Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3)
Conditions: Mild Cognitive Impairment (MCI), Alzheimer's Disease (AD)
Sponsor: University of Southern California

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3) Protocol 
 
Protocol Short Title:  ADNI3 
 
Protocol Number:  ATRI-001 
PROJECT DIRECTOR 
 
COORDINATION & DATA MANAGEMENT 
CENTER 
Michael Weiner, M.D. 
University of California, San 
Francisco 
michael.weiner@ucsf.edu  
Paul Aisen, M.D. 
University of Southern California  
paisen@usc.edu 
PROTOCOL PRINCIPAL 
INVESTIGATOR 
MEDICAL DIRECTOR  
 
 
Ronald Petersen, M.D., Ph.D. 
Mayo Clinic, Rochester, Minnesota 
peter8@mayo.edu  
Michael Rafii, M.D., Ph.D. 
University of Southern California  
mrafii@usc.edu  
BIOMARKER CORE 
 
NEUROPATHOLOGY CORE 
 
 
Leslie M. Shaw, Ph.D. 
John Trojanowski, M.D., Ph.D 
University of Pennsylvania Medical 
Center 
shawlmj@mail.med.upenn.edu  
trojanow@mail.med.upenn.edu  
 John C. Morris, M.D. 
Richard J. Perrin, M.D., Ph.D. 
Washington University School of Medicine 
 
morrisj@abraxas.wustl.edu  
rperrin@wustl.edu  
LABORATORY OF NEUROIMAGING 
GENETICS CORE 
 
 
Arthur Toga, Ph.D. 
University of Southern California  
toga@usc.edu  
Andrew Saykin, PsyD, ABCN 
Indiana University School of Medicine  
asaykin@iupui.edu 
MAGNETIC RESONANCE IMAGING 
POSITRON EMISSION TOMORGRAPHY 
 
Clifford Jack, M.D. 
Mayo Clinic, Rochester  
jack.clifford@mayo.edu  
William Jagust, M.D. 
University of California, Berkeley  
jagust@berkeley.edu  
PROTOCOL VERSION 
VERSION DATE 
 
Version 3.1 
04-December-2020 
 
 
 
 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 4 
SIGNATURE PAGE ..................................................................................................................... 6 
PROTOCOL SYNOPSIS ............................................................................................................. 7 
1.0 
INTRODUCTION ........................................................................................................... 8 
1.1 
Primary Aims ......................................................................................................................... 8 
2.0 
BACKGROUND AND SIGNIFICANCE ....................................................................... 8 
2.1 
Rationale for Study .............................................................................................................. 8 
3.0 
STUDY DESIGN & SAMPLE SIZE .............................................................................. 9 
4.0 
STUDY POPULATION .............................................................................................. 11 
4.1 
Inclusion Criteria .............................................................................................................. 11 
4.2 
Exclusion Criteria .............................................................................................................. 13 
4.3  
Recruitment and Retention Strategies ...................................................................... 14 
5.0 
STUDY TIMELINE ..................................................................................................... 15 
6.0  
DESCRIPTION OF STUDY VISITS ......................................................................... 16 
6.1 
Visit Scheduling ................................................................................................................. 17 
6.2 
Procedures for Newly Enrolled Participants ........................................................... 17 
6.3 
Procedures for Rollover Participants ........................................................................ 19 
6.4 Other Types of Study Visits (Applicable to both Newly Enrolled and Rollover 
Participants) ........................................................................................................................... 19 
7.0 
PERSONNEL REQUIREMENTS ............................................................................... 20 
8.0 
INSTRUMENTS .......................................................................................................... 21 
8.1 
Cognitive Evaluations ...................................................................................................... 21 
8.2 
Global, Functional, and Behavioral Evaluations ..................................................... 22 
9.0 
PROCEDURES ............................................................................................................. 23 
9.1 
Assessments ........................................................................................................................ 23 
9.2 
Biofluids ............................................................................................................................... 24 
9.3 
Magnetic Resonance Imaging (MRI) ........................................................................... 25 
9.4 PET scanning: FDG, Amyloid (Florbetapir or Florbetaben), and Flortaucipir 
PET Imaging ............................................................................................................................ 26 
9.5 
Neuropathology ................................................................................................................. 29 
9.6 
Global Unique Identifiers (GUIDs) .............................................................................. 31 
10.0 FITBIR .......................................................................................................................... 31 
11.0 POTENTIAL RISKS .................................................................................................... 31 
11.1 
FDG-PET, Florbetapir, Florbetaben, and Flortaucipir PET ................................. 31 
11.2 
MRI ......................................................................................................................................... 34 
11.3 
Lumbar Puncture .............................................................................................................. 34 
11.4 
Blood Draw .......................................................................................................................... 35 
11.5 
Genetic Risks ...................................................................................................................... 35 
11.6 
Loss of Privacy ................................................................................................................... 35 
12.0 ADVERSE EVENTS .................................................................................................... 36 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
12.1 
Definition of an Adverse Event (AE) ........................................................................... 36 
12.2 
Following up and reporting on Adverse Events ..................................................... 36 
12.3 
Definition of a Serious Adverse Event (SAE) ............................................................ 36 
12.4 
Reporting Serious Adverse Events (SAEs) ................................................................ 36 
12.5 
Data and Safety Monitoring Board .............................................................................. 37 
12.6 
Research Monitor .............................................................................................................. 37 
13.0 ETHICS AND REGULATORY CONSIDERATIONS .............................................. 37 
13.1 
Good Clinical Practice ...................................................................................................... 37 
13.2 
Institutional Review Boards (IRB) / Research Ethics Boards (REB) ............... 38 
13.3 
Informed Consent and HIPAA Compliance ............................................................... 38 
13.4 
Data Collection and Monitoring ................................................................................... 39 
13.5 
Procedures to Maintain Participant and Data Confidentiality .......................... 40 
13.6 
Requesting Genetic and Biomarker Samples for Research ................................ 43 
14.0 NIH DATA SHARING POLICY ................................................................................. 43 
15.0 STATISTICAL CONSIDERATIONS ......................................................................... 44 
15.1 
Analysis Goals and Strategies ....................................................................................... 44 
16.0 LITERATURE CITED ................................................................................................. 45 
APPENDIX 1  SCHEDULE OF EVENTS .............................................................................. 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
LIST OF ABBREVIATIONS  
 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale – Cognitive  
ADC 
Alzheimer’s Disease Center 
ADEAR 
Alzheimer’s Disease Education & Referral Center, under the 
NIA 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
ADNI1 
Alzheimer’s Disease Neuroimaging Initiative - 1 
ADNI2 
Alzheimer’s Disease Neuroimaging Initiative - 2 
ADNI-GO 
Alzheimer’s Disease Neuroimaging Initiative – Grand 
Opportunity 
PCORNet 
Patient Centered Outcomes Research Network  
AE 
Adverse Event 
AMNART 
American National Adult Reading Test  
APOE/APOE4 
Apolipoprotein E (APOE) epsilon 4 (APOE4) 
ATRI 
Alzheimer’s Therapeutic Research Institute 
Aβ 
Beta Amyloid 
ASL 
Arterial Spin Labeling  
CBB 
Cogstate Brief Battery  
CCI 
Cognitive Change Index 
CDR 
Clinical Dementia Rating 
CSF 
Cerebrospinal Fluid 
CT 
Computerized Tomography  
dbGaP 
Database of Genotypes and Phenotypes  
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) 
EMCI 
Early Amnestic Mild Cognitive Impairment  
ECog 
Everyday Cognition  
FCI-SF 
Financial Capacity Instrument – Short Form  
FAQ 
Functional Activities Questionnaire (Activities of Daily Living) 
FDG 
Fluorodeoxyglucose 
FLAIR 
Fluid Attenuation Inversion Recovery 
fMRI 
Functional Magnetic Resonance Imaging  
GCP 
Good Clinical Practice 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
GDS 
Geriatric Depression Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
LMCI 
Late Mild Cognitive Impairment  
LAR 
Legally Authorized Representative 
LONI 
Laboratory of Neuroimaging at USC  
LP 
Lumbar Puncture 
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 
NCRAD 
National Cell Repository for AD 
NIA 
National Institute on Aging, under the NIH 
NIH 
National Institutes of Health 
NPI 
Neuropsychiatric Inventory 
PET 
Positron-Emission Tomography 
PI 
Principal Investigator 
PT/PTT 
Prothrombin Time (PT)/Partial Thromboplastin Time (PTT) 
QA / QC 
Quality Assurance / Quality Control 
REB 
Research Ethics Board 
RNA 
Ribonucleic Acid  
SAE 
Serious Adverse Event 
T 
Tesla 
TFTs 
Thyroid Function Tests 
TSH 
Thyroid Stimulating Hormone 
vMRI 
Volumetric Magnetic Resonance Imaging 
 
 
 
 
 
 
 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
 
SIGNATURE PAGE 
 
(SIGNATURES ON FILE AT ATRI COORDINATING CENTER) 
 
 
 
 
 
______________________________________________  
 
_________________________ 
Michael Weiner, M.D. 
 
 
 
 
Date (MM/DD/YYYY) 
Project Director 
University of California, San Francisco 
 
 
 
 
 
______________________________________________  
 
_________________________ 
Paul Aisen, M.D. 
 
 
 
 
 
Date (MM/DD/YYYY)  
Director 
Coordination & Data Management Center 
Alzheimer’s Therapeutic Research Institute 
 
 
 
 
 
______________________________________________  
 
_________________________ 
Ronald Petersen, M.D., Ph.D. 
 
 
 
Date (MM/DD/YYYY) 
Protocol Principal Investigator  
Mayo Clinic, Rochester, Minnesota 
 
 
 
 
 
 
 
 
 
 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
Alzheimer’s Disease Neuroimaging Initiative 3 
(ADNI3) 
PROJECT DIRECTOR 
Michael W. Weiner, M.D. 
STUDY SPONSOR 
National Institute on Aging, National Institute of Health 
COORDINATING 
CENTER 
Alzheimer’s Therapeutic Research Institute (ATRI) 
STUDY DESIGN 
Non-randomized natural history non-treatment study 
DURATION OF STUDY 
PARTICIPATION 
Screening period will be open for approximately two 
years followed by a 2-5 year longitudinal follow-up 
period based on cohort. 
SAMPLE SIZE 
1,070-2000 total participants will be enrolled across 3 
cohorts: cognitively normal (CN), mild cognitive 
impairment (MCI), and mild AD dementia. 
Approximately, 700-800 will be rollover participants 
from ADNI2, and 370-1200 will be newly enrolled 
SUMMARY OF KEY 
ELIGIBILITY CRITERIA  
Newly enrolled participants will be 55-90 (inclusive) 
years of age, willing and able to undergo test 
procedures that include neuroimaging and lumbar 
punctures to be carried out longitudinally.  
Rollover participants must have been enrolled in ADNI 
previously and willing to continue participation. 
MMSE, CDR, and Logical Memory meeting cut-off 
scores for each diagnostic category.  
PRIMARY OBJECTIVE  
Discover, optimize, standardize, and validate clinical 
trial measures and biomarkers used in ongoing AD 
research. 
OUTCOME MEASURES 
/ STUDY PROCEDURES 
Rates of decline on cognitive, global, and functional 
tests; rate of conversion to MCI or dementia due to AD; 
volumetric and structural MRI measures; rates of 
change on each specified biochemical biomarker; 
correlations and change among biomarkers; 
longitudinal extent and rate of amyloid deposition; 
longitudinal changes in tau; subgroup analyses among 
all the biochemical and imaging biomarkers.   

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
1.0 INTRODUCTION  
Since its launch in 2004, the overarching aim of the Alzheimer’s Disease 
Neuroimaging Initiative (ADNI) has been realized in informing the design of 
therapeutic trials in AD. ADNI3 continues the previously funded ADNI1, ADNI-GO, 
and ADNI2 studies that have been combined public/private collaborations between 
academia and industry to determine the relationships between the clinical, 
cognitive, imaging, genetic and biochemical biomarker characteristics of the entire 
spectrum of Alzheimer’s disease (AD).  
1.1 
Primary Aims  
ADNI3 will continue to discover, optimize, standardize, and validate clinical trial 
measures and biomarkers used in AD research.  
Aim 1. Longitudinal changes in cognition and associated biomarkers  
Determine and define those measures of cognition and function, including 
composite measures, and those biomarker measures, which capture longitudinal 
change with the highest statistical power to detect treatment effects in clinical trials. 
Longitudinal change of cerebral tau measured with 18F-AV-1451 PET (flortaucipir) 
will be correlated/compared with other measures.  
Aim 2. Prediction of cognitive decline  
Determine which clinical, cognitive, and biomarker measures that best predict 
decline of cognition in CN, MCI, and AD participants. In addition, determine which 
biomarker changes correlate with cognitive decline, with focus on flortaucipir PET.  
Aim 3. Validation  
Validate biomarker measures obtained at Baseline and longitudinally by correlating 
results with “gold standard” clinical measurements and pathology.  
Aim 4. Clinical trial design  
Determine the optimum outcome measures with attention to cognitive decline and 
flortaucipir PET, predictors of cognitive decline, and inclusion/exclusion criteria for 
clinical trials of cognitively normal participants (for secondary preclinical AD trials), 
MCI patients (for prodromal AD trials) and participants with early dementia due to 
AD.  
Aim 5. Discovery  
To determine the effects of other known disease proteins found in AD brains and 
genes, as well as newly discovered genes, proteins, and analytes that provide useful 
information concerning the pathogenesis/diagnosis of AD.  
2.0 BACKGROUND AND SIGNIFICANCE 
2.1 
Rationale for Study  
ADNI plays a central role in improving treatment trials. Since the study’s launch, 
ADNI Investigators with regulators in both the US and abroad have facilitated the 
design of major completed and ongoing drug trials1-18.    

