.0 Study Compounds. 
 
 
7.4.2.4 [18F]NAV-4694 (for international sites only) 
Select sites may use NAV-4694 in place of Florbetaben with a prior agreement in 
their site’s contract with IU. International sites using NAV-4694 will follow Good 
Manufacturing Practice (GMP) pharmaceutical regulations.  
 
NAV-4694 will only be used for cohort assignment at screening. Sites that use NAV-
4694 in place of florbetaben will not complete longitudinal amyloid PET scans.  
 
NAV-4694 scanning entails 8.1 mCi (300 MBq) +/- 10% injection of tracer through 
an intravenous line and a 50 minute (+/- 5 minutes) uptake followed by a 20-minute 
image acquisition scan. Every effort should be made to scan at exactly 50 minutes 
post injection. A low dose CT scan will be acquired on all PET/CT scanners for 
attenuation correction prior to beginning acquisition. The injection site will be 
observed for evidence of inflammation or damage to the surrounding tissue where 
the dose was injected and adverse events will be monitored during the imaging 
session. Participants will be asked to void completely after completion of the scan.  
 

 
 
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Additional information regarding NAV-4694 (i.e., production, delivery, 
administration, safety) is provided in section 9.0 Study Compounds. 
 
7.4.2.5 Flutemetamol (for international sites only)  
Select sites may use Flutemetamol in place of Florbetaben with a prior agreement in 
their site’s contract with IU. International sites using Flutemetamol will follow Good 
Manufacturing Practice (GMP) pharmaceutical regulations.  
 
Flutemetamol will only be used for cohort assignment at screening. Sites that use 
Flutemetamol in place of florbetaben will not complete longitudinal amyloid PET 
scans.  
 
Flutemetamol scanning entails 5mCi (185 MBq) +/- 10% injection of tracer through 
an intravenous line and a 90 minute (+/- 5 minutes) uptake followed by a 20-minute 
image acquisition scan. Every effort should be made to scan at exactly 90 minutes 
post injection. A low dose CT scan will be acquired on all PET/CT scanners for 
attenuation correction prior to beginning acquisition. The injection site will be 
observed for evidence of inflammation or damage to the surrounding tissue where 
the dose was injected and adverse events will be monitored during the imaging 
session. Participants will be asked to void completely after completion of the scan.  
 
Additional information regarding Flutemetamol (i.e., production, delivery, 
administration, safety) is provided in section 9.0 Study Compounds. 
 
7.4.2.6 Flortaucipir  
Cognitively impaired and CN participants will undergo a flortaucipir PET as outlined 
in Appendix 1. Participants from select international sites will not complete Tau PET 
scans. The site study physicians will evaluate each participant prior to administration 
of flortaucipir to determine if they are still suitable to undergo the scan (e.g., 
previous research PET scan exposure in the previous 12 months). For women of 
childbearing potential, a urine pregnancy test will be obtained and negative result 
confirmed on the day of scanning.  
 
Baseline tau PET results for all newly recruited cognitively impaired participants, 
positive and negative, will be provided to sites. Participants from select international 
sites will not complete tau PET scans and therefore will not receive tau PET results. 
For sites with participants past their baseline timepoint at the time when protocol 
version 8.0 was implemented, tau PET scan results related to their next study visit 
timepoint will be provided. The Site PI or an affiliated study physician will be 
responsible for disclosing the results to the study participant and their family. The 
clinician should follow best practices in disclosing tau PET results. At Baseline, tau 
PET scan results and amyloid PET scan results should be disclosed at the same time. 
If this is not possible due to scheduling conflicts, the study clinician will provide 
amyloid PET scan results prior to disclosing tau PET scan results. Whenever 
feasible, results should be disclosed in person. If an in-person disclosure is not 
feasible due to geographic distance or other factors, a telemedicine appointment 
could be considered a viable substitute. Disclosure of results by phone call only is 

 
 
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discouraged but allowable at the discretion of the Site PI. 
 
Longitudinal tau PET scans for the EOAD and EOnonAD cohorts will not 
receive an official read, however trans-axial images may be provided to 
the participant at the discretion of the site PI. 
 
Tau PET scans from the CN cohort will not receive an official read and 
results will not be disclosed.  
 
Flortaucipir scans will be acquired on the PET scanner at each site using standard 
procedures. Flortaucipir scanning entails 10 mCi (370 MBq) +/- 10%injection of 
tracer through an intravenous line and a 75-80 minute uptake followed by 30-minute 
image acquisition scan. Every effort should be made to scan at exactly 75 minutes 
post injection. After approximately 75-minute-long uptake period, participants will 
undergo a 30-minute dynamic, 3D PET scan consisting of six 5-minute frames (i.e., 
from 75-105 minutes post-injection). A low dose CT scan will be acquired on all 
PET/CT scanners for attenuation correction prior to beginning acquisition. The 
injection site will be observed for evidence of inflammation or damage to the 
surrounding tissue where the dose was injected and adverse events will be monitored 
during the imaging session. Participants will be asked to void completely after 
completion of the scan.  
 
Study personnel, will consult with study physicians as needed and will assess the 
participant prior to discharge from the imaging center to determine well-being. 
Participants who experience an adverse event will not be discharged until the event 
has resolved or stabilized.  
 
Additional information regarding flortaucipir (i.e., production, delivery, 
administration, safety) is provided in section 9.0 Study Compounds. 
 
7.4.2.7 FDG PET  
EOnonAD and CN participants will undergo a FDG PET scan as outlined in 
Appendix 1. The study staff will evaluate each participant prior to administration of 
fluorodeoxyglucose to determine if they are still suitable to undergo the scan (e.g., 
previous research PET scan exposure in the previous 12 months). For women of 
childbearing potential, a urine pregnancy test will be obtained and negative result 
confirmed on the day of scanning. 
 
Clinical reads for EOnonAD participants will be provided to sites. The Site PI or an 
affiliated study physician will be responsible for disclosing the results to the study 
participant and their family. The clinician should follow best practices in disclosing 
FDG PET results. Whenever feasible, results should be disclosed in person. If an in-
person disclosure is not feasible due to geographic distance or other factors, a 
telemedicine appointment could be considered a viable substitute. Disclosure of 
results by phone call only is discouraged but allowable at the discretion of the Site 
PI. 
 

 
 
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FDG PET scans from the CN cohort will not receive an official read and results will 
not be disclosed. 
 
FDG PET scans for all participants will be reviewed locally for safety purposes and 
clinically significant findings (e.g., hypermetabolic lesion concerning for 
malignancy) will be disclosed to sites. Clinically significant incidental findings 
should be disclosed to participants by the site PI. 
 
Fluorodeoxyglucose scans will be acquired on the PET scanner at each site using 
standard procedures. Participants must be fasting for 4 hours or overnight; prior to 
the scan a blood glucose measurement will be made by fingerstick and scans will be 
postponed or rescheduled if the reading is > 180 mg/dL. Fluorodeoxyglucose 
scanning entails a 5 mCi (185MBq) +/- 10% injection of tracer through an 
intravenous line and a 30-minute uptake followed by a 30-minute image acquisition 
scan. A low dose CT scan will be acquired on all PET/CT scanners for attenuation 
correction prior to beginning acquisition. The injection site will be observed for 
evidence of inflammation or damage to the surrounding tissue where the dose was 
injected and adverse events will be monitored during the imaging session. 
Participants will be asked to void completely after completion of the scan.  
 
Study personnel will consult with study physicians as needed and will assess the 
participant prior to discharge from the imaging center to determine well-being. 
Participants who experience an adverse event will not be discharged until the event 
has resolved or stabilized. 
 
Additional information regarding fluorodeoxyglucose (i.e., production, delivery, 
administration, safety) is provided in section 9.0 Study Compounds. 
  
 
7.5 Fluid Biomarker Collection 
Biofluids will be collected at time points specified in the Schedule of Events (Appendix 1). 
Samples will be collected to accommodate the assay of the broadest range of the best 
antecedent biomarkers/analytes.  
 
Peripheral blood for biomarker analyses and CSF should be collected after a minimum 6-
hour fast, preferably in the morning. When fasting, only water (no food) will be permitted 
until the blood draw and the (optional) LP procedure are completed. Every effort to gather 
the samples fasting will be done. In special circumstances and on a case-by-case basis, non-
fasting collection will be allowed by the Site PI or their designee and not considered a 
protocol deviation.  
7.5.1 Peripheral Blood Collection for Fluid Biomarker Analyses 
Up to 80 mL of blood will be collected. This sample will be used to extract DNA, RNA, 
plasma, serum and PBMC. For sample processing please see section 7.7.  
7.5.2 Peripheral Blood Collection for Genetic Testing 
All cognitively impaired individuals will have a 6 ml blood sample collected at the Baseline 
Visit. This sample will be sent to and stored in NCRAD and will be used for CLIA 

 
 
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confirmation of a known pathogenic mutation, if it is found. If a known pathogenic mutation 
is found, the CLIA laboratory will utilize the stored blood sample to confirm the mutation 
identified through the research studies. The availability of this sample will also allow a 
participant to consent to genetic testing results at any time during the study.  
7.5.3 Lumbar Puncture and CSF (optional) 
Lumbar puncture (LP) is a technique to sample cerebrospinal fluid (CSF). The procedure 
involves introducing a needle into the subarachnoid space of the lumbar sac, at a level safely 
below the spinal cord. Lumbar puncture will be completed using standard collection 
procedures. CSF collection will be performed using a small caliber atraumatic needle. CSF 
should be obtained via gravity flow using the 22 gauge Sprotte needle, although aspiration 
through this or smaller needles is allowable. Prior approval from the Clinical Core is 
required before the aspiration method or use of other sized needles can be utilized. Sites 
must designate the method of CSF collection for data tracking purposes.  
 
Participants will be instructed to lie down for 30-60 min after the procedure, to drink plenty 
of fluids before and after the procedure and take OTC pain medications to alleviate any post-
procedure headache or back ache (see Section 10.0 Side Effects for more details).  
 
Approximately 2 ml of CSF will be sent to the site’s clinical laboratory for routine cell 
count, protein and glucose analyses. The remaining (up to 18 ml) CSF will be aliquoted at 
the site and shipped to NCRAD. iLEADS sites must send a minimum of 10 mL CSF; 
exceptions may be made at the discretion of the Genetics and Biorepository Core. 
 
International sites may have stored CSF that was collected previously for other EOAD 
studies or routine assessments in clinic. In order to avoid repeat lumbar puncture procedures 
and reduce participant burden, international sites may send these pre-existing CSF samples 
to LEADS if collected up to 12 months prior to a participant’s consent date and approval is 
received by the Genetics and Biorepository Core. These sites must contain applicable 
language in their consent form. If approval is obtained for LEADS, these samples will be 
shipped to NCRAD. 
 
For information about sample processing, see section 7.7. 
7.6 Safety Assessments 
7.6.1 Concomitant Medication Review  
Concomitant medications will be reviewed per SOE.  
7.6.2 Safety Laboratory Assessments  
Prior to lumbar puncture all participants will be subjected to the following safety labs. 
Safety labs will be conducted locally. However, if previous safety labs exist from a CLIA or 
appropriately certified laboratory within 60 days of LP, they can be used to review clinical 
significance and determine LP eligibility.  
• complete blood count with differential (CBC w/diff)  
• basic coagulation panel 
The laboratory reports must be reviewed and signed and dated by the Site PI (or a 
medically-qualified individual delegated by the PI) prior to conducting the study LP.  

 
 
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7.6.3 Urine Pregnancy Test  
On the day of each PET scan, prior to the scan, all females of childbearing potential will 
complete a urine pregnancy test. Participants with positive pregnancy test will be ineligible 
for amyloid, tau, and FDG PET scanning.  
7.6.4 Brain Imaging  
A brain image documenting absence of space occupying lesion, another reason for increased 
intracranial pressure and Arnold Chiari malformation should be performed prior to 
the baseline lumbar puncture, or if missed at baseline, prior to the first lumbar puncture and 
to assess overall eligibility (see exclusion #6). A previously existing MRI within 12 months 
of consent can be used to expedite eligibility determination. However, the site is still 
required to complete a study MRI scan at screening or baseline per the schedule of events. If 
no previous imaging from the past 12 months exists, the study MRI scan will need to be 
completed and reviewed locally by a neurologist or radiologist prior to the lumbar puncture 
procedure.  
7.7 Biofluid Sample Processing  
7.7.1 Site processing: 
1. Peripheral blood sample – up to 80mL of blood will be collected. The following will 
be extracted from this sample: 
i. 
DNA – buffy coat collected from a blood sample will be shipped to 
NCRAD where DNA will be extracted and used for a range of genomic 
analyses including whole genome sequencing and epigenetic analyses, and 
to enable future genomic analyses.  
ii. 
RNA - blood sample will be shipped to NCRAD where RNA will be 
extracted and used for expression analyses including RNA sequencing. 
iii. 
Peripheral blood mononuclear cells (PBMC) – blood sample will be 
shipped to NCRAD where PBMCs will be isolated and used for the 
development of induced pluripotent stem cells (iPSCs). These cells can also 
support other functional genomic studies. Some cells may be derived into 
new materials. PBMCs are optional for international sites and if collected, 
will be stored locally.  
iv. 
Plasma – the blood sample will be processed at the site. The plasma will be 
subaliquoted at the site and frozen. Frozen aliquots will be shipped to 
NCRAD for use in biomarker assay development and validation. 
v. 
Serum - the blood sample will be processed at the site. The serum will be 
subaliquoted at the site and frozen. Frozen aliquots will be shipped to 
NCRAD for use in biomarker assay development and validation. 
2. CSF (optional) - 2 mL will be sent to the site’s clinical laboratory for routine labs - 
cell count, protein and glucose analyses. The remaining (up to 18 ml) CSF will be 
aliquoted at the site and frozen as soon as possible, but at maximum, within 24 hours 
at -80oC. Frozen aliquots will be shipped to NCRAD for use in biomarker assay 
development and validation. 
3. 6 mL of blood from cognitively impaired participants will be shipped to NCRAD for 
CLIA genetic testing, as applicable. See section 7.2 Prior neurodegenerative disease 
genetic testing section for more information.  
 