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
2.1.1 Rationale for Outcome Measures and Biomarkers   
Our strategy is based on the concept that the AD process is characterized by the 
accumulation of Aβ and phosphorylated tau, synaptic loss and neurodegeneration, 
leading to cognitive decline. Clinical/cognitive measures lack both sensitivity and 
specificity to detect AD pathology. Instead, biomarkers are more reliably used to 
identify participants at risk for cognitive decline and to measure disease 
progression. This project will collect MRI (structural, diffusion weighted imaging, 
perfusion, and resting state sequences); amyloid PET using florbetapir F18 
(florbetapir) or florbetaben F18 (florbetaben); 18F-FDG-PET (FDG-PET); CSF for Aβ, 
tau, phosphorylated tau, and other proteins; flortaucipir PET; and genetic and 
autopsy data to determine the relationship of these biomarkers to baseline clinical 
status and cognitive decline.  
 
Predictors – We hypothesize that the imaging/biomarker measurements most likely 
to predict decline from normal or from initial significant memory concern will be 
measures of Aβ (CSF and PET) and measures of flortaucipir PET scan in combination 
with measures of CSF tau, FDG-PET, and MRI.  
 
Outcomes – We hypothesize that the biomarkers most likely to correlate with and to 
augment the utility of cognitive and clinical measures as outcomes in clinical trials 
are flortaucipir PET and MRI measures of volume (especially of hippocampus and 
temporal cortex) at early stages. Atrophy throughout the brain may be the most 
significant correlate with clinical and cognitive measures at later stages of AD. 
3.0 STUDY DESIGN & SAMPLE SIZE  
This is a non-randomized, natural history, non-treatment study.  Approximately 
1070 - 2000 participants will be enrolled at approximately 59 sites in the United 
States and Canada. Approximately, 700 - 800 will be rollover participants from 
ADNI2, and 370 - 1200 will be newly enrolled. Clinical/cognitive, imaging, 
biomarker, and genetic characteristics will be assessed across the three cohorts: CN, 
MCI, and mild AD dementia.  
Sample size by cohort  
• Cognitively normal (CN) cohort: 
§ 295-330 rollover participants  
§ 135-500 new participants  
• Mild Cognitive Impairment (MCI) cohort:  
§ 275-320 rollover  
§ 150-515 new  
• Mild Alzheimer’s Disease dementia (AD) cohort: 
§ 130-150 rollover  
§ 85-185 new  
 
Clinical/cognitive assessments, 3T MRI and collection of plasma and serum for 
biomarkers will be conducted annually for MCI and AD, and biennially for CN. Blood 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
samples will be collected for peripheral blood mononuclear cell (PBMC) banking for 
genetic analysis at the Baseline Visit for new participants, and at the Initial Visit for 
rollover participants (if not previously obtained). In addition, blood will be collected 
for longitudinal DNA and RNA genetic analyses at follow-up visits. Amyloid PET 
imaging and CSF collection for biomarkers will occur biennially.  
 
All participants will undergo two flortaucipir PET scans, with some receiving 
additional flortaucipir PET scans dependent on cohort and amyloid status. 
 
MCI and AD participants will undergo one FDG-PET scan at Initial/Baseline Visit 
only; CN group is not required to conduct FDG-PET.  
 
CN and MCI participants will be asked to perform computerized cognitive testing 
(Cogstate Brief Battery) at each annual or biennial in-clinic visit, and up to quarterly 
intervals remotely at a home computer or by other means (e.g., neighbor or 
community center).  
 
Neuropathological examination of brains obtained by autopsy will be performed. 
 
Visit frequency and assessments are outlined in more detail in section 6.0 
(Description of Study Visits) and Appendix 1(Schedule of Events).  
 

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ADNI Protocol v3.1: 04-December-2020 
4.0 STUDY POPULATION 
The study will enroll men and women aged 55-90 years across CN, MCI, and mild AD 
dementia participant groups, as specified in the entry criteria below. Exceptions to 
these guidelines may be considered on a case-by-case basis at the discretion of the 
project director and ADNI-CC.  
4.1 
Inclusion Criteria 
All newly enrolled participants must meet the following criteria:  
 
 
CN 
MCI 
AD 
1.  Participant with or without 
subjective memory 
complaints, verified by a 
study partner, beyond what 
one would expect for age 
Participant must express 
a subjective memory 
concern as reported by 
participant, or recalled by 
study partner or clinician. 
Participant must express a 
subjective memory 
concern as reported by 
participant, or recalled by 
study partner or clinician. 
2.  Normal memory function 
documented by scoring 
above education adjusted 
cutoffs on the Logical 
Memory II subscale (Delayed 
Paragraph Recall, Paragraph 
A only) from the Wechsler 
Memory Scale –Revised (the 
maximum score is 25): 
a. ³9 for 16 or more years 
of education 
b. ³5 for 8-15 years of 
education 
c. ³3 for 0-7 years of 
education 
Abnormal memory 
function documented by 
scoring below education 
adjusted cutoffs on the 
Logical Memory II 
subscale (Delayed 
Paragraph Recall, 
Paragraph A only) from 
the Wechsler Memory 
Scale –Revised (the 
maximum score is 25): 
a. < 11 for 16 or more 
years of education 
b. ≤ 9 for 8-15 years of 
education 
c. ≤ 6 for 0-7 years of 
education 
Abnormal memory function 
documented by scoring 
below education adjusted 
cutoffs on the Logical 
Memory II subscale 
(Delayed Paragraph Recall, 
Paragraph A only) from the 
Wechsler Memory Scale –
Revised (the maximum 
score is 25): 
a. ≤ 8 for 16 or more 
years of education 
b. ≤ 4 for 8-15 years of 
education 
c. ≤ 2 for 0-7 years of 
education 
3.  Mini-Mental State Exam score 
between 24 and 30 inclusive 
(Exceptions may be made for 
participants with less than 8 
years of education at the 
discretion of the Project 
Director) 
Same as CN 
Mini-Mental State Exam 
score between 20 and 26 
inclusive (Exceptions may 
be made for participants 
with less than 8 years of 
education at the discretion 
of the Project Director) 
4.  Clinical Dementia Rating = 0. 
Memory Box score must be 0 
Clinical Dementia Rating = 
0.5. Memory Box score 
must be at least 0.5 
Clinical Dementia Rating = 
0.5 or 1.0 

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ADNI Protocol v3.1: 04-December-2020 
5.  Cognitively normal, based 
on an absence of significant 
impairment in cognitive 
functions or activities of daily 
living 
General cognition and 
functional performance 
sufficiently preserved 
such that a diagnosis of 
Alzheimer’s disease 
cannot be made by the 
site physician at the time 
of the Screening Visit 
NINCDS/ADRDA criteria for 
probable AD 
6. Stability of Permitted 
Medications for at least 4 
weeks:  
a. Stable doses of 
antidepressants lacking 
significant anticholinergic 
side effects (if they are 
currently adequately 
treated for depressive 
symptoms and do not 
have a history of major 
depression within the 
past 1 years) 
b. Estrogen replacement 
therapy is permissible 
c. Gingko biloba is 
permissible, but 
discouraged 
d. Washout from 
psychoactive medication 
(e.g., excluded 
antidepressants, 
neuroleptics, chronic 
anxiolytics or sedative 
hypnotics, etc.) for at 
least 4 weeks prior to 
screening 
Same as CN plus:  
Cholinesterase 
inhibitors and 
memantine are 
allowable if stable for 
12 weeks prior to 
Screening Visit  
Same as MCI  
 
Additional inclusion criteria that applies to all diagnostic categories for newly 
enrolled participants: 
1. Geriatric Depression Scale score less than 6. 
2. Age between 55-90 years (inclusive). 
3. Study partner who has frequent contact with the participant (i.e., minimum 
average of 10 hours per week) and is available to accompany the participant 
to all clinic visits for the duration of the protocol.  
4. Visual and auditory acuity adequate for neuropsychological testing. 
5. Good general health with no diseases expected to interfere with the study. 

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ADNI Protocol v3.1: 04-December-2020 
6. Participant is not pregnant, lactating, or of childbearing potential (i.e., 
women must be two years post-menopausal or surgically sterile). 
7. Willing and able to participate in a longitudinal imaging study. 
8. Modified Hachinski Ischemic Score less than or equal to 4. 
9. Completed six grades of education or has a good work history (sufficient to 
exclude mental retardation). 
10. Must speak English or Spanish fluently. 
11. Willing to undergo repeated MRIs (3Tesla) and at least two PET scans  
12. Agrees to collection of blood for genomic analysis (including GWAS 
sequencing and other analysis), APOE testing and biospecimen banking. 
13. Agrees to collection of blood for biomarker testing. 
14. Agrees to at least one lumbar puncture for the collection of CSF (non- 
minority participants only).  
15. Agrees to share genomic data and biomarker samples.  
4.1.1 Inclusion Criteria Specific to Rollover Participants  
The following additional inclusion criteria apply to all diagnostic categories for 
rollover participants only: 
1. Must have been enrolled and followed in ADNI1, ADNIGO, or ADNI2 for at 
least one year.   
2. Willing and able to continue to participate in an ongoing longitudinal study. A 
reduced battery of tests is allowable if the participant is not able/willing to 
complete the full battery.  
4.2 
Exclusion Criteria 
All newly enrolled participants must not meet the following criteria: 
 
 
CN 
MCI 
AD 
1.  Any significant neurologic 
disease, such as Parkinson’s 
disease, multi-infarct 
dementia, Huntington’s 
disease, normal pressure 
hydrocephalus, brain tumor, 
progressive supranuclear 
palsy, seizure disorder, 
subdural hematoma, 
multiple sclerosis, or history 
of significant head trauma 
followed by persistent 
neurologic deficits or known 
structural brain 
abnormalities 
Any significant neurologic 
disease other than 
suspected incipient 
Alzheimer’s disease, such 
as Parkinson’s disease, 
multi-infarct dementia, 
Huntington’s disease, 
normal pressure 
hydrocephalus, brain tumor, 
progressive supranuclear 
palsy, seizure disorder, 
subdural hematoma, 
multiple sclerosis, or history 
of significant head trauma 
followed by persistent 
neurologic deficits or known 
structural brain 
abnormalities. 
Any significant neurologic 
disease other than 
Alzheimer’s disease, such 
as Parkinson’s disease, 
multi-infarct dementia, 
Huntington’s disease, 
normal pressure 
hydrocephalus, brain tumor, 
progressive supranuclear 
palsy, seizure disorder, 
subdural hematoma, 
multiple sclerosis, or history 
of significant head trauma 
followed by persistent 
neurologic deficits or known 
structural brain 
abnormalities. 

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ADNI Protocol v3.1: 04-December-2020 
 
Additional exclusion criteria apply to all diagnostic categories for newly enrolled 
participants: 
1. Screening/Baseline MRI brain scan with evidence of infection, infarction, or 
other focal lesions or multiple lacunes or lacunes in a critical memory 
structure  
2. Subjects that have any contraindications for MRI studies, including the 
presence of cardiac pacemakers, or metal fragments or foreign objects in the 
eyes, skin or body. 
3. Major depression, bipolar disorder as described in DSM-IV within the past 1 
year. Psychotic features, agitation or behavioral problems within the last 3 
months that could lead to difficulty complying with the protocol. 
4. Currently treated with medication for obsessive-compulsive disorder or 
attention deficit disorder. 
5. History of schizophrenia (DSM IV criteria). 
6. History of alcohol or substance abuse or dependence within the past 2 years 
(DSM IV criteria). 
7. Any significant systemic illness or unstable medical condition, which could 
lead to difficulty complying with the protocol. 
8. Clinically significant abnormalities in B12 or TFTs that might interfere with 
the study. A low B12 is exclusionary, unless follow-up labs (homocysteine 
(HC) and methylmalonic acid (MMA)) indicate that it is not physiologically 
significant. 
9. Residence in a skilled nursing facility. 
10. Current use of specific psychoactive medications (e.g., certain 
antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics). 
Current use of warfarin or other anticoagulants such as dabigatran, 
rivaroxaban and apixaban (exclusionary for lumbar puncture). 
11. Current use of any other exclusionary medications. 
12. Investigational agents are prohibited one month prior to entry and for the 
duration of the trial. 
13. Participation in clinical studies involving neuropsychological measures being 
collected more than one time per year. 
4.3  
Recruitment and Retention Strategies 
Serving as the third series of ADNI studies our goal is to retain as many ADNI2 
participants as possible. A multi-faceted recruitment and retention plan is being 
developed for ADNI3. The overall goal is to raise awareness of the ADNI trial among 
targeted populations.   
 
We will leverage existing resources, infrastructure and registries as recruitment 
tools to enroll new participants into ADNI3.  
 
Registries such as Brain Health Registry (BHR) will provide potential participants to 
ADNI3.  BHR is a research study that is overseen by University of California, San 

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ADNI Protocol v3.1: 04-December-2020 
Francisco (UCSF). This means that everything that the Brain Health Registry does is 
reviewed and approved by the UCSF Institutional Review Board (IRB). 
 
Other retention and recruitment efforts may include engaging public 
relations/communications firm(s) and or partnering with organizations which 
already serve to honor clinical trial volunteers.  ADNI3 will determine the special 
requirements of each site and pattern its individual public 
relations/communications support around those needs.  
 
In that context ADNI will develop targeted messages in flyers, brochures, press 
releases, and presentations.  Access to recruitment materials for the sites will also 
be available. Enrollment will be monitored and tracked.  Additional site support will 
be provided where needed based upon the recruitment tactic data tied to 
enrollment. 
4.3.1 Inclusion of Women and Minorities  
Women and members of minority groups will be actively recruited during this 
protocol. Targeted efforts will include BHR a registry that has successfully enrolled 
large numbers of African Americans and AD-PCORNet, which utilizes African-
Americans Against AD and Latinos Against AD to engage and enroll participants 
from these groups. 
 
Based on the participating sites data regarding enrollment of minorities, we expect 
12% of participants enrolled will be minorities. This is close to the aged minority 
population in the U.S., which is 14%. 
4.3.2 Re-entry into ADNI3   
In the event where a participant decides to stop ADNI participation to enroll in a 
treatment trial, they may be allowed the opportunity to return to full or partial 
participation in the ADNI3 study. Participants who return to ADNI3 after 
participation in a treatment trial will be asked to provide information about their 
participation in that trial. Contact the ATRI Coordinating Center for guidance on re-
entry.  
 
5.0 STUDY TIMELINE  
The site should expect to spend: 1) approximately 3-6 months for startup activities 
that include site IRB and regulatory approvals, as well as site training; 2) 
approximately 2-6 years in screening and longitudinal follow-up visits, with follow-
up duration dependent on cohort.  
CN and MCI cohorts 
Exceptions can be made to extend the time allowed for the rollover’s Initial Visit. 
Screening and enrollment for new participants may occur over 2 years. Longitudinal 
follow-up period for both rollover and new participants is approximately 4-6 years.  

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ADNI Protocol v3.1: 04-December-2020 
Neuropathology telephone checks should be performed every six months between 
visits to discuss autopsy consent. 
AD cohort 
New and rollover AD participants will follow the same timeline as described above. 
However, the in-clinic longitudinal follow-up period is shorter, at maximum 2 years. 
After that, only Neuropathology telephone checks should be performed every six 
months or, at minimum, annually, which offer opportunities to discuss autopsy.  
6.0  DESCRIPTION OF STUDY VISITS 
Frequency of visits will be dependent on cohort and flortaucipir PET imaging 
schedule. Visits have a scheduling window of 2 weeks before and after the target 
date.  Once the visit begins, all imaging, biofluid collection, and clinical/cognitive 
assessments must take place within the next 2 weeks.  
 
Where there is insufficient time to complete the full visit, the order of priority for 
clinical assessments is:   
1. Clinical Dementia Rating Scale 
2. ADAS-Cog 
3. Mini Mental State Examination 
4. Logical Memory I and II 
5. Concomitant Medications 
6. Adverse Events 
7. Diagnostic Summary 
8. Vital Signs 
 
Subjects should be encouraged to undergo all procedures. Where subjects do not 
wish to undergo all of the procedures, the order of priority for procedures is as 
follows. The ordered priority is provided as a guide to the clinical staff and the 
participants, not a rigid priority list: 
1. Amyloid PET scan 
2. Flortaucipir PET scan 
3. MRI  
4. Lumbar puncture 
5. FDG-PET scan 
 
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. A guide to the order of priority for assessments and procedures is listed 
above, but it should be emphasized that the major priority is to keep subjects 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. 

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Unless a participant has clearly refused brain autopsy, the neuropathology program 
should be discussed at each visit.  
6.1 
Visit Scheduling  
CN participants will be seen in the clinic every other year through the end of the 
study. CN participants may be required to come into the clinic more often for 
flortaucipir PET scans.  
 
MCI participants will be seen in the clinic annually through the end of the study.  
 
AD participants will be seen in the clinic annually for two years (an initial visit 
followed by two ongoing visits) and will then be followed by telephone through the 
end of study.  
 
Diagnostic category converters, even if converted back to CN, will be followed in the 
clinic annually for the remainder of the study. 
 
All participants should be contacted every six months or, at a minimum, annually 
(see section 9.5) through the end of the study to obtain autopsy consent, establish 
and confirm logistical support for autopsy, and maintain updated participant 
contact information. 
6.1.1 Newly Enrolled Participants 
New participants will go through Pre-screening and Screening periods as described 
in section 6.2 below. The Screening and Baseline visits must be completed in-person 
by both the participant and study partner. 
6.1.2 Rollover Participants 
Rollover participants who are being followed from ADNI2 should be enrolled into 
ADNI3 for a complete In-Clinic Visit without any need for screening. This will be the 
case, even if these participants had a complete (that is with tau PET, amyloid PET, 
MRI, and/or LP) In-Clinic Visit in the last year of ADNI2.  
6.1.3 Retrieved Dropouts 
Participants who miss visits will be encouraged to come in for subsequent visits 
until he/she withdraws consent.  
 
In cases where consent has been withdrawn in previous ADNI studies, participants 
are invited to consent and participate in ADNI3. 
6.2 
Procedures for Newly Enrolled Participants 
6.2.1 Pre-screening  
During the prescreen phase, sites will assess referred potential participants for 
eligibility criteria, such as age and ability to tolerate procedures. 

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ADNI Protocol v3.1: 04-December-2020 
6.2.2 Screening  
The purpose of the Screening Visit is to further determine eligibility and to complete 
the informed consent process. Only newly enrolled participants will have a 
Screening Visit. Screening activities are conducted in the following order:  
•  Consent  
•  Screening assessments listed in the Schedule of Events (SOE) (see Appendix 
1) up to but not including the MRI, which requires both Site PI/Site Clinician 
and monitor approval  
•  Proceed to MRI 
•  Local read of MRI 
•  Site PI/Site Clinician and monitor verifications of all eligibility requirements  
6.2.3 Baseline Visit  
The Baseline visit may only be initiated following completion of all Screening 
assessments and must take place within 28 days of Screening. There is an additional 
2 weeks to complete other Baseline procedures. The procedures conducted are 
based on current diagnosis at the Initial visit. 
Baseline procedures include cognitive, functional, and behavioral assessments, 
review of concurrent medications and adverse events, FDG-PET (MCI and AD groups 
only), amyloid PET, flortaucipir PET, and biofluid collection (blood and CSF from 
lumbar punctures). The complete list of all Baseline procedures is provided in the 
SOE (see Appendix 1).  
 
In no instance should cognitive assessments be performed while the participant is in 
a fasted state. Procedures that require fasting are the blood draw, lumbar puncture, 
and FDG-PET. The MRI scan should be conducted prior to the LP to rule out 
intracranial mass for safety.  
6.2.4 Ongoing In-Clinic Visits for New Participants 
The ongoing In-Clinic Visits will be timed every 12 months from Baseline Visit day 1. 
CN participants that are not selected for extra flortaucipir PET scans are seen in-
clinic every other year. Ongoing in-clinic visits include cognitive, functional, and 
behavioral assessments, review of concurrent medications and adverse events, 
blood collection, and MRI.  
 
Amyloid PET scans and LPs are conducted every two years.  
 
On all participants, flortaucipir PET is conducted at the Initial Visit/Baseline. 
Additionally: 
• AD participants will have a second and third flortaucipir PET scan. Flortaucipir 
PET scans will be performed at each annual In-Clinic Visit (including the 
Initial/Baseline, Year 1, and Year 2 visits). 
• CN, MCI, and Converter participants will receive a flortaucipir PET scan at the 
Year 4 visit. Additionally, 20% of amyloid-negative and 80% of amyloid-positive 
CN and MCI participants will be randomly selected for two additional 
flortaucipir PET scans (for a total of four flortaucipir PET scans). Randomization 

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ADNI Protocol v3.1: 04-December-2020 
will be done by the ATRI Coordinating Center and the sites will be notified of the 
flortaucipir PET schedule for CN and MCI participants. 
o CN participants that come into the clinic at Year 1 for a flortaucipir PET 
scan will also complete an ongoing in-clinic visit as outlined in the SOE. 
 
If a CN participant is not due for an In-Clinic Visit or selected for extra flortaucipir 
PET scans, then a Phone Check Visit will be conducted on “off years.”  
6.3 
Procedures for Rollover Participants  
6.3.1 Initial Visit  
Initial Visit procedures include a full battery of assessments for all rollover 
participants. This includes cognitive, functional, and behavioral assessments, review 
of concurrent medications and adverse events, FDG-PET (MCI and AD groups only), 
amyloid, flortaucipir PET, and biofluid collection (blood and CSF).  The procedures 
conducted are based on current diagnosis at the Initial Visit. 
6.3.2 Ongoing In-Clinic Visits for Rollovers 
Ongoing In-Clinic Visits for MCI and AD participants will be scheduled every 12 
months (annually) from the Initial ADNI3 Visit. CN participants that are not selected 
for extra flortaucipir PET scans will be followed in-clinic every other year.  
 
Assessments collected during ongoing In-Clinic Visits for rollover participants 
follow the same rules as outlined in the ongoing In-Clinic Visits for newly enrolled 
participants (section 6.2.4).  
 
6.4 
Other Types of Study Visits (Applicable to both Newly Enrolled and 
Rollover Participants) 
6.4.1 Telephone Visits in Replacement of In-Clinic Visits 
Participants that are no longer able or willing to be seen in the clinic may opt to 
have a Telephone Visit instead of an ongoing in-clinic visit. This option is available 
for ADNI2 rollover participants upon entry into ADNI3, as well as new ADNI3 
participants that have completed their Baseline Visit. This requires signature of a 
new informed consent form acknowledging the replacement procedures and 
schedules. See SOE for details on assessments collected at a Telephone Visit in 
replacement of in-clinic visit.  
 
6.4.2 Telephone Checks  
• For CN participants, the brief Telephone Check occurs on alternating years 
for up to 5 years. The brief Telephone Check will be a shorter version of the 
Telephone visit. Study partner will still join, and similar questions will be 
asked for the participant and the study partner. See SOE for details.  
• For all participants, the purpose of the 6-month Neuropathology Telephone 
Check is to discuss current wishes with regards to brain donation, update 
participant contact information to ensure continued contact until time of 

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ADNI Protocol v3.1: 04-December-2020 
death, ensure appropriate autopsy arrangements are in place, and reiterate 
who should be contacted at the time of death. If a participant decides that he 
or she is not interested in brain donation program, they will not be called. 
See SOE for details.  
 
6.4.3 Nursing Home Placement  
Transfers to a skilled nursing home will be recorded in the clinical database as part 
of an AE. All assessments will be completed to the extent possible. If the participant 
or substitute decision-maker withdraws consent to continue in the study, verbal 
assent will be obtained to conduct an early termination visit, which will consist of as 
many evaluations normally performed at the In-Clinic Visit as allowed by the 
participant or substitute decision-maker. Nursing home placement is associated 
with increased risk for death. It should be emphasized that long term follow-up of 
subjects for the purposes of brain collection by autopsy is a very high priority. 
Therefore, transfer to a skilled nursing home is an appropriate time to again discuss 
the possibility of long-term follow-up for autopsy with the participant and the 
family. 
 
6.4.4 Early Termination Visit 
If a participant wishes to exit the study, an Early Termination Visit will be 
scheduled. This should include as many evaluations as possible that are normally 
performed at the In-Clinic Visit, including clinical evaluation, cognitive tests, MRI, 
CSF collection, amyloid and flortaucipir PET imaging. The same order of priority as 
provided in Section 6.  
 
Please contact the ATRI Coordinating Center for guidance on what specific 
procedures should be conducted at an Early Termination Visit.  It should be 
emphasized that long term follow-up of subjects for the purposes of brain collection 
by autopsy is a very high priority. Even if a participant requests an early 
termination, this is an appropriate time to again discuss the possibility of long-term 
follow-up for autopsy with the participant and the family. 
 
7.0 PERSONNEL REQUIREMENTS 
The Site Principal Investigator (PI) is responsible for the overall conduct of the 
study at the site.  The PI is to supervise project personnel and ensure that clinical 
raters 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. Additional key 
personnel may be required as specified in the Procedures Manual.  