 
 
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All sample collection and shipment from international sites to the U.S. will follow local 
regulations. If regulation does not allow international sites to ship samples to the U.S., 
samples will be stored locally until plans for analyses and shipment comply with the 
regulations.  
7.7.2 National Centralized Repository for Alzheimer’s Disease and Related Dementias 
(NCRAD) Sample Processing  
Biofluids will be sent to NCRAD where samples will be processed, stored, and distributed to 
approved researchers for analysis. Most samples will be sent frozen; however, the blood 
sample for PBMC isolation will be sent the same day it is drawn to ensure maximal utility 
for subsequent analyses. NCRAD will request a re-sampling, if the condition of the sample 
on arrival prevents processing. All other blood samples, the plasma and serum aliquots and 
CSF aliquot will be shipped frozen in batches.  
 
The identity of participants will not be shared with NCRAD or with any investigators. A 
unique bar-code number will be affixed to all specimen tubes as well as affixed to the 
Sample Form/Draw Sheet. All transfer tubes, vessels and storage vials will be pre-labeled 
prior to sample processing. 
 
8.0 CRITERIA FOR REPEAT ASSESSMENTS, INCOMPLETE VISIT 
PROCEDURES, RESCREENING, EARLY TERMINATION, 
DISCONTINUATION, REMOTE PROCEDURES, AND RETURNING 
PARTICIPANTS. 
8.1 Re-screens 
A participant may be re-screened once after an initial screen failure. The re-screen should 
occur at least 3 months after the original screen failure date. Exceptions are allowed at the 
discretion of the Site PI.  
8.2 Repeat Assessments 
In the event of unforeseen circumstances or if the data quality is unsatisfactory, participants 
may be asked to return to the clinic for repeat assessments. At the discretion of the Site PI, 
data collection may be repeated. Please contact the ATRI Coordinating Center for guidance 
regarding repeat assessments.  
8.3 Incomplete Visit Procedures and Protocol Deviations 
All attempts should be made to complete visit procedures as outlined in Appendix 1 within 
the allowable visit window period. On occasion, a participant might not be able to complete 
some of the required procedures (i.e., too impaired to complete the full cognitive assessment 
battery, unable to tolerate the full 60 minute MRI scan protocol, etc.) If a participant is 
unable to complete the full visit procedure as outlined in Appendix 1, the study team will 
document the reason for non-completion in the source documents. Participants will be 
followed as long as they are willing, and every attempt should be made to retain participants 
for longitudinal follow-up as long as possible. If participants are not willing or able to 
complete the full schedule of assessments at any visit, those assessments or procedures they 
are willing to complete should be conducted. It should be emphasized that the major priority 

 
 
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is to keep participants in the study, even if data collection is limited. If participants are no 
longer willing or able to travel to the clinic for annual visits, as much information should be 
collected via telephone as long as is possible, see section 8.7. Unless a participant has 
clearly declined brain autopsy, the neuropathology program should be discussed at each 
visit. Whenever a study procedure cannot be completed, sites will properly document the 
reason and review with the study team or IU IRB to determine if a protocol deviation is 
required.  
 
A protocol deviation is an alteration/modification to the IRB-approved protocol that is not 
approved by the IRB prior to its initiation or implementation. The IRB-approved protocol 
includes the detailed protocol, informed consent document(s), recruitment materials, and any 
other information relating to the research study. A minor protocol deviation does not impact 
participant safety and/or affect the integrity of study data. Examples: Failure to follow the 
approved study procedure that, in the opinion of the Site PI, does not affect participant 
safety or data integrity (e.g., study procedure conducted out of sequence; omitting an 
approved portion of the protocol; missing lab results). A major protocol deviation is a 
deviation to the IRB-approved protocol that may place subjects at greater risk of harm, cause 
actual harm to subjects or others, or compromise the integrity of study data such that the 
subject’s data can no longer be used in analysis of study outcomes. Examples: Enrollment of 
a participant who did not meet all inclusion/exclusion criteria; performing a study procedure 
not approved by the IRB; study compound dispensing or dosing error; failure to perform a 
required lab test or any other events that, in the opinion of the Site PI or Study PIs, may 
affect subject safety and/or data integrity. For U.S. sites, if a protocol deviation is major, or 
prompt reportable, it needs to be reported to the IU IRB right away or within 5 days of 
becoming aware of the event. See the IU HRPP Policy on reportable events here: 
https://research.iu.edu/compliance/human-subjects/guidance/reportable.html. See the 
relevant study manuals for more information about reporting expectations and mechanisms.   
 
NOTE: Contact IU,  ATRI Regulatory Affairs, or the IU IRB with questions regarding 
protocol deviations. 
 
8.4 Early Termination Visit 
If a participant wishes to exit the study, an early termination visit will be scheduled (if the 
participant is willing). This should include as many evaluations as possible, with the 
exception of PET imaging (see Appendix 1 for visit procedure details). Please contact ATRI 
Coordinating Center for guidance on what specific procedures should be conducted at an 
early termination visit.  
8.5 Discontinuation 
Participants with known pathogenic mutation who have opted to receive results will be 
discontinued from the study after genetic counseling. A referral to research studies focused 
on familial neurodegenerative disorders, such as the DIAN study will be provided. 
8.6 Participant Re-Contact after Study Withdraw 
If a participant wishes to withdraw from the study, the participant will be asked to provide 
consent for the LEADS study team to contact them to request additional information or 
biospecimens if needed. If the participant is enrolled in brain donation, this re-contact will 

 
 
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include annual phone checks after completion of the LEADS study visits until death of the 
participant.  
8.7 Remote Procedures 
Approved visit procedures depicted within the Schedule of Events (Appendix 1) can occur 
remotely any time it is not possible to conduct the visit in-person due to participant barriers. 
Remote activities can be conducted via telephone or video bridge. Neuropsychological 
batteries must be completed via video bridge following the virtual testing procedures 
manual. Examples of obstacles preventing participants from coming in-person to their visits 
may include disease progression, or inability to travel for any reason. When possible, 
participants should still come in-person to complete blood draw, LP, MRI and PET scans as 
applicable. A combination of remote and in-person data collection is allowed for the same 
visit. The study team will reassess participant ability to attend in person visits annually. If 
participants can resume in person visits, they will do so. If not, they will continue remote 
visit procedures. Prior approval from the IU team is required to conduct fully remote visits 
and confirmation of method of remote data collection, i.e. via telephone or video must be 
approved by IU and local regulatory body.  
 
8.8 LEADS Participants Returning After Therapeutic Trial (Returning Participants 
(RPs)) 
RPs may return to LEADS after completing their participation on a therapeutic trial if they 
were enrolled in LEADS prior to entering the therapeutic trial and completed a LEADS 
baseline visit. Upon their return to LEADS, RPs will be reconsented to the study. Once 
reconsented, RPs will resume their study activities based on last completed study visit, 
continue to follow schedule of events, and be asked questions regarding their trial 
involvement. RPs will complete any tasks that they’re willing and able to complete. If there 
are missed activities, coordinating center review will determine if a protocol deviation is 
required.  
9.0 STUDY COMPOUNDS  
9.1 Florbetaben  
Florbetaben will be provided by Life Molecular Imaging Ltd. One mL (1 mL) of the 
solution for each injection/vial contains 300 MBq of florbetaben. The other ingredients are 
ascorbic acid, ethanol anhydrous, macrogol 400, sodium ascorbate, and water for injections.  
 
Florbetaben will be prepared at the site’s contracted radiopharmacy and delivered to each 
site’s PET facility by courier on the day of administration. The dose will be received by a 
trained nuclear medicine technologist at each site. The dose will be administered in its 
entirety according to the Schedule of Events (Appendix 1). Florbetaben dose of 8 mCi +/- 
10% will be used in this study. Post administration, the used syringe will be placed in the 
sharps disposal container for radioactive materials. If a dose is not administered, it will be 
destroyed and placed in the sharps disposal container for radioactive materials.  
 
9.2 C-Pittsburgh Compound B (11C-PiB) (for International sites only) 
C-Pittsburgh Compound B, also known as PiB, will be made available to select sites on the 
day of administration.  

 
 
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The dose will be administered in its entirety according to the Schedule of Events (Appendix 
1). PiB dose of 10 mCi (370 MBq) +/- 10% will be used in this study. Post administration, 
the used syringe will be placed in the sharps disposal container for radioactive materials. If a 
dose is not administered, it will be destroyed and placed in the sharps disposal container for 
radioactive materials.  
 
9.3 [18F]NAV-4694 (for international sites only) 
[18F]NAV-4694, also known as NAV, will be made available to select sites on the day of 
administration.  
 
The dose will be administered in its entirety according to the Schedule of Events (Appendix 
1). NAV-4694 dose of 8.1 mCi (300 MBq) +/- 10% will be used in this study. Post 
administration, the used syringe will be placed in the sharps disposal container for 
radioactive materials. If a dose is not administered, it will be destroyed and placed in the 
sharps disposal container for radioactive materials.  
 
9.4 Flutemetamol (for international sites only) 
Flutemetamol will be manufactured on site, at select international sites only.  
 
The dose will be administered in its entirety according to the Schedule of Events (Appendix 
1). Flutemetamol dose of 5mCi (185MBq) +/- 10% will be used in this study. Post 
administration, the used syringe will be placed in the sharps disposal container for 
radioactive materials. If a dose is not administered, it will be destroyed and placed in the 
sharps disposal container for radioactive materials.  
9.5 Flortaucipir  
Flortaucipir also known as [18F]AV-1451, or Tauvid, will be provided by Avid 
Radiopharmaceuticals, Inc. (Avid) or PETNET Solutions, Inc. Avid and PETNET will 
provide oversight of the dose deliveries from contract manufacturing 
organizations/radiopharmacies. 
 
Flortaucipir will be utilized in accordance with the Avid Investigator’s Brochure: 
“Flortaucipir (18F; 18F-AV-1451 ([F-18]T807) Injection for Brain Tau Imaging” for more 
information. 
 
Tauvid will be utilized in accordance with the Tauvid Package Insert. 
 
Flortaucipir will be prepared at the site’s contracted radiopharmacy and delivered to each 
site’s PET facility by courier on the day of administration following the standard procedures 
of acceptance and disposal of radioactive tracers. The dose will be received by a trained 
nuclear medicine technologist at each site. Some sites will manufacture their own batches of 
AV-1451 Injection, in accordance with a material transfer agreement with Avid and prior 
agreement in their site’s contract with IU. One dose, 10mCi (370MBq)+/- 10%, will be 
administered intravenously to each participant. The dose will be administered in its entirety 
according to the Schedule of Events (Appendix 1). Post administration, the used syringe will 
be placed in the sharps disposal container for radioactive materials. If a dose is not 

 
 
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administered, it will be destroyed and placed in the sharps disposal container for radioactive 
materials.  
9.6 FDG  
FDG will be prepared at the site’s contracted radiopharmacy and delivered to each site’s 
PET facility by courier on the day of administration following the standard procedures of 
acceptance and disposal of radioactive tracers. The dose will be received by a trained 
nuclear medicine technologist at each site. One dose, 5 mCi (185MBq) +/- 10%, will be 
administered intravenously to each participant. The dose will be administered in its entirety 
according to the Schedule of Events (Appendix 1). Post administration, the used syringe will 
be placed in the sharps disposal container for radioactive materials. If a dose is not 
administered, it will be destroyed and placed in the sharps disposal container for radioactive 
materials.  
 
10.0 SIDE EFFECTS 
10.1 Lumbar Puncture 
The most common complications of LP consist of post-LP back pain and post-LP headache 
(PLPH). PLPH typically begins within three days after the procedure in most participants. If 
a participant develops typical PLPH, bed rest, adequate hydration, and simple analgesics 
should be started.  
 
In a large multicenter LP study, 31% of participants reported post-LP complaints; however, 
these were mostly mild in nature. Severe complications were very rare [60].  
Common side effects included:  
• Back pain (17%) 
• Headache (19%) 
• Typical post-LP headache (PLPH) (9%) 
 
Lower rates of post-LP headache were noted when atraumatic (Sprotte) needles were used. 
[61, 62] Sprotte needles will be used in this study.  
 
Very rare (prevalence of <0.01%) but potential serious complications consist of post-LP 
infections, spinal and subdural cerebral hematoma, and cerebral venous thrombosis. In an 
effort to mitigate these risks, a trained clinician must perform the LP. 
 