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ADNI Protocol v3.1: 04-December-2020 
8.0 INSTRUMENTS 
8.1 
Cognitive Evaluations 
8.1.1 Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog13) 
The ADAS-Cog is an in-person examiner-administered, structured scale that 
evaluates memory (word recall, word recognition), reasoning (following 
commands), language (naming, comprehension), orientation, ideational praxis 
(placing letter in envelope) and constructional praxis (copying geometric designs). 
Ratings of spoken language, language comprehension, word finding difficulty, and 
ability to remember test instructions are also obtained19.  
8.1.2 American National Adult Reading Test (AMNART) 
The AMNART estimates premorbid verbal intelligence (VIQ) in patients with 
dementia20, 21. The test requires patients to read and correctly pronounce 50 
"irregular" words that do not follow common rules of phonography and 
orthography.   
8.1.3 Category Fluency Tests 
This is a measure of verbal fluency in which the participant is asked to generate 
examples from the semantic categories (animals) in successive one-minute trials22.  
8.1.4 Clock Drawing Test  
This task tests visuoperceptual constructional function. The Clock Drawing Test is 
effective for discriminating between participants with AD and normal elderly 
individuals23.  
8.1.5 Cogstate Brief Battery (CBB) 
The CBB is a 10-15 minute computerized cognitive battery developed by Cogstate 
Ltd. New Haven, CT, USA that measures attention, speed of information processing, 
working memory and learning. The web-based tests are accessed using a secure 
website with unique log-in credentials that do not require any protected health 
information.  
8.1.6 Logical Memory Test I and II (immediate and delayed paragraph recall) 
We will use a modified episodic memory measure from the Wechsler Memory Scale-
Revised (WMS-R) 24. In this modified version, free recall of one short story will be 
elicited immediately after it is read aloud to the participant and again after a thirty-
minute delay. 
8.1.7 Mini-Mental State Examinations (MMSE) 
The MMSE is a brief, frequently used screening instrument for Alzheimer’s disease 
drug studies25. The MMSE scale evaluates orientation, memory, attention, 
concentration, naming, repetition, comprehension, and ability to create a sentence 
and to copy two overlapping pentagons. 
8.1.8 Montreal Cognitive Assessment (MoCA) 
The Montreal Cognitive Assessment test (MoCA) is, similar to the MMSE, a brief, 30-
point cognitive assessment designed to detect participants at the MCI stage of 
cognitive dysfunction26. This instrument has been shown to have adequate 

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ADNI Protocol v3.1: 04-December-2020 
sensitivity and specificity in clinical settings to detect suspected MCI.  The 
performance of the MoCA will be followed to determine its ability to differentiate 
among the three diagnostic groups in ADNI3. 
8.1.9 Multi-Lingual Naming Test (MlNT) 
The Multilingual Naming Test (MlNT) is a test of object picture naming designed to 
include items that are comparable across English, Spanish, Mandarin and 
Hebrew27.  It replaces the Boston Naming Test in the Uniform Data Set of the NIA-
funded AD centers because the BNT contains items that are not of the same level of 
difficulty for Spanish and English speakers.   
8.1.10 Rey Auditory Verbal Learning Test (AVLT) 
The AVLT is a list-learning task, which assesses multiple cognitive parameters 
associated with learning and memory28.   
8.1.11 Trail Making Test: A and B 
These two tests progress from a numerical connect-the-dots puzzle to a more 
challenging alternation between alpha- and numerical order. Although both Parts A 
and B depend on visuomotor and perceptual-scanning skills, Part B also requires 
considerable cognitive flexibility in shifting from number to letter sets under time 
pressure29.  
8.2 
Global, Functional, and Behavioral Evaluations  
8.2.1 Modified Hachinski Ischemic Score 
The Modified Hachinski Ischemic Score is a brief questionnaire that incorporates 
questions about medical history, cognitive symptoms and features of stroke, as 
reported by a study partner and informed by the neurological examination and 
neuroimaging studies30. 
8.2.2 Cognitive Change Index (CCI) 
The Cognitive Change Index is a 20 item self-report and study partner (informant)-
report instrument. Items assess primarily memory with some coverage of executive 
and language changes. The CCI was first implemented in ADNI231, 32. A CCI-Memory 
Total Score is used to define the SMC group and information the participant and the 
study partner (informant) can be combined to yield a total score for memory or overall 
cognition.  
8.2.3 Clinical Dementia Rating Scale (CDR) 
The CDR describes five degrees of impairment in performance on each of 6 
categories of cognitive functioning including memory, orientation, judgment and 
problem solving, community affairs, home and hobbies, and personal care33, 34. 
Where a full CDR interview is not possible, the abbreviated CDR can be utilized. 
8.2.4 Activities of Daily Living / Functional Assessment Questionnaire (FAQ) 
Based on an interview with a caregiver or qualified partner, a participant is rated on 
his/her ability to carry out ten complex activities of daily living35.  

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8.2.5 Financial Capacity Instrument – Short Form (FCI-SF) 
The FCI-SF is a brief (15 minutes) performance measure of everyday financial skills 
that uses both performance and time to completion variables36. In prior research the 
FCI-SF performance and timing variables have discriminated between amyloid-
positive and negative CN, as well as CN vs MCI vs mild AD groups. 
8.2.6 Measurement of Everyday Cognition (ECog) 
This instrument assesses for very mild functional impairment as may occur in MCI. 
The ECog is an informant-rated questionnaire, but participants will be asked to 
complete a self-reported version of the same questionnaire37. Previous research on 
this instrument indicates that ECog correlates well with established measures of 
functional status and global cognition but only weakly with age and education.  
8.2.7 Neuropsychiatric Inventory (NPI) 
The NPI is a well-validated, reliable, multi-item instrument to assess 
psychopathology in AD based on an interview with a caregiver or qualified study 
partner (defined in this study as having direct contact 10 hours/week) 38, 39. It 
evaluates both the frequency and severity of: delusions, hallucinations, dysphoria, 
anxiety, agitation/aggression, euphoria, disinhibition irritability, lability, apathy, 
and aberrant motor behavior.  
8.2.8 Neuropsychiatric Inventory Q (NPI-Q)  
The NPI-Q was designed as a version of the NPI that could be administered more 
quickly and over the telephone40.  
8.2.9 Brain Health Registry (BHR) 
The BHR contains a University of California at San Francisco IRB-approved online 
battery of tests including self-report questions, neuropsychological tests, and 
assessments by study partners. BHR may be used for in-clinic assessment and at-
home assessment for those subjects and their study partners willing to participate. 
8.2.10 Geriatric Depression Scale (GDS) Short Form 
The GDS Short Form is a self-report scale designed to screen for symptoms of 
depression in the elderly41.  
9.0 PROCEDURES 
9.1 
Assessments 
9.1.1 Physical and Neurological Examination 
A medically qualified professional will perform a brief physical examination that 
consists of a review of the major body systems. Vital signs will include height (at 
screening only), weight, systolic and diastolic blood pressure, pulse, temperature, 
and respiration. Neurological examination will include an assessment of cranial 
nerves, strength, coordination, reflexes, sensation, tremor, and gait. 
9.1.2 Clinical Laboratory Evaluations 
A central laboratory will analyze all routine laboratory samples. Lab reports will be 
reviewed, signed and dated by the Site PI (or a medically-qualified individual 

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ADNI Protocol v3.1: 04-December-2020 
delegated by the PI).  Site clinicians will indicate whether abnormal lab results are 
clinically significant or not, with additional review by ATRI Medical Monitoring 
group.  Those results that are deemed clinically significant may need to be repeated 
and follow up with the participant’s treating physicians will be recommended by 
study personnel.   
9.2 
Biofluids    
The Procedures Manual will provide detailed instructions for the collection, 
processing and shipment of all biofluid samples. Samples will be collected to 
accommodate the assay of the broadest range of the best antecedent 
biomarkers/analytes. Fasting overnight (minimum 6 hours) is required for plasma, 
serum and CSF sample collection. Only water is permitted (no food but water is 
encouraged) until blood draws and the LP procedure are completed. ADNI3 will 
continue to measure Aβ1-42, total tau, and phosphorylated tau181 in CSF samples. 
Methods used for blood draw will continue as in ADNI2 for longitudinal biomarker 
and genetic data with the addition of PBMC collection.   
9.2.1 Baseline Blood Samples for PBMC and Cell Line Banking 
Whole blood samples will be collected at baseline for all participants and used for 
extraction of peripheral blood mononuclear cells (PBMCs). For newly enrolled 
participants, an additional blood sample will also be used to derive immortalized 
cell lines. Whole blood will be collected and shipped overnight under ambient 
conditions to the National Cell Repository for Alzheimer’s Disease (NCRAD). It is 
important to ship samples drawn for PBMCs the same day they are drawn and that 
they are received at NCRAD the next day; any delay will affect the viability of the 
cells. The Genetics Core will request a re-sampling, if the condition of the sample on 
arrival prevents processing. PBMC collection is being added in ADNI3 as they can be 
used in a variety of ways. 
 
PBMC has become an important source for the development of induced pluripotent 
stem cells (iPSCs) and also can support other functional genomic studies.  Some cells 
may be derived into new materials. Processing may be performed at other 
laboratories in which case aliquots of the derived materials will be returned to 
NCRAD for distribution to NIA approved investigators.  
9.2.2 Longitudinal Blood Samples for Genomic Analysis and Related Bioassays 
At baseline and follow-up visits, blood will be collected for extraction of DNA and 
RNA at NCRAD and to provide plasma and serum for the Biomarker Core (see 
section 9.2.4 below). Whole blood is processed at each site to separate plasma, 
serum, buffy coat (white blood cells), and red blood cell (RBC) components. The 
buffy coat and RBC components are aliquoted at the sites and shipped overnight 
under ambient conditions to NCRAD where DNA will be extracted, aliquoted and 
banked. RBCs will be banked for specialized assays requiring RBCs. RNA samples 
will also be collected at each visit using Paxgene kits supplied by the ATRI 
Coordinating Center. Paxgene samples will be shipped overnight under ambient 
conditions to NCRAD and RNA will be extracted, aliquoted and banked. The 
longitudinal genomic sample collection will be used to analyze changes in gene 

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ADNI Protocol v3.1: 04-December-2020 
transcription (RNA analysis) and epigenetic processes (e.g., DNA methylation, 
histone modification, and chromatin remodeling) and to enable future genomic 
analyses. 
9.2.3 Genetic and Genomic Analyses 
APOE and genome-wide genotyping will be completed for newly enrolled 
participants. For participants whose samples have not already undergone whole 
genome sequencing, resources will be sought during ADNI3 to perform these 
analyses. 
9.2.4 Plasma and Serum Collection for Biomarkers   
Plasma, serum, and buffy coat will be collected at Baseline from newly enrolled 
participants, and at the initial ADNI3 visit from rollover participants, and then 
ongoing during follow-up at In-Clinic Visits for all participants. All samples will be 
collected in the morning before breakfast and after an overnight fast (minimum 6 
hour fast). Plasma and serum must be prepared at the site, frozen and then sent to 
the Biomarker Core at the University of Pennsylvania (UPENN). As above, buffy coat 
and red blood cells will be extracted from blood at the site and shipped overnight 
under ambient conditions to NCRAD.    
9.2.5 CSF Collection for Biomarkers 
Both newly enrolled and rollover participants, will have CSF samples collected at 
Baseline and again every two years through the course of the ADNI3 study. All 
samples will be collected in the morning before breakfast and after an overnight fast 
(minimum 6 hour fast).  
 
Approximately, 2 ml of CSF should be sent to the clinical laboratory of the Site PI for 
routine cell count, protein and glucose analyses. The majority of the CSF, at least 20 
ml should be immediately frozen and sent frozen on dry ice directly to the UPENN 
ADNI Biomarker Fluid Bank.  
 
Each study participant or a person designated to speak on their behalf will be 
contacted by phone 24 hours after the lumbar puncture to confirm the participant’s 
well being and to query about any new adverse events.  
 
At the discretion of the Site PI (or Site Clinician), a coagulation panel (PT/PTT) may 
be obtained to rule out a clotting disorder. Also, per PI (or Site Clinician) discretion, 
anti-platelet agents (e.g., aspirin) may be discontinued for a period of time before 
and after the LP. 
9.3 
Magnetic Resonance Imaging (MRI) 
Participants will have a brain MRI scan as part of the screening evaluation, as well as 
at each ongoing in-clinic visit.  
9.3.1 Site Qualification 
Each site must be qualified for MRI.  The ADNI3 MRI protocol differs from that used 
in ADNI2 in that several of the sequences will be modernized. Therefore, all 
scanners will have to be qualified with the ADNI3 protocol MRI protocol.  

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The procedure for MRI site qualification will consist of a test imaging session on a 
human volunteer and/or phantom.  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.   
9.3.2 Data Acquisition 
All participants will be scanned on a 3T MRI System with a protocol consisting of 
several sequences that conform to FDA safety standards. The MRI protocol includes: 
a scout, structural T1-weighted MRI, FLAIR, T2 GRE, diffusion tensor imaging, ASL 
perfusion MRI, and task free resting state functional MRI. The total scan time will be 
approximately one hour but may be longer depending on technical factors. The total 
scan time will not exceed 2 hours. If the subject becomes uncomfortable, they can 
ask to be removed from the scanner at any time. 
 
Each MRI scan of brain will be performed at Screening (for new participants), or 
Initial Visit (for rollover participants) and then again annually (or at every In-Clinic 
Visit).   
9.3.3 Clinical Read of MRIs 
The research site is responsible to obtain a read from a local radiologist for each 
MRI completed in the ADNI Protocol.   
9.3.4 Data Management and Quality Control 
Images are uploaded by site users to the Laboratory of Neuroimaging (LONI) at the 
University of Southern California (USC). 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. 
9.4 
PET scanning: FDG, Amyloid (Florbetapir or Florbetaben), and 
Flortaucipir PET Imaging 
Each scan must be done on a separate day at least 12 hours after a prior scan.  
9.4.1 Site Qualification 
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. Qualification of the PET 

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ADNI Protocol v3.1: 04-December-2020 
scanner applies to FDG, florbetapir, florbetaben, and flortaucipir PET scan imaging 
protocols; a scanner requires qualification only once for all tracer studies. 
Qualification will employ the same methods utilized for site qualification in ADNI2.  
 
Sites will use a Hoffman brain phantom and a technical manual for the data 
acquisition using all PET tracers in the ADNI3 protocol. 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.  
 