10.2 PET Imaging 
10.2.1. Radiation Exposure 
The primary risk related to PET is that of radiation exposure associated with the injected 
radiotracers and accompanying CT (if a PET/CT scanner is used). There is also minor risk 
associated with the venipuncture, placement of an intravenous catheter, and radioisotope 
injection (pain and bruising or painful infiltration of a failed injection).  
 
The radiation doses for each PET scan are not themselves expected to produce any harmful 
effects, although there is no known minimum level of radiation exposure considered to be 

 
 
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totally free of the risk of causing genetic defects or cancer. The risk associated with the 
amount of radiation exposure participants receive in this study is considered low and 
comparable to everyday risks. If a female is not surgically sterile or post-menopausal by two 
years, a pregnancy test will be performed. Participants who may have other sources of 
radiation exposure (thallium testing, radiation therapy) should be evaluated by the study 
physician.  
 
There must be at least 365 days between the first PET scan of the previous visit and the first 
PET scan of the next yearly visit. There must also be at least 365 days from second-to-second 
PET, so that there are no more than two PET scans in a year. FDG PET is not subject to this 
consideration; it can be the third PET in 365 days.  
 
10.2.2 Other Side Effects Associated with Amyloid Tracers 
Specific risk information can be found in the tracer’s Package Insert or Investigator’s 
Brochure.  
 
10.2.3 Other Side Effects Associated with Flortaucipir 
A review of the safety information for flortaucipir showed that the product is generally well-
tolerated with a low incidence of mild and transient adverse events. More information about 
the known and expected benefits, risks, and reasonably anticipated adverse events (AEs) of 
flortaucipir may be found in the Investigator’s Brochure (IB) and the Tauvid Package Insert. 
Details on the clinical information to date regarding flortaucipir exposure and risks will be 
provided to participants in the informed consent form (ICF).  
 
10.3 Psychological Risks from Genetic Testing  
There may be a psychological impact from receiving genetic test results. Identifying a 
pathogenic mutation can solidify a participant’s diagnosis and increases the likelihood that 
close relatives of the participant will also develop a similar condition. It is also possible that 
genetic testing may reveal incorrect assumptions in family relationships (such as learning 
that a child is adopted or has a different father). These risks will be discussed with the 
participant either in person with a genetic counselor or with a video that is viewed by the 
participant and anyone who accompanies them to the visit (study partner, caregiver, family 
members, etc.). Participants viewing the video will have the opportunity to speak with a 
genetic counselor if they have additional questions. Any pathogenic mutations identified in 
this testing will also be communicated to the participant in a genetic counseling session. 
Participants at international sites may speak with the site PI or appropriately trained clinical 
investigator. 
 
10.4 Psychological Risks from PET Results  
It is possible that some participants may be upset by learning the results of their amyloid, 
tau, or FDG PET scan. Depending on the results, a participant may learn they are at 
increased or decreased likelihood that AD is causing their symptoms. It is possible that both 
positive and negative results could be psychologically upsetting. However, in a recent 
randomized clinical trial, there was no deleterious effect of learning amyloid status on 
depression or anxiety scales [63]. The Imaging Dementia – Evidence for Amyloid Scanning 
(IDEAS) study, led by Dr. Rabinovici, has scanned over 18,000 cognitively impaired 

 
 
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patients with amyloid PET. The study is monitoring all known deaths following amyloid 
PET disclosure, and thus far no suicides have been reported. The disclosure of results from a 
tau scan has not been rigorously studied; however, this study will monitor data collected 
throughout the disclosure process for any significant effects a participant may exhibit. 
 
10.5 Loss of Privacy 
In this study, a great deal of information about participant health status is collected.  
Study staff at the clinic sites will be collecting personal protected health information such as 
name, date of birth, social security number, address, phone number, and emails. All 
participants will be given a participant code number and all data will be associated with the 
code number. The clinic site will maintain the personal protected health information (such as 
name, date of birth, social security number, address, phone number, and emails) in a secure 
and locked location. The data, associated with the code number, will be distributed widely, 
but it will not be possible to identify an individual participant from the data. However, there 
is a very unlikely possibility that there will be a security failure, and that somehow the 
protected health information will be no longer protected. This is an extremely unlikely but 
possible occurrence and is a risk of this study. 
 
 
11.0 ADVERSE EVENTS/UNANTICIPATED PROBLEMS 
An adverse event (AE) is defined as any untoward medical occurrence. Adverse events, 
including but not limited to those deemed related to the study compounds or procedures by 
the Site PI will be tracked during the study.  
 
The following events are considered AEs: 
(1) worsening or change in nature, severity, or frequency of conditions or symptoms 
present at the start of the study 
(2) participant deterioration due to primary illness 
(3) intercurrent illness  
(4) drug interaction  
 
An abnormal laboratory result, imaging finding, and change to baseline medical conditions 
will only be reported as an AE if the Site PI or medical designee considers it to be clinically 
significant. 
 
The Site PI is obliged to follow participants with AEs until the events have subsided, the 
conditions are considered medically stable, or the participants are no longer available for 
follow-up. Participants who discontinue due to adverse experiences will be treated and 
followed according to established medical practice. All pertinent information will be entered 
into the eCRF.  
 
The Site PI should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the 
AE and not the individual signs or symptoms. Symptoms and conditions present at the 
beginning of the study will be characterized, so that AEs can be defined as any new 
symptom, or any increase in frequency or severity of an existing symptom. Adverse events 
should be described with medical terminology so that the event can be matched against a 

 
 
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medical coding dictionary, such as Medical Dictionary for Regulatory Activities 
(MedDRA).  
 
Site Pis should report their assessment of the potential relatedness of each AE to the protocol 
procedure(s). Following questioning and evaluation, all AEs, whether determined to be 
related or unrelated to the protocol procedure(s) by a medically qualified Site PI or medical 
designee must be documented in the participant’s records, in accordance with the Site PI’s 
normal clinical practice, and on the AE eCRF. 
 
For more detail, refer to the Code of Federal Regulation Title 21 Part 312: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32 
 
ATRI Coordinating Center staff will monitor the unanticipated problems for overall safety 
and scientific relevance on an ongoing basis and provide information to the Data Safety 
Monitoring Board.  
12.0 SERIOUS ADVERSE EVENTS (SAE) 
A serious adverse event is defined as an adverse event or suspected adverse reaction that 
results in any of the following outcomes:  
1. Death 
2. A life-threatening adverse event 
3. Inpatient hospitalization or prolongation of existing hospitalization (see below for 
more information regarding hospitalization) 
4. A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
5. A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
Hospitalizations that fulfill one of the following conditions will not have to be reported as 
SAE: 
• Admission for treatment of a pre-existing condition that is not associated with the 
development of a new AE or with a worsening of the pre-existing condition (i.e., 
work-up for persistent lab abnormality that occurred prior to the study) 
• Social admission (i.e., participant has no place to sleep) 
• Administrative admission (i.e., yearly physical exam) 
• Protocol-specified admission (i.e., for a procedure required by the study protocol) 
• Optional admission not associated with a precipitating clinical AE (i.e., pre-planned 
treatments, elective cosmetic surgery) 
 
For more detail, refer to the Code of Federal Regulation Title 21 Part 312: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32  

 
 
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12.1 Reporting of SAEs 
Serious adverse events will be reported to the Project Director/IU and the ATRI 
Coordinating Center within 24 hours of learning of the event. See relevant study manuals 
for SAE reporting and expectations. The principal Site PIs and Coordinating Center staff 
will monitor the study procedures for overall safety and scientific relevance on an ongoing 
basis and provide information to the Data Safety Monitoring Board.  
13.0 SITE QUALIFICATIONS 
Participants will be enrolled at approximately 25 clinical sites in the United States and 
abroad. All of these sites have significant experience with diagnosing and treating patients 
with EOAD and have agreed to participate in the study. 
13.1 Study Personnel 
The Site PI is responsible for the overall conduct of the study at the site. The Site PI is to 
supervise project personnel and ensure that clinical raters are trained and maintain a high 
level of skill and accuracy in conducting assessments. Additionally, the Site PI, to the extent 
possible, will personally perform or supervise clinical evaluation of all participants and 
ensure protocol adherence. 
13.2 MRI Instrument 
Each site must be qualified for MRI using the ADNI3 MRI protocol. If the site is planning 
to use a scanner that has already been ADNI3 qualified, the qualification process will be 
expedited by requesting that the site conducts only phantom and not human qualification 
(see below). Site scanners that are not ADNI3 qualified will need to undergo the full site 
qualification protocol. 
 
The procedures for MRI scanner qualification consist of two parts, phantom and human 
scanning. In terms of human scanning, each site will image a volunteer participant with the 
protocol and send the images to LONI. The MRI Core will check each parameter in each of 
the pulse sequences in the protocol. In the event that the scan has not been performed 
according to protocol, the site will be asked to perform another human volunteer scan. This 
will be repeated as many times as necessary until the site has demonstrated exact execution 
of the MR protocol in a volunteer participant, at which point they will have passed the 
human scanning portion of MR site qualification. The volunteers do not need to be elderly 
controls; in fact, scanning for site qualification may be more easily performed with normal 
younger volunteers. In the event that repeat attempts are needed, repeat scans need not be on 
the same volunteer participant. Once a site has demonstrated perfect execution of the 
protocol, the protocol will be stored permanently on the scanner at that site that will be used 
in the study.  
 
13.3 PET Instrument 
Each site must be qualified for PET. If the PET scanner being used has already been 
certified by the ADNI PET Core and has not experienced any major software or hardware 
upgrades, re-qualification will not be required. The PET scanner must be able to perform 
site’s applicable amyloid PET, tau PET, and FDG PET imaging protocols. Each scanner 
requires qualification only once for each tracer. Qualification will employ the same methods 
utilized for site qualification in ADNI3.  

 
 
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Sites will use a Hoffman brain phantom (if scanner not yet qualified for ADNI3) and a 
technical manual for the data acquisition using the PET tracers in the LEADS protocol and 
site’s contract. The phantom must be scanned on two sequential days using the protocol 
identical to that required for human imaging. This enables the PET Core to ascertain the 
characteristics of the scanner (particularly resolution and uniformity) and assure that sites 
are capable of performing the protocol for acquisition and image reconstruction. All 
phantom images will be forwarded to PET Core QC group for review and qualification.  
 
For all PET scans, either a PET transmission (PET-only scanners) or x-ray CT (PET/CT 
scanners) will be obtained for attenuation correction. PET/MRI scanners will not be 
qualified to perform PET scans in LEADS. 
 
14.0 DATA COLLECTION 
14.1 Data Summary  
The LEADS database will consist of data collected from three participant cohorts (EOAD, 
EOnonAD, and CN).  
 
The data collected in this study will be compared to ADNI LOAD participants (data freely 
available through the ADNI data sharing agreements and regulations). The LEADS data will 
include demographic information, clinical test results, MRI summary measures, amyloid, 
tau, and FDG PET summary measures, blood biomarker and selected genomic data. The 
actual imaging files will be stored at LONI. The genetic data will be stored in two locations, 
NCRAD and LONI. The cognitive tests will capture changes in the following cognitive 
domains – processing speed/attention, episodic memory, language, visuo-spatial, working 
memory/executive, and global cognition. Results will be obtained from several separate 
instruments within each category, which will be used to build domain-specific composite 
scores. MRI summary measures derived using Freesurfer will include estimates of 
subcortical gray matter (GM) volumes, cortical GM morphometrics (volume, thickness, 
surface area, and curvature measures), total hippocampal volume and hippocampal subfield 
measures. Amyloid and tau PET summary metrics (SUVR values) will be extracted after 
normalization to whole cerebellum or cerebellum gray matter regions to quantify amyloid 
and tau PET data, respectively. Fluid biomarker measurements will be included in the 
database.  
 
14.2 Case Report Form 
The Site PI or designee will record all original source data collected (either written or 
electronic record of data). Written or electronic data of record must be entered on the 
electronic Case Report Form (eCRF) provided for that purpose. The site will be suitably 
trained on the use of the eCRF and appropriate site personnel will be authorized to provide 
electronic signatures. The Site PI is responsible to verify the integrity of the data and 
acknowledge as such by signature. 
 

 
 
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All site entries will be made in a secured web site and the Site PI will review the record for 
completeness. If corrections are necessary to the eCRFs, the Site PI or designee will update 
the eCRF and provide the reason for change.  
 
15.0 DATA ENTRY AND STORAGE 
15.1 Clinical Data Storage and Sharing  
The official clinical data repository will be housed in the Informatics Core in LONI. This 
database will be frequently updated. Standard LEADS data acquired by the ATRI 
Coordinating Center and NACC will be provided to LONI. Only minimally necessary 
protected health information (PHI) and clinical data required for data analysis will be 
included in the LEADS database, and Site PIs will take reasonable steps to limit the use or 
disclosure of, and requests for, protected health information.   
 