9.4.2 Data Acquisition for FDG-PET 
MCI and AD participants will undergo a single FDG scan at Initial/Baseline visit; CN 
participants do not have an FDG-PET scan. 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. The procedure may take as long as 2 hours, from participant check-in at the 
scanning facility to injection of approximately 5 mCi of FDG through an intravenous 
catheter, followed by 30-minute uptake period until 30-minute image acquisition. 
9.4.3 Data Acquisition for Amyloid PET Scans with Florbetapir or Florbetaben  
All ADNI rollover participants will continue to complete amyloid PET scans every 
two years with florbetapir. A proportion of newly enrolled participants will have 
longitudinal florbetaben PET imaging instead of florbetapir.  Any subject who has 
their first scan in ADNI with florbetapir or florbetaben will have longitudinal scans 
done with the same ligand. Scans must be completed within 2 weeks before or 2 
weeks after the in-clinic assessments at Initial/Baseline visit and at two-year 
intervals. 
 
This procedure may take as long as 2 hours. Florbetapir scanning entails 10mCi 
injection of tracer through an intravenous line and a 50-minute uptake until 20-
minute image acquisition begins. Florbetaben imaging has a longer uptake period 
between injection and image acquisition, starting 90 minutes after 8mCi injection. 
Image acquisition occurs over a 20-minute period.  
 
9.4.4 Amyloid PET Early Frames Data Acquisition (optional) 
Participants at select sites will have the option to participate in obtaining early 
amyloid PET sequences. Participants that choose to participate and consent to the 
additional imaging, will be positioned in the scanner identically as they are 
positioned for the regular amyloid PET scan and data will be collected for 20 
minutes beginning immediately with the injection of the amyloid tracer. Participants 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
will continue with the same amyloid tracer based on participant classification; new 
or rollover, which is defined in above Section 9.4.3. Refer to the ADNI PET technical 
manual for procedural details.  
 
Data will be collected on approximately 100 participants distributed across the 
diagnoses of CN/MCI/AD once at their next annually scheduled amyloid PET scan. 
The identical procedure will be repeated again in two years following initial early 
frames PET scan.   
 
Sites are selected based on PET scanner and imaging center capabilities. Eligible 
sites must be collecting florbetapir and/or florbetaben images on a scanner capable 
of rapid dynamic images (peak 4 per min or list mode) for a total of 16 frames. Also, 
the site must have the capacity for injection with simultaneous scan start (typically 
requires two technologists).  
 
9.4.5 Data Acquisition for Flortaucipir PET  
AD participants will receive flortaucipir PET scans at each in-clinic visit for a total of 
three flortaucipir PET scans; AD participants are evaluated at Initial/Baseline, Year 
1 and Year 2. CN, MCI and Converter participants will receive flortaucipir PET scans 
at the Initial/Baseline and Year 4 visit. Based on the likelihood that amyloid-
negative participants will show slower rates of tau deposition, 80% of amyloid 
positive and 20% of amyloid negative CN and MCI participants will be randomly 
selected to receive two additional annual flortaucipir PET scans, for a total of four 
flortaucipir PET scans. Randomization will be done by the Clinical Core and the site 
will be notified of the flortaucipir PET schedule as soon as possible. The site will 
then notify the participant of the proposed schedule. Per schedule, normal controls 
(CN) are seen in-clinic every other year, therefore, if they are selected to complete 
four flortaucipir PET scans, it will require them to come into the clinic on Year 1 for 
flortaucipir PET imaging.  
Flortaucipir PET Standard Protocol  
ADNI3 will utilize flortaucipir PET for quantification of phosphorylated tau burden. 
The IND for this radioligand will be held by the USC ATRI.  
 
The data acquisition protocol for tau PET with flortaucipir will entail injection 
through an intravenous line of approximately 10 mCi of the tracer. Participants will 
be scanned beginning at 75 minutes post tracer injection, for 30 minutes. 
9.4.6 Data Management and Quality Control 
Images are uploaded by site users to the Laboratory of Neuroimaging (LONI) at the 
University of Southern California. Data are de-identified as part of the upload 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 also to standardize the images from the different sites (and hence the 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
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.  
9.5 
Neuropathology 
9.5.1 Discussing Autopsy and Obtaining Provisional Consent  
Participants should be contacted every six months to discuss autopsy with the goal 
of brain donation. At minimum, site clinicians will discuss brain donation at every 
visit (including In-Clinic Visits, Telephone Visits that have replaced in-clinic visits, 
and Phone Checks) unless the participant indicates refusal.  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 MCI and AD; 
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 not be offered where the participant has refused autopsy.  
 
It should be emphasized that an excellent time to revisit this issue is if and when a 
participant no longer wishes to participate in ADNI or experiences cognitive or 
physical decline to the extent that they are no longer able to participate. A 
participant may be retained in the ADNI study for “brain donation only.”  Every 
effort should be made to reenroll ADNI2 participants who had consented to brain 
donation or were undecided about brain donation into the ADNI3 study with “brain 
donation only” status. “Brain donation only” participants may also be reenrolled 
into subsequent ADNI studies upon the completion of ADNI3. 
 
The decision to participate in brain autopsy is entirely 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 ADNI Neuropathology Core makes 
available an Autopsy Brochure, which dispels some of the common myths and 
concerns regarding the autopsy. We encourage clinicians to use this tool when 
discussing autopsy with participants. Once the neuropathologic assessment is 
complete, a report describing the findings will be available to consenting members 
of the participant’s family.  
 
Although ADNI does not directly support the performance of complete autopsies, a 
complete autopsy may still be arranged locally at the discretion of the 
participant/family, if that service is available and can accommodate the ADNI NPC 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
protocol for brain donation. Complete autopsy and even organ and/or body 
donation to a separate organization need not be contraindications for brain 
donation to ADNI.  
 
Regular contact (e.g., at each In-Clinic Visit, Neuropathology phone checks every 6 
months) with individuals who have provided provisional consent will help ensure 
that autopsy arrangements are made in advance, which aids successful brain 
donation. This includes In-Clinic Visits and, to the extent possible, phone checks 
every 6 months after completion of the ADNI study and until the death of the 
participant. Periodically reviewing the procedures that should be followed at the 
time of death and reiterating the participant’s wish for donation to family members 
will increase the likelihood of a completed brain donation at time of death.  
9.5.2 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 ADNI Neuropathology Core has 
developed autopsy notification materials such as wallet cards and letters to primary 
care physicians and nursing homes to 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. As ADNI is a 
multi-center study involving many sites across the US and Canada, sites must follow 
their own state and local laws regarding autopsy consent procedures. 
 
Sites will emphasize to ADNI participants and caregivers the procedure for notifying 
the ADNI site at the time of death so that the autopsy protocol may be initiated. 
Wallet cards should be given to all participants and their family members that list 
contact information for the person they should notify at the time of death. 
9.5.3 At the Time of Expiration  
Sites will follow standard autopsy procedures as outlined in the ADNI 
Neuropathology Manual upon notification of the death of an ADNI participant. Sites 
with co-enrolled participants and established neuropathology programs may 
conduct their own neuropathologic examination, as long as the ADNI 
Neuropathology protocol can also be accommodated. Brain tissue should be 
provided to the ADNI Neuropathology Core within 3-6 months of autopsy.  After 
completion of the ADNI neuropathologic examination, a copy of the resulting report 
will be provided to the site PI so that the participant’s family members will have the 
option to learn what brain illnesses (if any) were identified. 
9.5.4 Infectious Disease Policy for Brain Donation  
If a participant expires with a potentially transmissible illness of high concern 
(including but not limited to COVID-19, Creutzfeldt-Jakob Disease [CJD], HIV, 
Hepatitis C, tuberculosis, MRSA or VRE sepsis/bacteremia) the ADNI site is advised 
to consult the ADNI Neuropathology Manual and contact the ADNI Neuropathology 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
Core for guidance regarding brain donation. Local restrictions on brain autopsy may 
differ from provider to provider. Further, policies governing the appropriate 
handling, treatment, shipment, and acceptance of potentially infectious brain 
specimens into the ADNI NPC laboratory are subject to change over time.  
 
9.6 
Global Unique Identifiers (GUIDs) 
ADNI3 will be incorporating Global Unique Identifiers (GUIDs) for all ADNI 
participants.  Each GUID unambiguously identifies a research study participant 
across different research studies without exposing protected health information 
(PHI).  When investigators pool data together from multiple studies, GUIDs provide 
the means to detect participants who participate in more than one study. 
 
ADNI sites will download a GUID generator to convert participant PHI (e.g., birth 
name, birth date, place of birth) into irreversible hash codes.  These hash codes will 
be sent to the GUID authority operated by LONI, which will assign GUIDs and store 
them along with ADNI participant information in the clinical database. 
10.0 FITBIR 
For some ADNI3 participants, the tau PET scans (flortaucipir) will be funded by the 
Department of Defense. Therefore, for those participants having flortaucipir scans 
and have consented, will have all their study data uploaded to the Federal 
Interagency Traumatic Brain Injury Research (FITBIR) Informatics System. FITBIR 
Informatics System is a collaborative effort involving the NIH Institutes and Centers 
(ICs) and the US Army Medical Research and Materiel Command (USAMRMC) to 
develop a biomedical informatics system and data repository for Traumatic Brain 
Injury (TBI) research. The purpose is to promote collaboration, accelerate research, 
and advance knowledge on the characterization, prevention, diagnosis and 
treatment of traumatic brain injury (TBI). Data submitted to the FITBIR will be de-
identified such that the identities of participants cannot be readily ascertained or 
otherwise associated with the data through the generation of Global 
Unique Identifiers (GUIDs).  
 
While this is not a Department of Defense (DOD) funded study, the DOD has funded 
a portion of the flortaucipir PET scans in ADNI3 participants, and in part explains 
the collaboration with FITBR. The DOD funds will cover 150 initial flortaucipir scans 
and up to 150 longitudinal flortaucipir scans.  
11.0 POTENTIAL RISKS 
11.1 FDG-PET, Florbetapir, Florbetaben, and Flortaucipir PET 
The primary risk related to PET is that of radiation exposure associated with the 
injected radiotracers and accompanying CT. 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).   

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
 
The early frames study does not entail additional radiation exposure from the 
injected radiopharmaceuticals, but it does require an additional CT scan with an 
effective dose of 0.4 mSv. Assuming that a participant has all of the PET scans 
described in this protocol, and undergoes the early frames protocol: 
•  An individual undergoing FDG, florbetapir, and flortaucipir would have an 
annual effective dose exposure of 20.83 mSv over a single year of the study.  
•  An individual undergoing FDG, florbetaben, and flortaucipir would have an 
annual effective dose of 19.42 mSv over a single year of the study.  
 
The table below shows effective doses for participants who do not enroll in the early 
frames study with a consequential 0.4 mSv lower dose. All of these doses are 
roughly equivalent to 7 years of background radiation. The organ that receives the 
maximum exposure is the gallbladder, which receives an annual dose of 6.949 rem 
for the combination including a florbetapir study, slightly less for florbetaben.  
 
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 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. No PET studies will be 
performed on pregnant or potentially pregnant women, as the protocol requires 
that female participants are postmenopausal. 
 
Details on the clinical information to date regarding flortaucipir exposure and risks 
will be provided in the informed consent form (ICF). More information about the 
known and expected benefits, risks, and reasonably anticipated AEs of flortaucipir 
may be found in the Investigator’s Brochure (IB).  
 
 
microSv/ 
MBq 
mSv/ 
study 
mSv/ Scan 
with CT 
mrem/ Scan 
with CT 
FDG  
19 
3.5 
3.9 
390 
Florbetapir 
19 
7.03 
7.43 
743 
Florbetaben 
19 
5.62 
6.02 
602 
Flortaucipir 
24 
8.70 
9.10 
910 
 
Organ dosimetry for each of these scenarios is provided below.  
 
 
 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
Organ dosimetry for a participant receiving 5 mCi FDG, 10 mCi florbetapir and 
10 mCi flortaucipir 
Organ 
mrad/        
5 mCi FDG 
mrad/        
10 mCi 
florbetapir 
mrad/      
10 mCi    
flortaucipir 
Total 
dose 
Adrenals 
240 
519 
526 
1284 
Brain 
350 
370 
311 
1031 
Breasts 
170 
222 
264 
656 
Gallbladder wall 
245 
5296 
1407 
6949 
Lower Large Intestine Wall 
255 
1037 
1289 
2581 
Small Intestine 
235 
2444 
3130 
5809 
Stomach 
205 
444 
467 
1116 
Upper Large Intestine wall 
230 
2741 
3537 
6508 
Heart wall 
1100 
481 
1100 
2681 
Kidneys 
370 
519 
1478 
2366 
Liver 
290 
2370 
2119 
4779 
Lungs 
320 
333 
1256 
1909 
Muscle 
195 
333 
333 
861 
Ovaries 
265 
667 
767 
1698 
Pancreas 
480 
519 
533 
1532 
Red marrow 
235 
519 
374 
1128 
Osteogenic Cells 
205 
1037 
426 
1668 
Skin 
150 
222 
221 
593 
Spleen 
700 
333 
378 
1411 
Testes 
205 
259 
257 
721 
Thymus 
220 
259 
318 
797 
Thyroid 
195 
259 
249 
703 
Urinary bladder wall 
1600 
1000 
1393 
3993 
Uterus 
310 
593 
674 
1577 
Total Body 
215 
444 
441 
1100 
 