There is a slight risk that there could be a breach in the security of the database system 
resulting in the access of information. However, safeguards are in place to minimize this 
risk. All participants will be assigned a participant ID code, that will be used for all data 
storage and communication with sites. Protected Health Information (PHI) will be recorded 
and kept under the need to know principle (i.e. only when necessary) at the enrolling site. 
The data key linking the participant personal information and participant study code 
numbers will only be available to a limited number of authorized study staff at the enrolling 
sites. The ATRI Coordinating Center, NACC and LONI will not have access to these keys. 
Hard copies of data will be stored in locked file cabinets at the study sites, while electronic 
data will be password protected and maintained on a secure network. PHI that the study 
team at ATRI and NACC UDS have access to in the EDC system will be limited to the 
minimum necessary for authorized oversight of the research study.  
15.1.1 National Alzheimer’s Disease Coordinating Center (NACC) Database 
NACC was selected to leverage their pre-existing infrastructure for data collection. The 
NACC Uniform Data Set (UDS) and Frontotemporal Lobar Degeneration (FTLD) module 
protocols will be utilized in LEADS. The electronic data capture through NACC’s available 
infrastructure is already available for ADC and non-ADC studies. Please note that a 
complete NACC UDS packet is required for submission to the NACC Data Repository. 
Partial visit procedure packets will not be accepted by NACC. There are some NACC forms 
required for LEADS that are not explicitly required for NACC. These include the A3, B5-
B7, and C4F-C6F.  
 
15.1.2 Unique LEADS data 
Completed LEADS database eCRFs will be submitted to the LEADS Data Portal according 
to ATRI Coordinating Center instructions. All personal identifying data will be kept in a 
secure location at the enrolling site. 
 
If necessary, data correction requests will be generated for resolution by the study site. Data 
will be transmitted securely via the Internet to ATRI at USC by enrolling sites. Database 
access will be granted to study team members based on role. Each user of the system has an 
individual account with a password which is required to be reset at set intervals to comply 
with USC password requirements. Users will be logged out of the system after a period of 

 
 
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inactivity. All communication to and from the data system will be encrypted. Data 
transmission will occur through a secure internet connection-https (hypertext transfer 
protocol secured) at 128 bit SSL. The ATRI Coordinating Center will provide web-based 
reporting on data flow and assure optimal data security and redundant data backups.  
 
Unique LEADS data will be stored and maintained on servers hosted on Amazon Web 
Services under an Enterprise Agreement with USC. All communication with the servers is 
encrypted. Access is controlled on a per-user basis and access logs are kept and monitored 
on an ongoing basis to ensure data security and integrity, keeping data protected from 
improper use and disclosure. 
 
15.2 MRI and PET Imaging Data Storage  
LONI at the University of Southern California (USC) was selected to leverage the pre-
existing infrastructure for imaging and clinical data storage. MRI and PET data will be 
transmitted by enrolling sites directly to LONI. All scans will be labeled using LEADS 
participant identifiers and scanner specific series descriptions. All scans will undergo a de-
identification process, which is embedded within the LONI upload process to ensure that no 
direct participant identifier information is present in the image files.  
 
• MRI Images: Images will be uploaded by sites directly to LONI. PHI will be limited 
to the minimum necessary for authorized oversight and placed into quarantine until 
they pass quality assurance evaluation conducted by the MRI Core. The MRI Core 
will perform a quality control review on each MRI scan. Quality control for MRI 
will result in failure of some scans, which may need to be repeated. Repeat scans 
must be scheduled as soon as possible and no later than four weeks of the visit date. 
Repeat scans will not be considered protocol deviations.  
 
• PET Images: Images are uploaded by site users to LONI. PHI will be limited to the 
minimum necessary for authorized oversight and placed into quarantine until they 
pass quality assurance evaluation conducted by the PET Core. The aim of this work 
is not only to make sure that all PET scans are acquired and reconstructed using the 
appropriate protocols and that image quality is good, but to standardize the images 
from the different sites (and hence the different PET scanner vendors and models) as 
much as possible in order to reduce inter-site differences. Quality control of scans 
could necessitate salvage with reprocessing of the raw imaging data. All sites are 
required to save original PET data for the duration of the study.  
 
15.3 Biospecimen Storage – NCRAD and NIH databases 
Samples including PBMCs, DNA, RNA, plasma, serum and CSF aliquots and their 
derivatives will be processed and stored indefinitely at NCRAD. PHI will be limited to the 
minimum necessary for authorized oversight. All samples will be stored in secure freezers 
within a secure facility at Indiana University. Since NCRAD is a NIH dedicated specimen 
repository designed for sample sharing, a general protocol has been approved by the IRB at 
Indiana University that covers all sample receipt, processing and distribution. The protection 
of participant confidentiality and the use of stored genetic specimens will be in accordance 
with the rules and procedures established by the Indiana University IRB. The protection of 

 
 
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participant confidentiality and the use of stored genetic specimens provided by international 
sites will comply with applicable local regulation, including GDPR. 
NCRAD will maintain a secure database for tracking all incoming LEADS samples. 
Information that will be maintained in this database may include the LEADS unique 
participant identifier, kit number (assigned to all tubes that come in a single shipment for an 
individual), specimen number (barcode #), type of sample received, date drawn, date 
received, initial volume collected for each tube type, time of draw, year of birth and gender. 
Other data related to the processing of the specimens will also be recorded in the database.  
Genomic and all other data can be linked to other de-identified clinical research data for 
purposes of scientific analyses. The only linkage of genetic test results to participant identity 
will be possible at the specific clinical site where they were enrolled. 
 
15.4 Audio Recording Transcription and Storage 
The audio files acquired in this study will be securely transmitted and stored in databases 
being used for the study. The audio recorded during the administration of select assessments 
should not contain PHI. Sites will be responsible for ensuring that no PHI is included in the 
recordings prior to upload. Audio files that are transmitted to contracted cloud-based remote 
servers for automatic transcription will not be stored on these servers and will be destroyed 
after the transcription is complete. 
 
15.5 Global Unique Identifiers (GUIDs) 
Global Unique Identifiers (GUIDs) for all LEADS participants will be acquired. Each GUID 
unambiguously identifies a research study participant across different research studies 
without exposing PHI. When investigators pool data together from multiple studies, GUIDs 
provide the means to detect participants who participate in more than one study. 
 
16.0 DATA SHARING 
Data from this research will be shared with other researchers pursuant to the 02/26/2003 
“NIH Final Statement on Sharing Research Data”. The NIH policy on data sharing can be 
found online at: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html. Data 
sharing is essential for further translation of research results into knowledge, products, and 
procedures to improve human health. The NIH endorses the sharing of final research data to 
serve these and other important scientific goals. To protect participants’ rights and 
confidentiality, PHI will be limited to the minimum necessary for authorized oversight 
before the data are shared. 
 
Instructions concerning how to access these data will be available on the LEADS website. 
Access to the LEADS study data will be facilitated in collaboration with Global Alzheimer’s 
Association Interactive Network (GAAIN) run by LONI. As a GAAIN Data Partner, data 
from this study will be shared in aggregate through the GAAIN portal (gaain.org). GAAIN 
provides a global infrastructure for cooperative research by linking data repositories that 
have collected information from thousands of participants who are at risk for or have been 
diagnosed with Alzheimer’s disease. Working with the GAAIN technical team, client 
software will be used to respond to the GAAIN server data requests. The data connection 

 
 
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will be updated to allow global researchers to visualize the available data, and in aggregate 
to evaluate the LEADS data in context of the 30+ other studies and nearly 500,000 clinical 
participants. GAAIN will allow for the global scientific community to visualize the metadata 
available through the LEADS study, while allowing the LEADS scientific team the 
opportunity to control access to the raw data from GAAIN-directed and other potential 
users.  
 
Metadata will be accessible through GAAIN as described above. The actual data files will 
be available for download from the LEADS Image and Data Archive overseen by the 
Informatics Core Leader. LONI has developed Data sharing environment for multiple other 
studies including but not limited to ADNI, Neuroimaging in Frontotemporal Dementia 
(NIFD), the 4-repeat Tau Neuroimaging Initiative (4RTNI), and the Parkinson’s Progression 
Markers initiatives (PPMI). MRI and PET data collected in the LEADS study will also be 
available for download from the LEADS Image and Data Archive (IDA) website. Both raw 
and processed scans will be available for download.  
 
Genetics, genomics, and related data will be shared with other researchers pursuant to the 
NIA Alzheimer’s Disease Genetics sharing Policy: 
http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan.  
National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), 
along with other NIA-approved sites, will make genetic, genomic and related data and 
associated phenotypic data available to qualified investigators in the scientific community 
for secondary analysis in accordance with standards established by NIA. These data 
repositories are under strict security provisions, including multiple firewalls, separate 
servers, and data encryption protocols. Investigators and their sponsoring institutions 
seeking access to data from the NIA-approved data repository must submit a data access 
request that specifies both the data to which access is sought and the planned research use, 
and agree to the terms of access set forth in the Data Use Certification. Investigators are 
approved by a Data Access Committee for access to specific datasets for a specific use(s). In 
addition, the Data Use Certifications include a provision that approved users and their 
institutions agree to store the requested data securely and to not share the requested data 
with third parties. 
 
17.0 REQUESTS FOR LEADS DATA 
In order to receive access to the LEADS data, investigators will be asked to provide a 
written request via a form available through the LEADS website (www.leads-study.org), 
which includes information about the identity of the investigator(s), data requested and plans 
for data analysis. Applications for data use will be reviewed by the LEADS Data Sharing 
and Publications Committee and as outlined in the LEADS Data Sharing and Publication 
Policy protocol.  
 
17.1 Biospecimen Data Requests  
Investigators and their sponsoring institutions seeking access to specimens from NCRAD 
must submit a sample request that specifies both the samples to which access is sought and 
the planned research use. Investigators will be approved by the LEADS Data Sharing 
Committee and when applicable, the NCRAD Biospecimen Review Committee for access to 

 
 
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specific samples for a specific use(s). All samples will be distributed by NCRAD with a 
Material Transfer Agreement (MTA). The MTA will include a provision that approved 
recipients and their institutions agree to store the requested samples securely and to not 
share the samples with third parties. Investigators must also agree to upload the results of 
their experimental analyses into a NIA-approved data repository. 
 
17.2 Terms & Obligations of Data Usage 
Acceptance of LEADS data obligates the recipient to reference the grant in any presentation 
or publication that may result from this research. 
 
Should publications result from the use of LEADS resources now or in the future, the 
recipient agrees to notify the LEADS Administrative Core with details (reference, PubMed 
and PubMedCentral ID#) and provide a copy of the publication so productivity derived from 
the LEADS resources can be reported to the funding agency (the NIA). Such publications 
require compliance with NIH public access policies and LEADS data sharing/publication 
policies. 
 
Should new funding result from research using LEADS data now or in the future, the 
recipient will be required to notify the LEADS Administrative Core within 30 days of the 
award and provide details (grant title, sponsor, number, dollar total, dates) so productivity 
derived from the LEADS resources can be reported to NIA. 
 
No sharing of data with a third party is allowed without written permission from the LEADS 
Administrative Core. 
 
18.0 DATA AND SAFETY MONITORING BOARD (DSMB) 
The Data Safety Monitoring Board (DSMB) is an independent group providing 
recommendations to the LEADS study leadership, and the NIA. The DSMB will be 
responsible for monitoring enrollment, participant progress, drop-out rates, ongoing conduct 
of the research, protocol deviations, and safety monitoring (review of AEs and safety 
mailings (if applicable). The DSMB members can ask questions and make comments and/or 
recommendations to the Site PIs. Data on study progress and safety will be reviewed by the 
Board at least semi-annually and more frequently if needed. Based on the review of these 
data, the DSMB will provide recommendations to continue, modify or terminate the study, 
and will communicate other recommendations or concerns as appropriate. The DSMB chair 
will communicate recommendations or findings by way of a DSMB letter that is issued after 
each meeting of the board. These letters are provided to the Project Director and the ATRI 
Coordinating Center for submission to the IRB based on IRB reporting requirements.  
 
Any reportable events will be immediately directed to the ATRI Coordinating Center to 
follow the reporting procedures for the Project Director and IRB (see section 12.1 for SAE 
reporting information).  
 

 
 
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19.0 STUDY MONITORING  
Ongoing study monitoring at U.S. sites will be completed by the ATRI coordinating center. 
Ongoing study monitoring for international sites will be completed by IU, in close 
collaboration with the ATRI coordinating center. The LEADS clinical monitors will be 
responsible for inspecting the electronic case report forms and source documentation at 
regular intervals at each participating site throughout the study to verify adherence to the 
protocol, completeness and accuracy of the data, and adherence to local regulations on the 
conduct of clinical research. The monitoring visits must be conducted according to the 
applicable ICH, GCP, and local guidelines to ensure protocol adherence, quality of data, 
study compound accountability, compliance with regulatory requirements and continued 
adequacy of the investigational site and its facilities. The Site PI will cooperate in the 
monitoring process by ensuring the availability of the eCRFs, source documents and other 
necessary documents at the time of the monitoring visits. The Site PI will promptly address 
any matters brought to his/her attention by the monitor. The Site PI may also be asked to 
meet in-person with the site monitor. 
 
20.0 ETHICS AND REGULATORY CONSIDERATIONS 
20.1 Good Clinical Practice  
This study will be conducted in compliance with the protocol, in accordance with GCP 
guidelines, and in full conformity with Regulations for the Protection of Human Subjects of 
Research codified in 45 CFR Part 46 – Protection of Human Subjects, 21 CFR Part 50 – 
Protection of Human Subjects, 21 CFR Part 56 - IRBs, and/or the ICH E6, HIPAA, State 
and Federal regulations and all other applicable local regulatory requirements and laws.  
 