 
Organ dosimetry for a participant receiving 5 mCi FDG, 8 mCi florbetaben and 
10 mCi flortaucipir 
Organ 
mrad/         
5 mCi FDG 
mrad/          
8 mCi 
florbetaben 
mrad/         
10 mCi      
flortaucipir 
Total 
dose 
Adrenals 
240 
385 
526 
1151 
Brain 
350 
385 
311 
1046 
Breasts 
170 
207 
264 
641 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
Gallbladder wall 
245 
4059 
1407 
5712 
Lower Large Intestine 
Wall 
255 
1037 
1289 
2581 
Small Intestine 
235 
919 
3130 
4283 
Stomach 
205 
356 
467 
1027 
Upper Large Intestine 
wall 
230 
1126 
3537 
4893 
Heart wall 
1100 
415 
1100 
2615 
Kidneys 
370 
711 
1478 
2559 
Liver 
290 
1156 
2119 
3564 
Lungs 
320 
444 
1256 
2020 
Muscle 
195 
296 
333 
824 
Ovaries 
265 
474 
767 
1506 
Pancreas 
480 
415 
533 
1428 
Red marrow 
235 
356 
374 
965 
Osteogenic Cells 
205 
444 
426 
1075 
Skin 
150 
207 
221 
579 
Spleen 
700 
296 
378 
1374 
Testes 
205 
267 
257 
729 
Thymus 
220 
267 
318 
804 
Thyroid 
195 
237 
249 
681 
Urinary bladder wall 
1600 
2074 
1393 
5067 
Uterus 
310 
474 
674 
1458 
Total Body 
215 
326 
441 
982 
11.2 MRI  
There are no proven biologic risks associated with MRI scanning. All participants 
will be rigorously screened by MR personnel to be certain that they do not have any 
medical contraindications for MRI, which include metallic foreign bodies in the 
brain or eye or cardiac pacemakers. However, there is a slight risk that someone will 
accidently bring metal into the MRI scanner room, which might be pulled into the 
MRI magnet and injure the participant. There is a slight risk of anxiety due to 
claustrophobia and noise. Any participant who experiences anxiety when placed 
into the MR scanner will be removed from the scanner, offered reassurance by the 
MR tech doing the scan, and offered the option of continuing or terminating the 
study.  There will be no attempt to coerce participants to complete exams that they 
are uncomfortable with.  Use of anxiolytic agents for completion of MRI scans is at 
the discretion of site clinicians, in consultation with the Project Director. 
11.3 Lumbar Puncture  
Lumbar puncture may be associated with pain during the performance of the 
procedure. This is usually temporary and confined to the lower back. Headache may 

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ADNI Protocol v3.1: 04-December-2020 
occur in about 5% of elderly people who undergo lumbar puncture. Less commonly, 
in about 1-4% of participants, a persistent low-pressure headache may develop, 
probably due to leakage of CSF. Lower rates of post-LP headache have been noted in 
elderly patients, and when atraumatic (Sprotte) needles are used. If a post-LP 
headache persists it may need additional treatment, e.g. additional fluids and 
analgesics. Uncommonly a blood patch (injection of some of the participant’s blood 
to patch the CSF leak) may be needed. Potential but rare risks of lumbar puncture 
include infection, damage to nerves in the back, and bleeding into the CSF space. The 
risk of these is much less than 1%. In an effort to mitigate these risks, an 
experienced clinician must perform the LP. 
11.4 Blood Draw 
The risks of blood draw include pain from the needle, bruising or infection at the 
site of venipuncture, or fainting as a response to blood draw. 
11.5 Genetic Risks 
NIH policy requires that de-identified genomic data is uploaded to a secure 
government sponsored health research database for broad sharing with approved 
investigators (see section 12.5.3 below).  This information will be de-identified and 
will not contain any traditional identifiers. There is a slight risk that there could be a 
breach in the security of this database system resulting in the unauthorized access 
to de-identified information.  Safeguards at the government health database are in 
place to minimize this risk. 
 
Another possible risk from participation in this study involves a loss of privacy as a 
result of providing genetic material (nucleic acids) for research.  Although genetic 
information is unique to each individual it is also shared with their children, 
parents, brothers, sisters, other blood relatives and other members of their ethnic 
group.  Although prohibited by NIH and ADNI policy, it may be possible that genetic 
information could be used to identify study participants or relatives. Methods to 
allow someone to link the genetic or medical information back to the study 
participant could be developed in the future but authorized users agree to not 
attempt to identify any study participants. 
11.6 Loss of Privacy 
This project collects a great deal of information about participant health status.  
Individuals 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 subject 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 

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ADNI Protocol v3.1: 04-December-2020 
unlikely, but possible occurrence, and is a risk of this study (and almost all other 
medical research studies).  
 
There is also a risk that MRI scans could be re-identified using facial recognition 
technology. Prior to receiving shared data, all investigators must agree that they will 
not attempt to identify any study participant.   
 
12.0 ADVERSE EVENTS 
All participants will be evaluated for adverse events at each clinical visit.  
12.1 Definition of an Adverse Event (AE) 
An Adverse Event is any adverse change from the participant’s baseline condition 
including clinical or laboratory tests, or abnormalities that occur during the course 
of the study after consent. 
12.2 Following up and reporting on Adverse Events  
The investigator is obliged to follow participants with AE’s 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 Events 
will be treated and followed according to established medical practice.  All pertinent 
information will be entered into the eCRF.  
12.3 Definition of a Serious Adverse Event (SAE) 
Serious Adverse Events include any event that is fatal, life threatening, significantly 
or persistently disabling or incapacitating, results in hospitalization, prolongs a 
hospital stay, or is associated with a congenital abnormality or birth defect.  In 
addition, any experience which the investigator regards as serious, or which would 
suggest significant hazard, contraindication, side effect, or precaution associated 
with participation in the study should be reported as a Serious Adverse Event. 
Medical and scientific judgment should be exercised in deciding whether reporting a 
serious adverse event is appropriate. All Serious Adverse Events (SAEs) will be 
reported to the independent Data Safety Monitoring Board (DSMB).   
12.4 Reporting Serious Adverse Events (SAEs) 
Any such experience due to any cause, which occurs during the course of the 
investigation or within 30 days of the last study visit, must be reported to the ATRI 
Coordinating Center within 24 hours after learning of the event.  This in turn will 
trigger an alert to the appropriate ATRI Coordinating Center personnel, which will 
lead to the initiation of the creation of a report. A notification will be distributed to 
all participating sites, the study’s DSMB and the NIA.  Sites will report SAEs based on 
local IRB requirements.   
 
A serious adverse event (SAE) reported to have occurred within 24 hours of amyloid 
or tau PET tracer administration (florbetapir, florbetaben, or flortaucipir) will be 
reported, regardless of the investigator’s opinion of causation. Thereafter, sites must 

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ADNI Protocol v3.1: 04-December-2020 
continue to report any serious or life-threatening adverse event whether or not it is 
related to study procedures. A subset of those SAEs may then be reported to Avid 
and Life Molecular Imaging (LMI), formerly Piramal, for events related to 
florbetapir, flortaucipir and florbetaben, respectively.  
12.5 Data and Safety Monitoring Board   
The ATRI Coordinating Center currently has an active DSMB that reviews the safety 
of all participants enrolled in trials on an ongoing basis. The DSMB will review 
Serious Adverse Event reports on a quarterly basis. 
12.6 Research Monitor    
The Research Monitor will provide an independent evaluation of serious adverse 
events and unanticipated problems involving risk to subjects or others, to the 
principal investigator. The Research Monitor has the authority to recommend 
stopping research study in progress, and take whatever steps are necessary to 
protect the safety and well-being of research volunteers. In coordination with the 
ATRI Clinical Core, all unanticipated problems involving risk to subjects or others, 
serious adverse events related to participation in the study, and subject deaths 
related to participation in the study should be promptly reported by phone (301-
619-2165), by email (hsrrb@det.amedd.army.mil), or by facsimile (301-619-7803) 
to the USAMRMC, Office of Research Protections, Human Research Protection Office. 
A complete written report will follow the initial notification. In addition to the 
methods above, the complete report will be sent to the U.S. Army Medical Research 
and Materiel Command, ATTN: MCMR-ZB-PH, 504 Scott Street, Fort Detrick, 
Maryland 21702-5012. 
13.0 ETHICS AND REGULATORY CONSIDERATIONS 
13.1 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 task(s) in accordance with GCP.   
 
No study document shall be destroyed without prior written agreement between 
the ATRI Coordinating Center and the investigator.  Should the investigator 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.  

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ADNI Protocol v3.1: 04-December-2020 
13.2 Institutional Review Boards (IRB) / Research Ethics Boards (REB) 
Institutional Review Boards and Research Ethics Boards must be constituted and 
their authority delegated through the institution's normal process of governance 
according to applicable State and Federal requirements for each participating 
location. Each participating institution must provide for the review and approval of 
this protocol and the associated informed consent documents and recruitment 
material by an appropriate IRB registered with the Office for Human Research 
Protections (OHRP). Any amendments to the protocol or consent materials must 
also be approved before they are placed into use. In the United States, only 
institutions holding a current US Federal-wide Assurance (FWA) issued by OHRP 
may participate. Refer to: http://www.hhs.gov/ohrp/assurances/. 
 
The Site PI must obtain approval from the IRB for all subsequent protocol 
amendments and, when warranted, changes to the informed consent document. 
Protocol and informed consent form amendments can be made only with the prior 
approval of the Coordinating Center.  The Site PI may not implement any protocol 
deviation without prior notification to the ATRI Coordinating Center and prior 
review and documented approval of the IRB, except where necessary to eliminate an 
immediate hazard to study participants, or when change(s) involve only logistical or 
administrative aspects of the trial (ICH 4.5.4). The investigator shall notify the IRB of 
deviations from the protocol or serious adverse events occurring at the site, in 
accordance with local procedures. 
13.3 Informed Consent and HIPAA Compliance 
Informed consent will be obtained in accordance with US 21 CFR 50.25, the Tri-
Council Policy Statement: Ethical Conduct of Research Involving Humans and the 
Health Canada and ICH Good Clinical Practice.  Applicable HIPAA privacy 
notifications will be implemented and HIPAA authorizations signed before protocol 
procedures are carried out. Information should be given in both oral and written 
form as deemed appropriate by the site’s IRB. 
 
Prior to the beginning of the trial, the investigator should have the IRB’s approval of 
both, the informed consent form and any other information to be provided to 
participants. The ATRI Regulatory Affairs department, at the ATRI Coordinating 
Center, will collect, QC, and maintain the IRB’s approval documents.  Consent forms 
must be in a language fully comprehensible to the prospective participants and/or 
their authorized representatives and study partners. Participants, their relatives, 
guardians, or authorized representatives and study partners will be given ample 
opportunity to inquire about the details of the study. Prior to a participation in the 
trial, the informed consent form should be signed and personally dated by the 
participant or by the participant’s legally acceptable representative, and by site 
personnel who conducted the informed consent discussion.  Participants should be 
provided a copy of the signed ICF. 
 
The informed consent will not only cover consent for the trial itself, but also for the 
genetic samples/data/storage, biomarker samples/data/storage, and imaging 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
scans/data/storage to be shared with study collaborators and co-investigators.  
Consent forms will specify that genetic and biomarker samples are for research 
purposes only; the tests on the genetic and biomarker samples are not diagnostic in 
nature and participants will never receive results.  
 
It is the general policy of this study not to reveal research results to participants. 
However, if information is obtained that is viewed by the physician caring for the 
participant to be clinically relevant, such information can be disclosed. The ATRI 
Coordinating Center must be notified in these instances. Similarly, MRI scan findings 
of clinical significance, determined by the site radiologist, may be shared with 
participants.  
13.4 Data Collection and Monitoring   
The Site PI or designee will record all 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. In some instances, 
no prior written or electronic record of data may exist, and data recorded directly 
on the eCRF is considered source data.  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 for verifying the integrity of the data and 
acknowledge as such by signature. 
 
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 documentation for the reason for change.  
 
Completed eCRFs will be submitted according to the ATRI Coordinating Center 
instructions and reviewed by the ATRI Coordinating Center to determine their 
acceptability.  If necessary, data correction requests will be generated for resolution 
by the study site.  
 
The clinical monitor is responsible for inspecting the electronic case report forms 
and source documentation at regular intervals 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 and GCP guidelines to ensure protocol 
adherence, quality of data, drug 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. 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 during certain visits. 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
13.5 Procedures to Maintain Participant and Data Confidentiality 
Patient confidentiality is strictly held in trust by the participating investigators and 
research staff.  This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants.  
 
All data will be transmitted securely via the Internet to ATRI at USC. Access is 
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. 
Users are logged out of the system after a period of inactivity. All communication to 
and from the data system is encrypted. Data transmission will occur through a 
secure internet connection-https (hypertext transfer protocol secured) at 128-bit 
SSL.  
 
The study protocol, documentation, data and all other information generated will be 
held in strict confidence.  No information concerning the study or the data will be 
released to any unauthorized third party, without prior written approval of the 
sponsoring institution. Authorized representatives of the sponsoring institution may 
inspect all documents and records required to be maintained by the Site PI including 
but not limited to, medical records (office, clinic or hospital) and pharmacy records 
for the participants in this study.  The clinical 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, PTID) 
to maintain confidentiality.  All records will be kept in a locked file cabinet.  All 
computer entry and networking programs will be done using PTIDs only. 
Information will not be released without written permission of the participant, 
except as necessary for monitoring by IRB, the FDA, the NIA, and the OHRP. 
 