Study personnel involved in conducting this study will be qualified by education, training 
and experience to perform their respective tasks in accordance with GCP.  
 
No study document shall be destroyed without prior written agreement between the 
Coordinating Center and the Site PI. Should the Site PI wish to assign study records to 
another party or move them to another location, he/she may do so only with the prior written 
consent of the Coordinating Center.  
 
Institutions must hold a current US Federal-Wide Assurance (FWA) issued by OHRP to 
participate. Refer to: http://www.hhs.gov/ohrp/assurances/. 
 
20.2 Informed Consent  
Informed consent will be obtained in accordance with 45 CFR 46, 21 CFR 50, 21 CFR Part 
56 and in adherence to ICH GCP. Informed consent and HIPAA authorization for research 
will be obtained from all participants, their legally authorized representative (LAR), or their 
court-appointed guardian prior to starting study procedures.  
 
The participant’s capacity to consent will be assessed whenever consent is collected. 
Guidelines for assessing capacity to consent will be left at the local level to adhere to 
institutional-specific standard operating procedures (SOPs). Clinical monitors will review 

 
 
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that capacity to consent was assessed during their interim monitoring visits against the local 
SOPs. The relying sites’ plan for assessing participants’ capacity to consent is to be provided 
to the reviewing IRB through completion of a relying site form. If the local process for 
assessing capacity to consent changes at the relying site during the study, the relying site 
must submit an amendment with an updated site form to the reviewing IRB along with the 
corresponding SOP, as applicable. 
20.3 Confidentiality and HIPAA/GDPR Compliance 
Participant confidentiality is strictly held in trust by the Site PIs and study personnel. This 
confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Some of the data collected as part 
of this protocol is of potential medical relevance including cognitive and neuropsychological 
testing, brain MRI, PET, and genetic testing. These are all tests that can be obtained as part 
of routine medical care for patients with symptoms suspected as being due to Alzheimer’s 
disease, and are being collected in this study using clinically standard methods. The results 
of these tests may be disclosed to our study participants and their study partners.  
 
Due to the clinical relevance, the MRI report (or summary of the findings), summary of the 
cognitive testing, clinical diagnosis and summary of PET results (CI cohorts only) can be 
placed in medical records by the study team or the participant. Participants will be informed 
of this in the informed consent. Since genetic testing results are sensitive information, 
participants will be explicitly asked for permission to place genetic results from LEADS in 
their medical record. In the rare occasion where the institutional policies require that all 
genetic testing results are part of the medical record, the participant will be informed and 
have the option to opt out of participation in LEADS. 
 
Authorized representatives of the sponsoring institution may inspect all research documents 
and records required to be maintained by the Site PI, as well as medical records (office, 
clinic or hospital) and pharmacy records for the participants in this study. The enrolling 
study site will permit access to such records. Any data, specimens, forms, reports, and other 
records that leave the site will be identified only by a participant identification number 
(Participant ID, PID) to maintain confidentiality. All records will be kept in a locked file 
cabinet. All computer entry and networking programs will be done using PIDs only. 
Information will not be released without written permission of the participant, except as 
necessary for monitoring by IRB/IEC, the FDA, the NIA, and the OHRP. 
 
Information about U.S. study participants will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed participant HIPAA Authorization informing the participant 
of the following:  
• What PHI will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a U.S. participant revokes authorization to collect or use PHI, the Site PI, 
by regulation, retains the ability to use all information collected prior to the revocation of 
participant authorization. Each Site PI, under the guidance of the IRB, is responsible for 

 
 
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ensuring that all applicable HIPAA regulations and State laws are met. International Site 
PIs, under the guidance of their IRB are responsible for ensuring that all applicable local 
regulations are met.  
 
Information about international study participants will be kept confidential and managed 
according to the requirements of the General Data Protection Regulation (GDPR), or their 
local regulations.  
 
In the event that an international participant revokes authorization to collect or use PHI, the 
Site PI, by regulation, retains the ability to use all information collected prior to the 
revocation of participant authorization. Each international Site PI, under the guidance of 
their local regulatory body is responsible for ensuring that all applicable GDPR regulations 
and/or local laws are met.  
 
20.4 Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
automatically issued by the NIH to protect identifiable research information from forced 
disclosure. It allows the Site PI and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, 
administrative, legislative, or other proceeding, whether at the federal, state, or local level. 
By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy 
to participants. 
 
21.0 STATISTICAL CONSIDERATIONS 
21.1 Analysis Goals and Strategies  
The Biostatistics Core will conduct interim and final analyses of the clinical, imaging and 
genomic data for the hypotheses and aims of the study. The goals of the analyses are briefly 
described below.  
21.1.2 Statistical analysis  
The analysis of the data will focus on comparing the cognitive and biomarker measures 
between LEADS EOAD and LEADS CN and LEADS EOAD and ADNI LOAD 
participants. We will also compare APOE4+ and non-carriers within and between diagnostic 
groups (EOAD, CN, and LOAD). We will study the associations between our cognitive 
composite scores and imaging and other biomarkers. Longitudinal analyses will be 
conducted to identify differences of longitudinal changes in cognitive, imaging and fluid 
biomarker measures between LEADS EOAD and ADNI LOAD participants and between 
APOE4+ and non-carriers within and between diagnostic groups (EOAD and LOAD). 
Finally, we will perform exploratory analysis of EOnonAD patient data.  
Aim 1 
Baseline composite cognitive scores will be developed using clustering techniques 
such as kNN clustering. The cognitive data will be collected in integer scales for 
each test. Differences of the composite scores within cognitive domains between 

 
 
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LEADS EOAD and ADNI LOAD participants will be assessed using multivariate 
linear regression controlling for the effects of candidate confounders such as 
education and sex. The results will be presented using graphical methods and tables 
of statistical summary estimates and test results. Longitudinal changes in cognitive 
scores will be assessed using linear mixed models and machine learning approaches.  
Aim 2 
MRI and PET based biomarker volumes computed at the mm3 scale, will be used to 
assess baseline and longitudinal associations of composite cognitive scores and 
imaging metrics and identify differences between LEADS EOAD and ADNI LOAD 
participants. Specifically, multiple linear regression analysis will be used to identify 
differences between imaging-based metrics in LEADS EOAD vs. ADNI LOAD at 
baseline and to assess correlations between composite cognitive and imaging 
measures, while longitudinal data will be analyzed using mixed effects models when 
data for more than 2 visits per participant is collected. Relevant confounders (e.g. 
sex, education) will be included as covariates. In addition, summary MRI and PET 
measures will be analyzed using machine learning techniques to identify a composite 
metric capturing change across LEADS EOAD participants.  
Aim 3 
Memory sparing will be compared between APOE4+ and APOE4- participants using 
Fisher’s exact tests to compare the proportion of APOE4+ and APOE4- participants 
between the LEADS participants in each atypical subtype of EOAD. Differences 
between MRI/PET measures of APOE+ and non-carriers will be assessed at baseline 
and longitudinally using multiple linear models and linear mixed models after 
controlling for potential confounders (e.g. education and sex). The results will be 
presented using graphical representations. The rates of APOE4+ and APOE4- 
participants will be compared between EOAD and EOnonAD participants will be 
compared using Fisher’s exact tests.  
Aim 4  
Research-based genetic screening will be performed in a research laboratory. 
Established pipelines will be used for processing and annotating sequencing variants. 
Known pathogenic mutations in the six screened genes will be confirmed by a CLIA-
certified laboratory. Sequence data will be generated in a research laboratory and 
combined with publicly available sequence data from the Alzheimer Disease 
Sequencing Project (ADSP; phs000572.v1.p1). Gene-based case-control tests will be 
used to identify genes and pathways with a greater burden of rare variants in 
cognitively impaired as compared with CN individuals.  
Aim 5 
t-tests, non-parametric tests, and Analysis of Variance (ANOVA) models will be 
used to compare clinical domain scores between CN and EOnonAD participants. 
Multiple linear regression models will be used to investigate whether FDG PET is 
more sensitive than MRI when identifying changes in neurodegeneration in 
EOnonAD cohort. Unsupervised clustering methods will be utilized to find groups of 
participants in the EOnonAD cohort with similar imaging and clinical characteristics 
and identify potential etiologies in EOnonAD.  
 

 
 
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21.1.3 Missing Data  
Data collection will be monitored on an ongoing basis to ensure that the scores and imaging 
biomarkers are within the expected ranges and scales and missing data is rare. Multiple 
imputation will be used for missing data. Although we do not anticipate extensive missing 
data for a large proportion of participants in the study, participants with such extensive 
missing data (e.g. ≥50% cognitive scores) will be removed from analyses.  
21.1.4 Sample Size 
Sample size considerations were developed for each aim and are presented below. The 
computations of sample size assumed a target power of 90% at significance level of 0.05. A 
total sample size of 650 EOAD participants is envisioned for the study. The specific effect 
sizes for each of the aims are presented below. In general, these effect sizes are smaller or 
equal to those observed in our preliminary data.  
Aim 1  
We will have 90% power to identify a -0.26 group difference in mean composite 
cognitive Z-scores between EOAD and LOAD participants after controlling for 
episodic memory performance. We will have 90% power to detect an average 
difference of 0.7 in decline in CDR-SB between EOAD and ADNI LOAD. 
Similarly, we will have 90% power to identify an effect size of -1.5 for decline in 
MMSE.  
Aim 2  
We will have 90% power to detect cross-sectional differences in cortical gray matter 
volumes of at least -0.2. We will have 90% power to detect a cross-sectional 
difference of 0.2 mm3 in flortaucipir SUVR. For longitudinal data, we will have 90% 
power to detect a difference of -0.001 in annualized Jacobian values between EOAD 
and LOAD in the region-of-interest. Preliminary longitudinal flortaucipir data in 
EOAD were too sparse to estimate effect size or power. We will have power of 90% 
to observe correlations of 0.1 or greater between MRI/ flortaucipir and clinical 
composite scores - these correlations are considerably lower than the smallest 
flortaucipir-cognitive correlations observed in our preliminary data. 
Aim 3  
Assuming ~50% APOE4+, we will have 90% power to detect a difference of 20% in 
the proportion of non-amnestic (lvPPA/PCA) participants in APOE4+ vs. APOE4- 
participants. We will have 90% power to detect a cross-sectional mean difference in 
TIV-adjusted MTL volume of -4.4 ml between carriers and non-carriers and an 
average difference in flortaucipir MTL SUVR 0.1 between the two groups. 
Aim 4:  
When testing 171 genes in AD pathways, we have 80% power to detect genes 
contributing to disease risk having an odds ratio of 1.5-3.0 if we assume 50% of the 
variants retained following filtering contribute to disease risk/resilience (alpha = 2.9 x 
10-4).  
 
 

 
 
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22.0 REFERENCES 
 
1. Savva, G.M., et al., Age, neuropathology, and dementia. N Engl J Med, 2009. 360(22): 
p. 2302-9. 
2. Schneider, J.A., et al., Mixed brain pathologies account for most dementia cases in 
community-dwelling older persons. Neurology, 2007. 69(24): p. 2197-204. 
3. Szigeti, K. and R.S. Doody, Should EOAD patients be included in clinical trials? 
Alzheimers Res Ther, 2011. 3(1): p. 4. 
4. Wingo, T.S., et al., Autosomal recessive causes likely in early-onset Alzheimer disease. 
Arch Neurol, 2012. 69(1): p. 59-64. 
5. Koedam, E.L., et al., Early-versus late-onset Alzheimer's disease: more than age alone. 
J Alzheimers Dis, 2010. 19(4): p. 1401-8. 
6. Mendez, M.F., et al., Nonamnestic presentations of early-onset Alzheimer's disease. 
Am J Alzheimers Dis Other Demen, 2012. 27(6): p. 413-20. 
7. Snowden, J.S., et al., Cognitive phenotypes in Alzheimer's disease and genetic risk. 
Cortex, 2007. 43(7): p. 835-45. 
8. Jacobs, D., et al., Age at onset of Alzheimer's disease: Relation to pattern of cognitive 
dysfunction and rate of decline. Neurology, 1994. 44: p. 1215-1220. 
9. Koss, E., et al., Clinical and neuropsychological differences between patients with 
earlier and later onset of Alzheimer's disease: A CERAD analysis, Part XII. Neurology, 
1996. 46(1): p. 136-41. 
10. Xia, C.F., et al., [(18)F]T807, a novel tau positron emission tomography imaging agent 
for Alzheimer's disease. Alzheimers Dement, 2013. 9(6): p. 666-676. 
11. Frisoni, G.B., et al., Structural correlates of early and late onset Alzheimer's disease: 
voxel based morphometric study. J Neurol Neurosurg Psychiatry, 2005. 76(1): p. 
112-4. 
12. Kim, E.J., et al., Glucose metabolism in early onset versus late onset Alzheimer's 
disease: an SPM analysis of 120 patients. Brain, 2005. 128(Pt 8): p. 1790-801. 
13. Rabinovici, G.D., et al., Increased metabolic vulnerability in early-onset Alzheimer's 
disease is not related to amyloid burden. Brain, 2010. 133(Pt 2): p. 512-28. 
14. Lehmann, M., et al., Diverging patterns of amyloid deposition and hypometabolism in 
clinical variants of probable Alzheimer’s disease. Brain, 2013. 136(3): p. 844-858. 
15. Murray, M.E., et al., Neuropathologically defined subtypes of Alzheimer's disease with 
distinct clinical characteristics: a retrospective study. Lancet Neurol, 2011. 10(9): p. 
785-96. 
16. Ossenkoppele, R., et al., Atrophy Patterns in Early Clinical Stages Across Distinct 
Phenotypes of Alzheimer’s Disease. Human Brain Mapping, 2015. 36(11): p. 4421-
4437. 
17. Ossenkoppele, R., et al., The behavioural/dysexecutive variant of Alzheimer's disease: 
clinical, neuroimaging and pathological features. Brain, 2015. 138(Pt 9): p. 2732-49. 
18. Farrer, L.A., et al., Effects of Age, Sex, and Ethnicity on the Association Between 
Apolipoprotein E Genotype and Alzheimer Disease: a Meta-analysis. JAMA, 1997. 
278(16): p. 1349-1356. 
19. Bettens, K., K. Sleegers, and C. Van Broeckhoven, Genetic insights in Alzheimer's 
disease. Lancet Neurol, 2013. 12(1): p. 92-104. 
20. Blacker, D., et al., ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics 
initiative. Neurology, 1997. 48(1): p. 139-47. 

 
 
Page 58 of 69 
Version (10.0): MAY 23, 2024 
21. van der Flier, W.M., et al., Early-onset versus late-onset Alzheimer's disease: the case 
of the missing APOE 4 allele. Lancet Neurol, 2011. 10(3): p. 280-8. 
22. Andrews-Zwilling, Y., et al., Apolipoprotein E4 causes age- and Tau-dependent 
impairment of GABAergic interneurons, leading to learning and memory deficits in 
mice. J Neurosci, 2010. 30(41): p. 13707-17. 
23. Filippini, N., et al., Anatomically-distinct genetic associations of APOE epsilon4 allele 
load with regional cortical atrophy in Alzheimer's disease. Neuroimage, 2009. 44(3): 
p. 724-8. 
24. Knickmeyer, R.C., et al., Common variants in psychiatric risk genes predict brain 
structure at birth. Cereb Cortex, 2014. 24(5): p. 1230-46. 
25. Leung, L., et al., Apolipoprotein E4 causes age- and sex-dependent impairments of 
hilar GABAergic interneurons and learning and memory deficits in mice. PLoS One, 
2012. 7(12): p. e53569. 
26. Wolk, D.A., B.C. Dickerson, and I. Alzheimer's Disease Neuroimaging, Apolipoprotein 
E (APOE) genotype has dissociable effects on memory and attentional-executive 
network function in Alzheimer's disease. Proc Natl Acad Sci U S A, 2010. 107(22): p. 
10256-61. 
27. Geroldi, C., et al., APOE-epsilon4 is associated with less frontal and more medial 
temporal lobe atrophy in AD. Neurology, 1999. 53(8): p. 1825-32. 
28. Hashimoto, M., et al., Apolipoprotein E epsilon 4 and the pattern of regional brain 
atrophy in Alzheimer's disease. Neurology, 2001. 57(8): p. 1461-6. 
29. Hirono, N., et al., The effect of APOE epsilon4 allele on cerebral glucose metabolism in 
AD is a function of age at onset. Neurology, 2002. 58(5): p. 743-50. 
30. Lehtovirta, M., et al., Clinical and neuropsychological characteristics in familial and 
sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism. Neurology, 
1996. 46(2): p. 413-9. 
31. Schott, J.M., et al., Apolipoprotein e genotype modifies the phenotype of Alzheimer 
disease. Arch Neurol, 2006. 63(1): p. 155-6. 
32. van der Flier, W.M., et al., The effect of APOE genotype on clinical phenotype in 
Alzheimer disease. Neurology, 2006. 67(3): p. 526-7. 
33. van der Vlies, A.E., et al., Cognitive impairment in Alzheimer's disease is modified by 
APOE genotype. Dement Geriatr Cogn Disord, 2007. 24(2): p. 98-103. 
34. Crutch, S.J., et al., Posterior cortical atrophy. Lancet Neurol, 2012. 11(2): p. 170-8. 
35. Migliaccio, R., et al., Clinical syndromes associated with posterior atrophy: early age 
at onset AD spectrum. Neurology, 2009. 73(19): p. 1571-8. 
36. Cacace, R., K. Sleegers, and C. Van Broeckhoven, Molecular genetics of early-onset 
Alzheimer's disease revisited. Alzheimers Dement, 2016. 12(6): p. 733-748. 
37. Nicolas, G., et al., Screening of dementia genes by whole-exome sequencing in early-
onset Alzheimer disease: input and lessons. Eur J Hum Genet, 2016. 24(5): p. 710-6. 
38. Miller, Z.A., et al., Handedness and language learning disability differentially 
distribute in progressive aphasia variants. Brain, 2013. 136(Pt 11): p. 3461-73. 
39. Rogalski, E., et al., Increased frequency of learning disability in patients with primary 
progressive aphasia and their first-degree relatives. Arch Neurol, 2008. 65(2): p. 
244-8. 
40. Miller, Z.A., et al., TDP-43 frontotemporal lobar degeneration and autoimmune 
disease. J Neurol Neurosurg Psychiatry, 2013. 84(9): p. 956-62. 

 
 
Page 59 of 69 
Version (10.0): MAY 23, 2024 
41. Miller, Z.A., et al., Increased prevalence of autoimmune disease within C9 and 
FTD/MND cohorts: Completing the picture. Neurol Neuroimmunol Neuroinflamm, 
2016. 3(6): p. e301. 
42. Morris, J.C., The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology, 1993. 43(11): p. 2412-4. 
43. Pfeffer, R.I., et al., Measurement of functional activities in older adults in the 
community. Journal of Gerontology, 1982. 37(3): p. 323-9. 
44. Cummings, J.L., et al., The Neuropsychiatric Inventory: comprehensive assessment of 
psychopathology in dementia. Neurology, 1994. 44(12): p. 2308-14. 
45. Yesavage, J.A., et al., Development and validation of a geriatric depression screening 
scale: a preliminary report. Journal of Psychiatric Research, 1982. 17(1): p. 37-49. 
46. Panchal, H., et al., Neuropsychological and Neuroanatomical Correlates of the Social 
Norms Questionnaire in Frontotemporal Dementia Versus Alzheimer's Disease. Am J 
Alzheimers Dis Other Demen, 2016. 31(4): p. 326-32. 
47. Nasreddine, Z.S., et al., The Montreal Cognitive Assessment, MoCA: a brief screening 
tool for mild cognitive impairment. J Am Geriatr Soc, 2005. 53(4): p. 695-9. 
48. Monsell, S.E., et al., Results From the NACC Uniform Data Set Neuropsychological 
Battery Crosswalk Study. Alzheimer Dis Assoc Disord, 2016. 30(2): p. 134-9. 
49. Rey, A., L'examen psychologique dans les d'encephalopathie traumatique. Archives de 
Psychologie, 1941. 28: p. 286-340. 
50. Rey, A., L'examen Clinique En Psychologie. 1964, Paris, France: Presses 
Universitaires de France. 
51. Benton, A.L. and K. Hamsher, Multilingual apahasia examination. 1989, Iowa City, 
Iowa: AJA Associates. 
52. Reitan, R.M. and D. Wolfson, The Halstead-Reitan Neuropsychological Test Battery: 
Therapy and Clinical Interpretation. 1985, Tucson, AZ: Neuropsychological Press. 
53. McKoon, G. and R. Ratcliff, Semantic associations and elaborative inference. J Exp 
Psychol Learn Mem Cogn, 1989. 15(2): p. 326-38. 
54. Weintraub, S., et al., The northwestern anagram test: measuring sentence production 
in primary progressive aphasia. Am J Alzheimers Dis Other Demen, 2009. 24(5): p. 
408-16. 
55. Lee, J. and C.K. Thompson, Phonological facilitation effects on naming latencies and 
viewing times during noun and verb naming in agrammatic and anomic aphasia. 
Aphasiology, 2015. 29(10): p. 1164-1188. 
56. Rosen, W.G., R.C. Mohs, and K.L. Davis, A new rating scale for Alzheimer's disease. Am 
J Psychiatry, 1984. 141(11): p. 1356-64. 
57. Wechsler, D., Manual for the Wechsler Adult Intelligence Scale - Third Edition. 1997, 
San Antonio, TX: The Psychological Corporation. 
58. Folstein, M.F., S.E. Folstein, and P.R. McHugh, Mini-Mental State: a practical method 
for grading the cogntive state of patients for the clinician. J Psychiatric Res, 1975. 12: 
p. 189-98. 
59. Possin, K.L., et al., The Brain Health Assessment for Detecting and Diagnosing 
Neurocognitive Disorders. Journal of the American Geriatrics Society, 2018. in 
press. 
60. Duits, F.H., et al., Performance and complications of lumbar puncture in memory  
clinics: Results of the multicenter lumbar puncture feasibility study. Alzheimers Dement, 
2016. 12(2): p. 154-163. 

 
 
Page 60 of 69 
Version (10.0): MAY 23, 2024 
61. Engelborghs, S., et al., Consensus guidelines for lumbar puncture in patients with 
neurological diseases. Alzheimers Dement (Amst), 2017. 8: p. 111-126. 
62. Peskind, E., et al., Safety of lumbar puncture procedures in patients with Alzheimer's 
disease. Curr Alzheimer Res, 2009. 6(3): p. 290-2. 
63. Pontecorvo, M.J., et al., Effectiveness of Florbetapir PET Imaging in Changing Patient 
Management. Dement Geriatr Cogn Disord, 2017. 44(3-4): p. 129-143. 
64. Sikkes, A.M., et al., A new informant-based questionnaire for instrumental activities of 
daily Living In dementia. Alzheimer’s and Dementia, 2012. 8: p. 536-543. 
65. Sikkes, A.M., et al., Validation of the Amsterdam IADL Questionnaire, a New Tool to 
Measure Instrumental Activities of Daily Living in Dementia. Neuroepidemiology, 
2013. 41: p. 35-41.  
66. Koster, N., et al., The sensitivity to change over time of the Amsterdam IADL 
Questionnaire. Alzheimer’s and Dementia. 2014. p. 1-10. 
67. ADI: Singh, G.K. Area Deprivation and Widening Inequalities in US Mortality, 1969–
1998. (2003). American Journal of Public Health, 93, 1137-1143.  
68. ADI: Kind, A.J.H, Jencks, S., Brock, J., Yu, M., Bartels, C., Ehlenbach, W., ... Smith, M. 
(2014). Neighborhood Socioeconomic Disadvantage and 30-Day Rehospitalization: 
A Retrospective Cohort Study. Annals of Internal Medicine, 161(11), 765-774.  
69. Monsell SE, Dodge HH, Zhou XH, Bu Y, Besser LM, Mock C, Hawes SE, Kukull WA, 
Weintraub S; Neuropsychology Work Group Advisory to the Clinical Task Force. 
Results From the NACC Uniform Data Set Neuropsychological Battery Crosswalk 
Study. Alzheimer Dis Assoc Disord. 2016 Apr-Jun;30(2):134-9. doi: 
10.1097/WAD.0000000000000111. PMID: 26485498; PMCID: PMC4834278. 
 