Information about 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 protected health information (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 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 his/her 
IRB, is responsible for ensuring that all applicable HIPAA regulations and State laws 
are met. 
 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
To further protect the privacy of study participants, a Certificate of Confidentiality 
will be obtained from the NIH. This certificate protects identifiable research 
information from forced disclosure. It allows the investigator 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. 
13.5.1 Clinical data - ATRI / LONI  
In order to provide the clinical data from this project to ADNI investigators, 
Pharmaceutical Industry and the public through LONI in an anonymized manner 
(free of any identifying information such as name, address, or phone number), this 
will be linked to the imaging database at LONI. The database will be frequently 
updated, and all clinical data acquired by the ATRI Coordinating Center will be 
provided to LONI in real-time.  No personal identifying data will be in this database. 
All the personal identifying data will be kept in a secure location at the clinic where 
the participant is seen. 
 
All study data is stored and maintained on servers hosted on Amazon Web Services 
under an Enterprise Agreement with USC. Study data is not stored at USC facilities. 
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.  
 
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 subjects will be assigned a code, and this will be used for all data storage and 
communication between sites. PHI will be recorded and kept under the “need to 
know” principle (i.e., only when necessary). 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 sites. The ADNI Coordinating Center 
does not have access to these keys. At the sites, a participant's PHI is not located on 
any data collection documents or on any audio recording, nor is it stored with data. 
Hard copies of data are stored in locked file cabinets at the study sites, while 
electronic data are password protected and maintained on a secure network. PHI 
that the study team at ATRI has access to in the EDC system is limited to the 
minimum necessary for authorized oversight of the research study and includes 
participant’s DOB and hospital admission/discharge dates.  
 
All data will be transmitted securely via the Internet to ATRI at USC. Access to the 
database is role-based and will be limited to key personnel at sites and USC. Access 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
is granted to study team members based on role. Each user of the system has an 
individual account with a password that is required to be reset at set intervals to 
comply with USC password requirements. Users are logged out of the system after a 
period of inactivity. All communication to and from the data system is encrypted. 
Data transmission will occur through a secure internet connection. The ATRI Clinical 
Operations and Informatics Cores will also provide real-time web-based reporting 
on data flow; assure optimal data security and redundant data backups.  
 13.5.2 MRI and PET Imaging and Data Storage - LONI  
MRI and PET scans will be labeled according to each site’s imaging machine 
capabilities using ADNI participant identifiers and scanner specific series 
descriptions. All MRI and PET scans will undergo de-identification, which is 
embedded within the LONI Image Upload process to ensure that no participant 
identification information is present in the image files. MRI scan findings of clinical 
significance, determined by the site radiologist, will be shared with the participant 
and the participant’s local physician. 
13.5.3 Genomic Material - NIH/NIA & NCRAD  
De-identified samples including immortalized cell lines, PBMCs, DNA, RNA, buffy 
coats, and their derivatives will be processed and stored indefinitely at NCRAD.  All 
samples are stored in a secure freezer 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 patient 
confidentiality and the use of stored genetic specimens will be in accordance with 
the rules and procedures established by the Indiana University IRB.  
The de-linking of the sample from the participant identity occurs at the time the 
biospecimen is sent by each site to NCRAD. The identity of participants will not be 
shared with NCRAD or with any investigators. A unique bar-code number is affixed 
to all specimen tubes as well as affixed to the Sample Form/Draw Sheet. All transfer 
tubes; vessels and storage vials are pre-labeled prior to sample processing.  NCRAD 
maintains a secure database for tracking all incoming ADNI samples.  The only 
information that will be maintained in this database is an genomic individual 
number (to preserve confidentiality), 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.  
Genomic and all other data can be linked to other clinical research data for purposes 
of scientific analyses, but the only linkage of genetic test results to participant 
identity is at the specific clinical site where they are enrolled. 
NIH/NIA Databases  
For genetics, genomics, and related data, 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.  

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
NIAGADS, along with other NIA-approved sites, will make these genetic 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 (DUC). Investigators are approved by a Data 
Access Committee (DAC) for access to specific datasets for a specific use(s). In 
addition, the DUCs 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. 
13.5.4 Biomarker Data and Storage of Biomarker Material - UPENN 
At the University of Pennsylvania (UPENN), the ADNI Biomarker Core has 
established and maintains a database for the inventory of stored samples in 
conjunction uses a bar code reading system. Bar code labels affixed to each sample 
vial will contain the following information: sample ID# (to preserve confidentiality), 
date of collection and processing, total initial volume collected, sample type (plasma, 
serum, CSF), volume, aliquot number, freezer, shelf, rack, box, location in the box. A 
bar code label will be used on the sample tracking form. The database system, 
LDMS, is powered by Oracle database version 11b resides on the University of 
Pennsylvania Healthcare System (UPHS) network under the high level protection 
with the UPHS Enterprise class perimeter firewall that includes a default deny 
policy.  Access to LDMS has 4 layers of security: controlled building access, 
controlled laboratory access, PC password and LDMS password.  VPN access is 
disabled so data is available only locally.  The data is backed-up daily with 256-bit 
encryption and a copy is stored in a secure location.   
 
Samples handled by the ADNI Biomarker Core are banked in a secure facility, in 
locked and alarmed freezers at 80°C with 24/7 temperature monitoring, dedicated 
to the ADNI study.  
13.6 Requesting Genetic and Biomarker Samples for Research   
Specific procedures for requesting and accessing genetic and biomarker specimens 
have been created by the Resource Allocation Review Committee (RARC) in 
accordance with recommendations proposed in the NBAC Human Biological 
Materials Report. These guidelines have also been developed in accordance with the 
American Society for Human Genetics position paper on the NBAC report and the Ad 
Hoc Committee on Stored Tissue of the College of American Pathologists. 
14.0 NIH DATA SHARING POLICY   
All de-identified ADNI data is shared with investigators who request it on the 
USC/LONI/ADNI website and are approved by the ADNI DPC.  Instructions 
concerning how to access this data are on the public ADNI website.  

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
 
Data from this research will be shared in compliance with the NIH’s Policies on Data 
Sharing for NIH funded research.  The ADNI3 grant contains a data sharing policy 
consistent with the goals of the NIH, but which also respects the rights of 
commercial partners. The NIH Data Sharing Polices and Related Guidance for NIH-
Funded Research can be found online at: https://grants.nih.gov/policy/sharing.htm.  
 
NIH believes that data sharing is important 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. As above, to protect participants’ rights and confidentiality, 
identifiers will be removed from the data before they are shared. 
15.0 STATISTICAL CONSIDERATIONS 
15.1 Analysis Goals and Strategies  
The Biostatistics Core will carry out interim and final analyses of ADNI3 data, 
separately and in combination with previous phases, for the primary aims and 
hypotheses. Strategies for the five analysis goals are summarized briefly below. 
 
All analyses will follow best practices for reproducible research. Final validated 
code for data preparation and analysis will be share on the LONI website and via 
GitHub.  
15.1.1 Specific Analysis Goals 
ADNI3 will continue to discover, optimize, standardize, and validate clinical trial 
measures and biomarkers used in AD research.  
Goal 1 
Baseline characteristics of biomarkers and distribution of clinical variables will be 
summarized by standard descriptive statistics and graphics. Performance of 
baseline biomarkers as predictors of cognitive and functional change, disease 
progression, and post-mortem findings will be assessed by regression models 
(linear, logistic, survival, et al.)  
Goal 2 
We will assess potential of biomarkers for reducing sample size or shortening 
follow-up by use for inclusion/exclusion, stratification, or covariate analysis.  
Goal 3 
Will use longitudinal models to characterize change in biomarkers and its 
association with clinical, functional, and other biomarkers changes and post-
mortem findings. 
Goal 4 
We will assess longitudinal biomarker change for potential use in clinical trials as an 
outcome measure, considering signal-to-noise ratio for various study designs.  

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
Goal 5 
We will formally compare performance across biomarkers for all 4 previous aims. 
The role of genes and gene expression in these analyses will be examined in 
collaboration with the Genetics Core.  
15.1.2 Sample Size  
Sample sizes have been chosen to have both adequate numbers of participants in 
each diagnostic group and adequate numbers of observations per participant to 
yield minimum 80% power for aims 1-4 above. Examples: we will have 80% power 
to detect a difference between high-risk and low-risk groups in ADAS change/ year 
of 0.43 (0.96, 2.28) for CN (MCI, AD). We will be able detect correlations between 
imaging biomarker change and cognitive or functional change as small as 0.16 for 
CN or MCI and 0.21 for AD. 
16.0 LITERATURE CITED 
1. Donohue, M.C., et al., The relative efficiency of time-to-threshold and rate of 
change in longitudinal data. Contemp Clin Trials, 2011. 32(5): p. 685-93. 
2. Donohue, M.C., A.C. Gamst, and P.S. Aisen, Requiring an amyloid-beta1-42 
biomarker for prodromal Alzheimer's disease or mild cognitive impairment does 
not lead to more efficient clinical trials. Alzheimers Dement, 2011. 7(2): p. 245-6; 
author reply 247-9. 
3. Donohue, M.C. and P.S. Aisen, Mixed model of repeated measures versus slope 
models in Alzheimer's disease clinical trials. J Nutr Health Aging, 2012. 16(4): p. 
360-4. 
4. Donohue, M.C., et al., Estimating long-term multivariate progression from short-
term data. Alzheimers Dement, 2014. 10(5 Suppl): p. S400-10. 
5. Aisen, P.S., et al., Report of the task force on designing clinical trials in early 
(predementia) AD. Neurology, 2011. 76(3): p. 280-6. 
6. Vellas, B., et al., Alzheimer's disease therapeutic trials: EU/US Task Force report 
on recruitment, retention, and methodology. J Nutr Health Aging, 2012. 16(4): p. 
339-45. 
7. Bernick, C., et al., Age and rate of cognitive decline in Alzheimer disease: 
implications for clinical trials. Arch Neurol, 2012. 69(7): p. 901-5. 
8. Grill, J.D., et al., Effect of study partner on the conduct of Alzheimer disease 
clinical trials. Neurology, 2013. 80(3): p. 282-8. 
9. Henley, D.B., et al., Alzheimer's disease progression by geographical region in a 
clinical trial setting. Alzheimers Res Ther, 2015. 7(1): p. 43. 
10. Grill, J.D., et al., Comparing recruitment, retention, and safety reporting among 
geographic regions in multinational Alzheimer's disease clinical trials. 
Alzheimers Res Ther, 2015. 7(1): p. 39. 
11. Sperling, R.A., C.R. Jack, Jr., and P.S. Aisen, Testing the right target and right drug 
at the right stage. Sci Transl Med, 2011. 3(111): p. 111cm33. 
12. Vellas, B., et al., Prevention trials in Alzheimer's disease: an EU-US task force 
report. Prog Neurobiol, 2011. 95(4): p. 594-600. 

Protocol Number:  ATRI-001 
 
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ADNI Protocol v3.1: 04-December-2020 
13. Aisen, P.S., B. Vellas, and H. Hampel, Moving towards early clinical trials for 
amyloid-targeted therapy in Alzheimer's disease. Nat Rev Drug Discov, 2013. 
12(4): p. 324. 
14. Andrieu, S., et al., Prevention of sporadic Alzheimer's disease: lessons learned 
from clinical trials and future directions. Lancet Neurol, 2015. 14(9): p. 926-44. 
15. Salmon, D.P., et al., Age and apolipoprotein E genotype influence rate of cognitive 
decline in nondemented elderly. Neuropsychology, 2013. 27(4): p. 391-401. 
16. Sano, M., et al., Adding delayed recall to the Alzheimer Disease Assessment Scale 
is useful in studies of mild cognitive impairment but not Alzheimer disease. 
Alzheimer Dis Assoc Disord, 2011. 25(2): p. 122-7. 
17. Sperling, R.A., et al., Toward defining the preclinical stages of Alzheimer's 
disease: Recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. 
Alzheimers Dement, 2011. 7(3): p. 280-92. 
18. Sperling, R.A., et al., The A4 study: stopping AD before symptoms begin? Sci 
Transl Med, 2014. 6(228): p. 228fs13. 
19. Rosen, W.G., Mohs, R.C., & Davis, K.L., A new rating scale for Alzheimer’s disease. 
American Jounral of Psychiatry. 1984. 141(11): 1356-1364.  
20. Grober, E., Sliwinski M., Development and validation of a model for estimating 
premorbid verbal intelligence in elderly. J Clin Exp Neuropsychol, 1991. 13(6): 
933-49. 
21. Nelson, H.E., O’Connell A., Dementia: the estimation of premorbid intelligence 
levels using the New Adult Reading Test. Cortex, 1978. 14(2): 234-44.  
22. Butters, N., Granholm, E., Salmon, D.P., Grant, I., & Wolfe, J., Episodic and 
semantic memory: a comparison of amnesic and demented patients. J of Clin Exp 
Neuropsychol, 1987. 9(5): 479-497.  
23. Cahn, D.A., et al., Screening for dementia of the Alzheimer type in the community: 
the utility of the Clock Drawing Test. Arch Clin Neuropsychol, 1996. 11(6): 529-
39. 
24. Wechsler, D., Wechsler Memory Scale. Revised Manual, 1987.  
25. Folstein orig ref and some other that validates is as a longitudinal AD measure. 
26. Nasreddine, Z.S., et al., Sensitivity and Specificity of The Montreal Cognitive 
Assessment (MoCA) for Detection of Mild Cognitive Deficits. Can J Neurol Sci, 
2003. 30(2): 30.  
27. Gollan, T.H., et al., Self-ratings of Spoken Language Dominance: A Multi-Lingual 
Naming Test (MlNT) and Preliminary Norms for Young and Aging Spanish-
English Bilinguals. Biling (Camb Engl), 2012. 15(3): 594-615.  
28. Rey, A., L’examen Clinique en psychologie. Paris, Presses Universitaires de 
France, 1964.   
29. Reitan, R. M., Validity of the trail-making test as an indicator of organic brain 
damage. Percept Mot Skills, 1958. 8: 271-276. 
30. Rosen, W.G., Terry, R.D., Fuld, P.A., Katzman, R. & Peck, A. Pathological 
verification of ischemic score in differentiation of dementias.  Ann. Neurol. 7, 
486-488 (1980). 

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ADNI Protocol v3.1: 04-December-2020 
31. Rattanabannakit, C., et al. The Cognitive Change Index as measure of self and 
informant perception of cognitive decline: relation to neuropsychological tests. J 
Alzheimer’s Dis 51, 1145-1155 (2016). 
32. Risacher, SL., et al. APOE effect on Alzheimer’s disease biomarkers in older 
adults with significant memory concern. Alzheimer’s Dement 12, 1417-1429 
(2015). 
33. Morris, J.C.  The Clinical Dementia Rating (CDR): current version and scoring 
rules.  Neurology 43, 2412-2414 (1993).  
34. Hughes, C.P., Berg, L., Danziger, W.L., Coben, L.A. & Martin, R.L.  A new clinical 
scale for the staging of dementia.  Br J Psychiatry 140, 566-572 (1982). 
35. Pfeffer, R. I., Kurosaki, T. T., Harrah, C. H., Jr., Chance, J. M., & Filos, S. (1982). 
Measurement of functional activities in older adults in the community. J Gerontol, 
37(3), 323-329. 
36. Marson, D., Investigating Functional Impairment in Preclinical Alzheimer’s 
Disease. Journal of Prevention of Alzheimer’s Disease. 2015. 2(1): 4-6. 
37. Farias, S.T., Mungas, D.M., Reed, B.R., Cahn-Weiner, D., Jagust, W., Baynes, K., 
DeCarli, C. (2008) The Measurement of Everyday Cognition (ECog): Scale 
Development and Psychometric Properties.  Neuropsychology 22(4), 531-544. 
38. Cummings, J.L.  The Neuropsychiatric Inventory: assessing psychopathology in 
dementia patients.  Neurology 48, S10-16 (1997).  
39. Cummings, J.L., et al.  The Neuropsychiatric Inventory: Comprehensive 
assessment of psychopathology in dementia.  Neurology 44, 2308-2314 (1994). 
40. Kaufer, D. I., Cummings, J. L., Ketchel, P., Smith, V., MacMillan, A., Shelley, T., et al. 
(2000). Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric 
Inventory. J Neuropsychiatry Clin Neurosci, 12(2), 233-239. 
41. Sheikh, J. & Yesavage, J. Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version.  in Clinical gerontology: A guide to assessment 
and intervention (ed. Brind, T.L.) 165-173 (Haworth Press, New York, 1986).

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ADNI Protocol v3.1: 04-December-2020 
APPENDIX 1 
 
SCHEDULE OF EVENTS 
Rollover Participants: CN, MCI, and AD 
 
Clinic Visit Name 
Initial1 
Year 
12, 3,4 
Year  
2 
Year  
3 
Year  
4 
Year  
5 
CN 
Phone 
Check5 
Telephone Visit 
In replacement 
of in-clinic 
Explain Study and Obtain consent13 
X 
 
 
 
 
 
 
X13 
Neuropath discussion / Provisional consent6 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
 
Mini Mental State Examination (MMSE) 
X 
X 
X 
X 
X 
X 
 
 
Cogstate Brief Battery (CBB)7 
X 
X 
X 
X 
X 
X 
 
 
Logical Memory I and II 
X 
X 
X 
X 
X 
X 
 
 
Everyday Cognition (ECog) 
X 
X 
X 
X 
X 
X 
 
X 
Montreal Cognitive Assessment (MoCA) 
X 
X 
X 
X 
X 
X 
 
 
Category Fluency (Animals) 
X 
X 
X 
X 
X 
X 
 
 
Trails A & B 
X 
X 
X 
X 
X 
X 
 
 
Multi-Lingual Naming Test (MlNT)  
X 
X 
X 
X 
X 
X 
 
 
Auditory Verbal Learning Test 
X 
X 
X 
X 
X 
X 
 
 
Geriatric Depression Scale 
X 
X 
X 
X 
X 
X 
 
X 
Clock drawing 
X 
X 
X 
X 
X 
X 
 
 
Neuropsychiatric Inventory (NPI) / (NPI-Q 
for Phone Check) 
X 
X 
X 
X 
X 
X 
X 
X 
ADAS-Cog 13 (w/ Delayed Recall and 
Number Cancellation) 
X 
X 
X 
X 
X 
X 
 
 
Clinical Dementia Rating Scale 
X 
X 
X 
X 
X 
X 
 
X 
Activities of Daily Living (FAQ) 
X 
X 
X 
X 
X 
X 
 
X 
Financial Capacity Instrument – Short Form 
(FCI-SF) 
X 
X 
X 
X 
X 
X 
 
 
Plasma and Serum Biomarker Collection 
X 
X 
X 
X 
X 
X 
 
 
DNA Sample Collection 
X 
 
 
 
 
 
 
 
PMBC Sample Collection 
X 
 
 
 
 
 
 
 
RNA and Buffy Coat Sample Collection 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Diagnostic Summary 
X 
X 
X 
X 
X 
X 
 
 
3T MRI Imaging8  
X 
X 
X 
X 
X 
X 
 
 
FDG-PET Imaging9 
X 
 
 
 
 
 
 
 
Florbetapir Imaging10 
X 
 
X 
 
X 
 
 
 
Flortaucipir PET Imaging11  
X 
X11 
X11 
 
X 
 
 
 
CSF Collection by Lumbar Puncture (LP)10 
X 
 
X 
 
X 
 
 
 
LP Safety lab test: PT/PTT (coagulation 
profile) 12 
 
 
X 
 
X 
 
 
 
 
1Rollover participants who are being followed from ADNI2 begin ADNI3 with a complete Initial in-
clinic visit or Telephone visit in replacement of in-clinic visit.  
2CN participants are seen in the clinic biennially (every other year) unless they are required to come in 
on an off year for flortaucipir PET imaging (see footnote 11).  
3MCI and Converter participants are seen in the clinic annually.  

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4AD participants are seen in-clinic for 24 months from Baseline (total of 3 in-clinic visits at Initial, Year 
1, and Year 2) and then ongoing phone follow-up should continue every 6 months or, at minimum, 
annually for those that have consented or are undecided about Neuropathology program. 
5Applies to CN participants on off years when an ongoing in-clinic visit is not called for or needed for 
flortaucipir PET imaging.  
6Neuropath discussion to confirm consent/interest should occur every 6 months or, at minimum, 
annually (see section 9.5). If a participant has refused to participate, no further inquiry should take 
place. 
7CBB will be conducted at each In-Clinic Visit and up to quarterly interval remotely for the CN and MCI 
cohorts only.  
8Onoging MRI conducted at each in-clinic visit. 
9FDG-PET is only assessed at baseline for MCI and AD participants only; CN participants are not 
required to conduct FDG-PET. 
10Florbetapir and LP for CSF starts at Initial Visit and is then repeated every two years. 
11Flortaucipir PET Imaging is at the Initial/Baseline Visit for all participant groups. AD participants 
will have a flortaucipir PET scan at each in-clinic visit (for a total of three scans). CN, MCI, and 
Converter participants will receive a scan at the Y4 visit (for a total of two scans). Additionally, 20% 
amyloid negative, and 80% amyloid positive CN and MCI participants will have two more scans (for a 
total of four scans).  
12PT/PTT test is an optional procedure at the discretion of PI or Site Clinician  
13Telephone visit in replacement of in-clinic visit:  new consent form is required for those 
participants opting into a Telephone visit in replacement of in-clinic visit for Initial visit or Ongoing 
Visits. 
 
 
 
 

Protocol Number:  ATRI-001 
 
Page 50 of 51 
 
ADNI Protocol v3.1: 04-December-2020 
 
Newly Enrolled Participants: CN, MCI, and AD 
Clinic Visit Name 
Screen 
Base-
line1,2,3 
Year 
1 
Year 
2 
Year 
3 
Year 
4 
Year  
5 
CN 
Phone 
Check4 
Telephone Visit 
In replacement 
of in-clinic 
Explain Study and Obtain consent 12 
X 
 
 
 
 
 
 
 
X 12 
Neuropath discussion / Provisional 
consent5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics, Family History, 
Inclusion and Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Medical History, Physical Exam, 
Neurological Exam, Modified 
Hachinski Ischemic Score 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Screening Labs (hematology, 
chemistry panel, urinalysis, B12, TSH) 
X 
 
 
 
 
 
 
 
 
American National Adult Reading Test 
 
X 
 
 
 
 
 
 
 
Cognitive Change Index (CCI) 
X 
 
 
 
 
 
 
 
 
Mini Mental State Examination 
(MMSE) 
X 
 
X 
X 
X 
X 
X 
 
 
Cogstate Brief Battery (CBB)6 
 
X 
X 
X 
X 
X 
X 
 
 
Logical Memory I and II 
X 
 
X 
X 
X 
X 
X 
 
 
Everyday Cognition (ECog) 
 
X 
X 
X 
X 
X 
X 
 
X 
Montreal Cognitive Assessment 
(MoCA) 
 
X 
X 
X 
X 
X 
X 
 
 
Category Fluency (Animals) 
 
X 
X 
X 
X 
X 
X 
 
 
Trails A & B 
 
X 
X 
X 
X 
X 
X 
 
 
Multi-Lingual Naming Test (MlNT)  
 
X 
X 
X 
X 
X 
X 
 
 
Auditory Verbal Learning Test 
 
X 
X 
X 
X 
X 
X 
 
 
Geriatric Depression Scale 
X 
 
X 
X 
X 
X 
X 
 
X 
Clock drawing 
 
X 
X 
X 
X 
X 
X 
 
 
Neuropsychiatric Inventory (NPI) / 
(NPI-Q for Phone Check) 
 
X 
X 
X 
X 
X 
X 
X 
X 
ADAS-Cog 13 (w/ Delayed Recall and 
Number Cancellation) 
 
X 
X 
X 
X 
X 
X 
 
 
Clinical Dementia Rating Scale 
X 
 
X 
X 
X 
X 
X 
 
X 
Activities of Daily Living (FAQ) 
 
X 
X 
X 
X 
X 
X 
 
X 
Financial Capacity Instrument – Short 
Form (FCI-SF) 
 
X 
X 
X 
X 
X 
X 
 
 
Plasma and Serum Biomarker 
Collection 
 
X 
X 
X 
X 
X 
X 
 
 
DNA Sample Collection 
 
X 
 
 
 
 
 
 
 
Cell Immortalization Sample 
Collection 
 
X 
 
 
 
 
 
 
 
RNA and Buffy Coat Sample Collection 
 
X 
X 
X 
X 
X 
X 
 
 
PBMC Sample Collection 
 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diagnostic Summary 
X 
X 
X 
X 
X 
X 
X 
 
 
3T MRI Imaging7  
X 
 
X 
X 
X 
X 
X 
 
 
FDG-PET Imaging8  
 
X 
 
 
 
 
 
 
 
Amyloid Imaging9 
 
X 
 
X 
 
X 
 
 
 
Flortaucipir PET Imaging10 
 
X 
X10 
X10 
 
X 
 
 
 

Protocol Number:  ATRI-001 
 
Page 51 of 51 
 
ADNI Protocol v3.1: 04-December-2020 
CSF Collection by Lumbar Puncture 
(LP)9 
 
X 
 
X 
 
X 
 
 
 
LP Safety lab test: PT/PTT 
(coagulation profile) 11 
 
X 
 
X 
 
X 
 
 
 
 
1CN participants are seen in the clinic biennially (every other year) unless they are required to come in 
on an off year for flortaucipir PET imaging (see footnote 10).  
2MCI and Converter participants are seen in the clinic annually.  
3AD participants are seen in-clinic for Screening, Baseline, two Ongoing in-clinic visits and then AD 
phone checks should continue every 6 months or, at minimum, annually for those that have consented or 
are undecided about Neuropathology program. 
4Applies to CN participants on off years when ongoing in-clinic visit is not called for or needed for 
flortaucipir PET imaging.  
5Neuropath discussion to confirm consent/interest should occur every 6 months or, at minimum, 
annually (see section 9.5). If a participant has refused to participate, no further inquiry should take 
place. 
6CBB will be conducted at each In-Clinic Visit and up to quarterly interval remotely for the CN and MCI 
cohorts only. 
7Onoging MRI conducted at each in-clinic visit. 
8FDG-PET is only assessed at Baseline for MCI and AD participants only; CN participants are not 
required to conduct FDG-PET. 
9Amyloid Imaging (florbetapir or florbetaben) and LP for CSF starts at Baseline and is then repeated 
every two years. 
10Flortaucipir-PET Imaging is at the Initial/Baseline Visit for all participant groups. AD participants 
will have a flortaucipir PET scan at each in-clinic visit (for a total of three scans). CN, MCI, and 
Converter participants will receive a scan at the Y4 visit (for a total of two scans). Additionally, 20% 
amyloid negative, and 80% amyloid positive CN and MCI participants will have two more scans (for a 
total of four scans). 
11PT/PTT test is an optional procedure at the discretion of PI or Site Clinician  
12 Telephone visit in replacement of in-clinic visit: A new consent form is required for those 
participants opting into a Telephone visit in replacement of in-clinic visit for Ongoing Visits. Not 
allowed at Baseline.