 
 
 
 
 

 
 
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APPENDIX 1 
 
SCHEDULE OF EVENTS 
All (EOAD, EOnonAD, and CN) Participants– Screening and Baseline 
              Visit 
 
Procedure 
Screeninga 
Baselinea 
 
Genetics  
Status 
Disclosure 
Window Period (days) 
< 60  
See footnote b  
Informed Consentu 
X 
 
 
Brain donation discussion/provisional consentc,u 
 
X 
 
Vital Signs 
X 
 
 
Neurological and Physical Exams 
X 
 
 
Demographics & Medical Historyu 
X 
 
 
Clinical Diagnosis and Clinical Symptom Assessment 
X 
 
 
Family Historyu 
X 
 
 
Early Developmental History Questionnaireu 
 
X 
 
Autoimmune History Questionnaireu 
 
X 
 
Sex and Reproductive Health Questionnaireu 
 
X 
 
Area Deprivation Indexu,w 
 
X 
 
Concomitant Medicationsu 
X 
 
 
NACC UDS and FTLD Modules, and Neuropsychological Batteryd,u 
Xe,f  
 
 
MMSEu  
Xe 
 
 
Digit Symbol  
Xf 
 
 
Amsterdam IADL Questionnaireu 
Xf 
 
 
ADAS-Cog13u 
Xf 
 
 
Rey Auditory Verbal Learning Test (RAVLT)u 
Xf 
 
 
TabCat: Flanker, Line Length, Line Orientation, and Match 
 
X 
 
CDRu  
X 
 
 
Pregnancy Testg 
X 
X 
 
3T MRI/fMRIi 
Xh 
 
 
Amyloid PET Scan 
 
Xj 
 
Tau PET Scanv 
 
Xj 
 
Adverse Eventu 
 
X 
 
Genetic Counselingo,t, u  
Xk 
Amyloid & Tau Status Disclosureu,v  
 
Xl 
 
PET Scan: FDGr 
 
Xm 
 
FDG Status Disclosureu 
 
Xml 
 
Wellness Checkn,u 
 
X 
 
Study Participation Reporto 
 
X 
 
Blood for Genetic testingp 
 
X 
 
Blood for AD blood biomarkersrr, DNA, and RNA, PBMCq 
 
X 
 
(continued on next page) 

 
 
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Version (10.0): MAY 23, 2024 
LP Safety Labs (CBC, coagulation profile) 
X 
 
 
Lumbar Puncture (optional)r,s 
 
X 
 
a) 
Visit procedures may be split over multiple days without constituting a protocol deviation. 
b) 
Timing for result disclosure is not set and dependent on the availability of the genetic screening results.  
c) 
Post mortem brain donation discussion to confirm consent/interest. If participant refuses to participate, no 
further inquiry should take place. Undecided participants will be approached at each study visit until they 
consent or refuse to participate. 
d) The NACC UDS and FTLD modules include demographics, clinical, cognitive, functional, and behavioral 
assessments.  
• 
Version C2 the NACC UDS Neuropsychological Battery will be used in this study  
• 
UDS forms A1, A3, A5, B4-B9, C2, D1, and D2 are required for LEADS  
• 
UDS forms A5/D2, D1a, and D1b will take the place of A5, D2, and D1 if using UDSv4  
• 
FTLD forms B3F, B9F, C1F-C6F, E2F, and E3F are required for LEADS  
e) 
The MMSE and MoCA cannot be administered on the same day. MMSE is required at screening to confirm CN 
eligibility. MMSE can be done anytime between screening and baseline for CI participants.  
f) 
Can be conducted anytime between screening and baseline for CI participants if sufficient testing has been 
completed to meet NIA-AA criteria for MCI due to AD or probable AD. These activities must occur at Screening 
for CN participants.   
g) 
If a female is not surgically sterile or post-menopausal by two years, a pregnancy test will be performed prior to 
amyloid, tau, and FDG PET. Only participants with a negative result will be eligible for PET scanning. 
h) The first MRI scan should be done at screening unless a previously existing MRI within 12 months can be used to 
assess overall eligibility and safety prior to LP procedure. If a previous scan is not available, the study MRI must 
be completed at the Screening Visit to facilitate eligibility determination. A study MRI must be completed within 
the 60 day visit window regardless of a pre-existing MRI being used to assess study eligibility. See section 7.6.4 
for more detail. 
i) 
All attempts should be made to acquire the full 60 minute MRI protocol; however the MPRAGE and 3D FLAIR 
should be prioritized. The MPRAGE and 3D FLAIR are the mandatory sequences for enrollment. If needed, the 
other sequences may be skipped for any reason without constituting a protocol deviation. Note the reason for 
non-completion in the source documents.  
j) 
The amyloid and tau PET scans can be conducted anytime between screening and baseline following MRI. 
Inclusion/exclusion must be confirmed prior to both scans. The amyloid and tau PET scans must be conducted 
at least 12 hours apart. 
k) 
At the Screening Visit, EOAD and EOnonAD participants will view a video that will discuss the implications of 
mutations in known ADAD loci. The participant will also be asked if they would like to speak with a genetic 
counselor to verify their understanding of the implications of genetic testing and answer any questions the 
participant may have. These participants at international sites may meet with a genetic counselor or investigator 
with appropriate clinical training in genetic counseling as opposed to watching the video. Written informed 
consent will be obtained on all participants prior to genetic testing (see section 7.2 Genetic Counseling and 
Testing section for more detail). Disclosure will be performed as outlined in section 7.1.6.  
l) 
Amyloid and tau disclosure is required for EOAD and EOnonAD participants only and should be conducted 
between  screening and baseline. Amyloid disclosure should be conducted within the 60 day visit window. Tau 
disclosure may be conducted outside of the 60 day visit window due to the timing of the scan and availability of 
the PET read. FDG PET disclosure is required for EOnonAD participants only. FDG disclosure may be conducted 
outside of the 60 day visit window due to the timing of the scan and availability of the PET read. 
m) The FDG PET scan at Baseline applies to CN and EOnonAD participants only. EOAD participants do not receive 
an FDG PET scan. The FDG PET scan for EOnonAD participants cannot be scheduled until after amyloid 
disclosure. For sites that have radiation safety committees (RSC), ability to conduct FDG PET scans will also be 
contingent on local RSC approval.  
n) To be completed within 48 hours of lumbar puncture. Additionally, a telephone call will be made within two 
weeks post amyloid results disclosure. See section 7.1.4 for more detail.  
o) 
May be provided to participants at the discretion of the PI. See section 7.1.8 for more detail.  
p) Blood for genetic testing will be drawn for EOAD and EOnonAD participants only; CN participants will not have 
blood drawn for genetic testing. 
q) 
PBMC samples must be collected and shipped the same day. Fasting is not required. PBMC sample collection is 
optional for international sites. If collected, international sites will store PBMC samples locally. See NCRAD 
Biospecimen, Collection, and Shipping manual for more details.  
r) 
LP should be collected after a minimum 6-hour fast (preferably in the morning after an overnight fast). FDG-PET 
should be collected after an overnight fast for scans conducted in the morning, or a minimum 4-hour fast for 
scans collected later in the day; prior to the scan, a blood glucose measurement will be made by finger stick and 
scans will be postponed or rescheduled if the reading is > 180 mg/dL. 
s) 
Can be conducted anytime between screening and baseline. Completion of safety lab report and MRI review with 
PI signature are required prior to LP. See section 7.6.2 for more detail. 

 
 
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Version (10.0): MAY 23, 2024 
t) 
The CN cohort does not receive their genetic results and therefore do not require genetic counseling. Positive 
genetic results require genetic couseling for the CI cohort if they have agreed to receive their genetic results. 
Participants at international sites may speak with the site PI or appropriately trained clinical investigator.   
u) Visit procedures noted with “u” can be completed remotely. See section 8.7 for more information.  See the 
procedures manual for more information on collecting the NACC UDS and FTLD modules remotely. 
v) 
Tau PET scan is not required for select international sites. Participants from select international sites will not 
complete tau PET scans and therefore will not receive tau PET results. 
w) The Area Deprivation Index is only collected at U.S. sites.  
 
 
 
 
 
 
(continued on next page) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Version (10.0): MAY 23, 2024 
EOAD Participants – Longitudinal Visits 
              Visit 
 
Procedure 
Genetics 
Status 
Disclosure 
Month 12a 
Month 24a 
Month 36 a 
Month 48 / 
Ongoing 
Annual Visitsa 
Annual 
Neuropath. 
Phone Checkc 
Early 
Terminationd 
Window Period (days) 
See footnote 
e  
+/- 60b 
 
Brain donation discussion/provisional consentc,r 
 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
X 
 
X 
Neurological and Physical Exams 
 
X 
X 
X 
X 
 
X 
Demographics & Medical Historyr 
 
X 
X 
X 
X 
 
X 
Clinical Diagnosis and Clinical Symptom Assessment 
 
X 
X 
X 
X 
 
X 
Sex and Reproductive Health Questionnairer 
 
Xo 
 
 
Area Deprivation Index Scorer 
 
Xo 
 
 
Concomitant Medicationsr 
 
X 
X 
X 
X 
 
X 
NACC UDS and FTLD Modules, and 
Neuropsychological Batteryf,r 
 
X 
X 
X 
X 
 
X 
Amsterdam IADL Questionnairer 
 
X 
X 
X 
X 
 
X 
ADAS-Cog13r 
 
X 
X 
X 
X 
 
X 
Rey Auditory Verbal Learning Test (RAVLT)r 
 
X 
X 
X 
X 
 
X 
TabCat: Flanker, Line Length, Line Orientation, and 
Match 
 
X 
X 
X 
X 
 
X 
CDRr 
 
X 
X 
X 
X 
 
X 
Pregnancy Testg 
 
X 
X 
X 
 
 
 
3T MRI/fMRIh 
 
X 
X 
X 
 
 
X 
Amyloid PET Scani 
 
X 
X 
X 
 
 
 
Tau PET Scani,p,q 
 
X 
X 
X 
 
 
 
Adverse Eventr 
 
X 
X 
X 
X 
 
X 
Tau Status Disclosurep,q,r 
 
Xp 
 
 
 
Genetic Counselingr,s,t 
X 
 
 
 
 
 
 
Study Participation Reportj 
 
X 
X 
X 
X 
 
X 
Blood for AD blood biomarkersm, DNA, and RNA,   
PBMCk 
 
X 
X 
X 
X 
 
X 
LP Safety Labs (CBC, coagulation profile)  
 
X 
X 
X 
 
 
X 
Lumbar Puncture (optional) l,m 
 
X 
X 
X 
 
 
X 
Wellness Checkn,r 
 
X 
X 
X 
 
 
X 
 
a) 
Visit procedures may be split over multiple days without constituting a protocol deviation.   
b) 
Longitudinal visits should commence within 365 days +/- 60 days from the previous visit. However, there must 
be at least 365 days between the first PET scan of the previous visit and the first PET scan of the next yearly 
visit. There must also be at least 365 days from second-to-second PET, so that there are no more than two PET 
scans in a year. FDG PET is not subject to this consideration; it can be the third PET in 365 days. Every attempt 
should be made to complete longitudinal visits within 60 days. 
c) 
Those who have consented to brain donation will be contacted annually by phone and until death once unable 
to come into the clinic. Post mortem brain donation discussion should occur to confirm/review consent even if 
participant has already agreed. Follow up continues after all LEADS study visits have been completed until 

 
 
Page 65 of 69 
Version (10.0): MAY 23, 2024 
participant death. If participant has refused to participate, no further inquiry should take place. Undecided 
participants will be approached at each study visit until they consent or refuse to participate. See section 7.1.7 
for more detail. 
d) Contact ATRI Coordinating Center for guidance on what specific procedures should be conducted at this visit. 
e) 
Timing for result disclosure is not set and dependent on the availability of the genetic screening results.  
f) 
The NACC UDS and FTLD modules include demographics, clinical, cognitive, functional, behavioral assessments.  
• 
Version C2 the NACC UDS Neuropsychological Battery will be used in this study  
• 
UDS forms A1, A3, A5, B4-B9, C2, D1, and D2 are required for LEADS   
• 
UDS forms A5/D2, D1a, and D1b will take the place of A5, D2, and D1 if using UDSv4 
• 
FTLD forms B3F, B9F, C1F-C6F, E2F and E3F are required for LEADS  
g) 
If a female is not surgically sterile or post-menopausal by two years, a pregnancy test will be performed prior to 
amyloid and tau PET scans. Only participants with a negative result will be eligible for PET scanning. 
h) All attempts should be made to acquire the full 60 minute MRI protocol; however the MPRAGE and 3D FLAIR 
should be prioritized. The MPRAGE and 3D FLAIR are the mandatory sequences. If needed, the other sequences 
may be skipped for any reason without constituting a protocol deviation. Note the reason for non-completion in 
the source documents.  
i) 
For sites that have radiation safety committees (RSC), ability to conduct the PET scans will be contingent on 
local RSC approval.  
j) 
May be provided to participants at the discretion of the PI. See section 7.1.8 for more detail.  
k) 
PBMC samples must be collected and shipped the same day. Fasting is not required. PBMC sample collection is 
optional for international sites.  If collected, international sites will store PBMC samples locally. See NCRAD 
Biospecimen, Collection, and Shipping manual for more details.  
l) 
Review of LP safety lab report with PI signature prior to LP is mandatory for participants who consented to the 
lumbar procedure. See section 7.6.2 for more detail. 
m) LP should be collected after a minimum 6-hour fast (preferably in the morning after an overnight fast).  
n) To be completed within 48 hours of lumbar puncture.  
o) 
The Sex and Reproductive Health Questionnaire and the Area Deprivation Index are only to be collected one 
time and should be completed at the next in-clinic visit. Participants who completed Sex and Reproductive 
Health Questionnaire at Baseline will not complete the Sex and Reproductive Health Questionnaire at any 
longitudinal visits. Participants who completed the Area Deprivation Index at Baseline will not complete the 
Area Deprivation Index at any longitudinal visits. The Area Deprivation Index is only collected at U.S. sites.  
p) If tau PET results were not disclosed at Baseline, results of the most recent or to-be-conducted tau PET scan 
should be disclosed at the next in-person visit. Only one tau PET scan is read per participant. 
q) 
Tau PET scan is not required for select international sites. Participants from select international sites will not 
complete tau PET scans and therefore will not receive tau PET results. 
r) 
Visit procedure noted with “r” can be completed remotely. See section 8.7 for more information. 
s) 
The CN cohort does not receive their genetic results and therefore do not require genetic counseling. Positive 
genetic results require genetic cousenling for the CI cohort if they have agreed to receive their genetic results. 
Participants at international sites may speak with the site PI or appropriately trained clinical investigator.   
 
 
 
(continued on next page) 

 
 
Page 66 of 69 
Version (10.0): MAY 23, 2024 
 EOnonAD Participants – Longitudinal Visits 
              Visit 
 
Procedure 
Genetics 
Status 
Disclosure 
Month 12a 
Month 24a 
Month 36 a 
Month 48 / 
Annual Visit a 
Anuual 
Neuropath. 
Phone Checkc 
Early 
Terminationd 
Window Period (days) 
See footnote 
e 
+/- 60b 
 
Brain donation discussion/provisional consentc,s 
 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
X 
 
X 
Neurological and Physical Exams 
 
X 
X 
X 
X 
 
X 
Demographics & Medical Historys 
 
X 
X 
X 
X 
 
X 
Clinical Diagnosis and Clinical Symptom Assessment 
 
X 
X 
X 
X 
 
X 
Sex and Reproductive Health Questionnaires 
 
Xp 
 
 
Area Deprivation Indexs  
 
Xp 
 
 
Concomitant Medicationss 
 
X 
X 
X 
X 
 
X 
NACC UDS and FTLD Modules, and 
Neuropsychological Batteryf, s 
 
X 
X 
X 
X 
 
X 
Amsterdam IADL Questionnaires 
 
X 
X 
X 
X 
 
X 
ADAS-Cog13s 
 
X 
X 
X 
X 
 
X 
Rey Auditory Verbal Learning Test (RAVLT)s 
 
X 
X 
X 
X 
 
X 
TabCat: Flanker, Line Length, Line Orientation, and 
Match 
 
X 
X 
X 
X 
 
X 
CDRs  
 
X 
X 
X 
X 
 
X 
Pregnancy Testg 
 
X 
X 
X 
 
 
 
3T MRI/fMRIh 
 
X 
X 
X 
 
 
X 
Amyloid PET Scan 
 
 
 
X 
 
 
 
Tau PET Scanr 
 
 
 
Xi 
 
 
 
FDG PET Scann 
 
Xj 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
 
X 
Amyloid Status Disclosures 
 
 
 
X 
 
 
 
Tau Status Disclosurer,s 
 
Xq 
 
 
 
FDG Status Disclosures 
 
Xj 
 
 
 
Genetic Counselings,t 
X 
 
 
 
 
 
 
Study Participation Reportk 
 
X 
X 
X 
X 
 
X 
Blood for AD blood biomarkersn, DNA, and RNA, 
PBMCl 
 
X 
X 
X 
X 
 
X 
LP Safety Labs (CBC, coagulation profile)  
 
X 
X 
X 
 
 
X 
Lumbar Puncture (optional) m,n 
 
X 
X 
X 
 
 
X 
Wellness Checko,s 
 
X 
X 
X 
 
 
X 
 
 
(continued on next page) 
 

 
 
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Version (10.0): MAY 23, 2024 
a) 
Visit procedures may be split over multiple days without constituting a protocol deviation. 
b) 
Longitudinal visits should commence within 365 days +/- 60 days from the previous visit. However, there must 
be at least 365 days between the first PET scan of the previous visit and the first PET scan of the next yearly 
visit. There must also be at least 365 days from second-to-second PET, so that there are no more than two PET 
scans in a year. FDG PET is not subject to this consideration; it can be the third PET in 365 days. Every attempt 
should be made to complete longitudinal visits within 60 days. 
c) 
Those who have consented to brain donation will be contacted annually by phone and until death once unable to 
come into the clinic. Post mortem brain donation discussion should occur to confirm/review consent even if 
participant has already agreed. Follow up continues after all LEADS study visits have been completed until 
participant death. If participant has refused to participate, no further inquiry should take place. Undecided 
participants will be approached at each study visit until they consent or refuse to participate. See section 7.1.7 
for more detail.  
d) Contact ATRI Coordinating Center for guidance on what specific procedures should be conducted at this visit. 
e) 
Timing for result disclosure is not set and dependent on the availability of the genetic screening results. 
f) 
The NACC UDS and FTLD modules include demographics, clinical, cognitive, functional, behavioral assessments.  
• 
Version C2 the NACC UDS Neuropsychological Battery will be used in this study  
• 
UDS forms A1, A3, A5, B4-B9, C2, D1, and D2 are required for LEADS   
• 
UDS forms A5/D2, D1a, and D1b will take the place of A5, D2, and D1 if using UDSv4 
• 
FTLD forms B3F, B9F, C1F-C6F, E2F and E3F are required for LEADS  
g) 
If a female is not surgically sterile or post-menopausal by two years, a pregnancy test will be performed prior to 
amyloid, tau, and FDG PET scans. Only participants with a negative result will be eligible for PET scanning. 
h) All attempts should be made to acquire the full 60 minute MRI protocol; however the MPRAGE and 3D FLAIR 
should be prioritized. The MPRAGE and 3D FLAIR are the mandatory sequences for enrollment. If needed, the 
other sequences may be skipped for any reason without constituting a protocol deviation. Note the reason for 
non-completion in the source documents.  
i) 
The tau PET scan applies only to EOnonAD participants that become amyloid positive and cannot be scheduled 
until after Month 36 amyloid disclosure. EOnonAD participants (who remain amyloid negative) will not receive 
the Month 36 tau PET scan and the associated disclosure and pregnancy test.  
j) 
The FDG PET scan and FDG PET status disclosure are only to be conducted one time and should be completed at 
the next in-clinic visit. Participants who completed FDG PET scan at Baseline will not complete an FDG PET scan 
and the associated FDG status disclosure at any longitudinal visits. For sites that have radiation safety 
committees (RSC), ability to conduct FDG PET scans will also be contingent on local RSC approval.  
k) 
May be provided to participants at the discretion of the PI. See section 7.1.8 for more detail. 
l) 
PBMC samples must be collected and shipped the same day. Fasting is not required. PBMC sample collection is 
optional for international sites.  If collected, international sites will store PBMC samples locally. See NCRAD 
Biospecimen, Collection, and Shipping manual for more details.  
m) Review of LP safety lab report with PI signature prior to LP is mandatory for participants who consented to the 
lumbar procedure. See section 7.6.2 for more detail. 
n) LP should be collected after a minimum 6-hour fast (preferably in the morning after an overnight fast). FDG-PET 
should be collected after an overnight fast for scans conducted in the morning, or a minimum 4-hour fast for 
scans collected later in the day; prior to the scan, a blood glucose measurement will be made by finger stick and 
scans will be postponed or rescheduled if the reading is > 180 mg/dL. 
o) 
To be completed within 48 hours of lumbar puncture. Additionally, a telephone call will be made within two 
weeks post amyloid results disclosure. See section 7.1.4 for more detail.  
p) The Sex and Reproductive Health Questionnaire and the Area Deprivation Index are only to be collected one 
time and should be completed at the next in-clinic visit. Participants who completed the Sex and Reproductive 
Health Questionnaire at Baseline will not complete the Sex and Reproductive Health Questionnaire at any 
longitudinal visits. Participants who completed the Area Deprivation Index at Baseline will not complete the 
Area Deprivation Index at any longitudinal visits. The Area Deprivation Index is only collected at U.S. sites.  
q) 
If tau PET results were not disclosed at Baseline, results of the most recently conducted tau PET scan should be 
disclosed at the next in-person visit.  
r) 
Tau PET scan is not required for select international sites. Participants from select international sites will not 
complete tau PET scans and therefore will not receive tau PET results. 
s) 
Visit procedure noted with “s” can be completed remotely. See section 8.7 for more information. 
t) 
The CN cohort does not receive their genetic results and therefore do not require genetic counseling. Positive 
genetic results require genetic cousenling for the CI cohort if they have agreed to receive their genetic results. 
Participants at international sites may speak with the site PI or appropriately trained clinical investigator.   
 
 
 
 
 
 

 
 
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Version (10.0): MAY 23, 2024 
(continued on next page) 
Cognitively Normal Participants – Longitudinal Visits 
              Visit 
 
Procedure 
Month 12a 
Month 24a 
Annual 
Neuropath. 
Phone Checkc 
Early 
Terminationd 
Window Period (days) 
+/- 60b 
 
 
Neuropathology discussion/ provisional consentc,q 
X 
X 
X 
 
Vital Signs 
X 
X 
 
X 
Neurological and Physical Exams 
X 
X 
 
X 
Demographics and Medical Historyq 
X 
X 
 
X 
Clinical Diagnosis and Clinical Symptom Assessment 
X 
X 
 
X 
Sex and Reproductive Health Questionnaireq 
Xo 
 
 
Area Deprivation Indexq  
Xo 
 
Concomitant Medicationsq 
X 
X 
 
X 
NACC UDS and FTLD Modules and Neuropsychological 
Batterye,q 
X 
X 
 
X 
Amsterdam IADL Questionnaireq 
X 
X 
 
X 
ADAS-Cog13q 
X 
X 
 
X 
Rey Auditory Verbal Learning Test (RAVLT)q  
X 
X 
 
X 
TabCat: Flanker, Line Length, Line Orientation, and Match 
X 
X 
 
X 
CDRq  
X 
X 
 
X 
Pregnancy Testf 
X 
 
 
3T MRI/fMRIg 
Xp 
X 
 
 
FDG PET Scan 
Xi 
 
 
Adverse Eventsq 
X 
X 
 
X 
Study Participation Reportj 
X 
X 
 
X 
Blood for AD Biomarkersk, DNA, and RNA, and PBMCl 
X 
X 
 
X 
LP Safety Labs (CBC, coagulation profile) 
 
X 
 
 
Lumbar Puncture (optional)k, m, n 
 
X 
 
 
Wellness Checkh, q 
 
X 
 
 
 
a) 
Visit procedures may be split over multiple days without constituting a protocol deviation. 
b) 
Month 12 and 24 visits should commence within 365 days +/- 60 days from the previous visit. However, there 
must be at least 365 days between the first PET scan of the previous visit and the first PET scan of the next 
yearly visit. There must also be at least 365 days from second-to-second PET, so that there are no more than 
two PET scans in a year. FDG PET is not subject to this consideration; it can be the third PET in 365 days. Every 
attempt should be made to complete longitudinal visits within 60 days. 
c) 
Those who have consented to brain donation will be contacted annually by phone and until death once unable to 
come into the clinic. Post mortem brain donation discussion should occur to confirm/review consent even if 
participant has already agreed. Follow up continues after all LEADS study visits have been completed until 
participant death. If participant has refused to participate, no further inquiry should take place. Undecided 
participants will be approached at each study visit until they consent or refuse to participate. See section 7.1.7 for 
more detail.  
d) Contact ATRI Coordinating Center for guidance on what specific procedures should be conducted at this visit. 
e) 
The NACC UDS and FTLD battery includes clinical, cognitive, functional, behavioral assessments.  

 
 
Page 69 of 69 
Version (10.0): MAY 23, 2024 
• 
Version C2 the NACC UDS Neuropsychological Battery will be used in this study  
• 
UDS forms A1, A3, A5, B4-B9, C2, D1, and D2 are required for LEADS   
• 
UDS forms A5/D2, D1a, and D1b will take the place of A5, D2, and D1 if using UDSv4 
• 
FTLD forms B3F, B9F, C1F-C6F, E2F and E3F are required for LEADS  
f) 
If a female is not surgically sterile or post-menopausal by two years, a pregnancy test will be performed prior to 
the FDG PET scan. Only participants with a negative result will be eligible for scanning. 
g) 
All attempts should be made to acquire the full 60 minute MRI protocol; however the MPRAGE and 3D FLAIR 
should be prioritized. The MPRAGE and 3D FLAIR are the mandatory sequences for enrollment. Other 
sequences be skipped for any reason without constituting a protocol deviation. Note the reason for non-
completion in the source documents.  
h) To be completed within 48 hours post lumbar puncture. See section 7.1.4 for more detail. 
i) 
The FDG PET scan is only to be conducted one time and should be completed at the next in-clinic visit. 
Participants who completed FDG PET scan at Baseline will not complete an FDG PET scan at any longitudinal 
visits. For sites that have radiation safety committees (RSC), ability to conduct FDG PET contingent on local RSC 
approval.  
j) 
May be provided to participants at the discretion of the PI. See section 7.1.8 for more detail.  
k) 
LP should be collected after a minimum 6-hour fast (preferably in the morning after an overnight fast). FDG 
PET should be collected after an overnight fast for scans conducted in the morning, or a minimum 4-hour fast 
for scans collected later in the day; prior to the scan, a blood glucose measurement will be made by finger stick 
and scans will be postponed or rescheduled if the reading is > 180 mg/dL. 
l) 
PBMC samples must be collected and shipped the same day. Fasting is not required. PBMC sample collection is 
optional for international sites.  If collected, international sites will store PBMC samples locally. See NCRAD 
Biospecimen, Collection, and Shipping manual for more details.  
m) Review of LP safety lab report with PI signature prior to LP is mandatory for participants who consented to the 
lumbar procedure. See section 7.6.2 for more detail. 
n) If LP was unsuccessful at baseline, participants can be reapproached and LP collected at Month 12. 
o) 
The Sex and Reproductive Health Questionnaire and the Area Deprivation Index are only to be collected one time 
and should be completed at the next in-clinic visit. Participants who completed the Sex and Reproductive Health 
Questionnaire at Baseline will not complete the Sex and Reproductive Health Questionnaire at any longitudinal 
visits. Participants who completed the Area Deprivation Index at Baseline will not complete the Area Deprivation 
Index at any longitudinal visits. The Area Deprivation Index is only collected at U.S. sites.  
p) MRI at M12 will only be conducted for CN participants who are undergoing an FDG PET scan at their M12 visit. If 
the participant is not undergoing an FDG PET at M12, no MRI scan will be conducted at M12. 
q) 
Visit procedure noted with “q” can be completed remotely. See section 8.7 for more information.