Trial Ready Cohort for the Prevention of Alzheimer's Dementia (TRC-PAD)
Conditions: Preclinical Alzheimer's Disease, Prodromal Alzheimer's Disease, Alzheimer Disease, Dementia
Sponsor: University of Southern California

TRC-PAD Program:  In-Clinic Trial-Ready Cohort  
 
Short Title:  TRC 
Protocol Number: ATRI-004 
Principal Investigators: Paul Aisen, Reisa Sperling, Jeffrey Cummings 
 
Funded by: National Institute on Aging 
Version Number:  v.4.1 
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SIGNATURE PAGE 
 
(SIGNATURES ON FILE AT COORDINATING CENTER) 
 
 
 
 
 
 
 
 
_____________________________________                       _________________________ 
Paul Aisen, MD  
 
 
 
 
               Date (MM/DD/YYYY) 
Project Director 
Alzheimer’s Therapeutic Research Institute 
University of Southern California 
 
 
 
 
_____________________________________                      _________________________ 
Michael Rafii, MD, PhD  
 
 
 
 
 Date (MM/DD/YYYY) 
Medical Monitor 
Alzheimer's Therapeutic Research Institute 
University of Southern California 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 4 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale and background ...................................................................................................... 5 
2.2 
Overview ............................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment ................................................................................................................... 6 
2.3.1 
Known Potential Risks .................................................................................................... 6 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................... 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 8 
4 
STUDY DESIGN ............................................................................................................................................ 8 
4.1 
Overall Design ..................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design ............................................................................................... 8 
4.3 
End of Study Definition ....................................................................................................................... 9 
5 
STUDY POPULATION for in-clinic TRC ..................................................................................................... 9 
5.1 
Inclusion Criteria .................................................................................................................................. 9 
5.2 
Exclusion Criteria ................................................................................................................................ 9 
5.3 
Screen Failures ................................................................................................................................. 10 
5.4 
Clinical Trial Participation and TRC status .................................................................................... 10 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 11 
6 
PET TRACERS ............................................................................................................................................ 11 
6.1 
Dosing and Administration of Amyloid PET Tracers .................................................................... 11 
7 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ............................................................................ 12 
7.1 
Participant Discontinuation/Withdrawal from the In-Clinic TRC Study ...................................... 12 
7.1.1 
Clinical Trial Participation ............................................................................................. 12 
7.2 
Lost to Follow-Up .............................................................................................................................. 12 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 13 
8.1 
Clinical and Cognitive Assessments .............................................................................................. 13 
8.1.1 
Prescreen phase ............................................................................................................ 13 
8.1.2 
Screening  ....................................................................................................................... 13 
8.1.3 
Active Study Phase (ongoing 6-month Assessments) ............................................. 15 
8.1.4 
Physical and Neurological Examination ..................................................................... 15 
8.1.5 
Vital signs ........................................................................................................................ 15 
8.1.6 
Medical History .............................................................................................................. 15 
8.1.7 
Cognitive, Functional, and Well-being Assessments ............................................... 15 
8.2 
Lumbar Puncture ............................................................................................................................... 16 
8.3 
Genomic and Plasma AD Biomarker Samples ............................................................................. 17 
8.3.1 
Samples for Biomarker Storage and Future Research ............................................ 18 
8.4 
Safety and Other Assessments ....................................................................................................... 18 
8.4.1 
Concomitant Medication Review ................................................................................. 18 
8.4.2 
Clinical Laboratory Assessments ................................................................................ 18 
8.5 
Adverse Events and Serious Adverse Events .............................................................................. 18 
8.5.1 
Definition of Adverse Events ........................................................................................ 18 

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8.5.2 
Definition of Serious Adverse Events (SAE) .............................................................. 19 
8.5.3 
Classification of an Adverse event (AE) ..................................................................... 20 
8.5.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 21 
8.5.5 
Adverse Event Reporting .............................................................................................. 21 
8.5.6 
Serious Adverse Event Reporting ............................................................................... 21 
8.5.7 
Reporting Events to Participants ................................................................................. 21 
8.5.8 
Events of Special Interest ............................................................................................. 21 
8.5.9 
Reporting of Pregnancy ................................................................................................ 21 
8.6 
Unanticipated Problems ................................................................................................................... 22 
8.6.1 
Definition of Unanticipated Problems (UP) ................................................................ 22 
8.6.2 
Unanticipated Problem Reporting ............................................................................... 22 
8.6.3 
Reporting Unanticipated Problems to Participants ................................................... 22 
8.7 
Global Unique Identifier .................................................................................................................... 22 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 23 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 25 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 25 
10.1.1 
Informed Consent Process ........................................................................................... 25 
10.1.2 
Study Discontinuation and Closure ............................................................................. 25 
10.1.3 
Confidentiality and Privacy ........................................................................................... 26 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 26 
10.1.5 
Key Roles and Study Governance .............................................................................. 27 
10.1.6 
Safety Oversight ............................................................................................................ 27 
10.1.7 
Clinical Monitoring ......................................................................................................... 27 
10.1.8 
Quality Assurance and Quality Control ...................................................................... 28 
10.1.9 
Data Handling and Record Keeping ........................................................................... 28 
10.1.10 
Protocol Deviations ....................................................................................................... 30 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 30 
10.1.12 
Conflict of Interest Policy .............................................................................................. 31 
10.1.13 
Data and Coordinating Center ..................................................................................... 31 
10.2 
Additional Considerations ................................................................................................................ 32 
10.3 
Abbreviations ..................................................................................................................................... 33 
10.4 
Protocol Amendment History ........................................................................................................... 34 
11 
REFERENCES ............................................................................................................................................. 35 
 

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STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the protocol, in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) guidelines, and in full conformity with Regulations for the 
Protection of Human Participants of Research codified in 45 CFR Part 46 – Protections of Human Participants, 24 
CFR Part 50 – Protection of Human Participants, 21 CFR Part 56 – IRBs, and/or the ICH E6, HIPAA, State and Federal 
regulations and all other applicable local regulatory requirements and laws.   
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the 
conduct, management, or oversight of NIH-funded clinical studies are required to be qualified by education, 
training and experience and must have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the Institutional Review Board (IRB) for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  In addition, all changes to the consent form 
will be IRB-approved; a determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent using a previously approved consent form. 
No study document shall be destroyed without prior written agreement between the 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.  
Only institutions holding a current Federal-Wide Assurance (FWA) issued by the Office of Human Research 
Protections (OHRP) may participate in the study. Refer to: http://www.hhs.gov/ohrp/assurances/. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
TRC-PAD Program:  In-Clinic Trial-Ready Cohort (TRC) 
Study Description: 
Development of a large, well-characterized, biomarker-confirmed, trial-ready cohort 
to facilitate rapid enrollment into AD preclinical/prodomal trials utilizing feeder 
registries into the APT Webstudy and subsequent referral to in-clinic evaluation and 
biomarker confirmation. Participants with known biomarker status may have direct 
referral to the trial-ready cohort. 
Objectives: 
1. To build an efficient and sustainable recruitment system in order to enroll an 
initial TRC-PAD Cohort. 2. To optimize an innovative, adaptive risk algorithm to 
efficiently identify the most appropriate trial participants. 3. To develop and validate 
web-based cognitive and functional outcome measures for future clinical trials. 
Study Population: 
At least 2,000 (1,000 preclinical + 1,000 prodromal AD) trial-ready individuals aged 
50-85  
Description of Sites: Approximately 60 AD clinical trials sites   
Description of Study 
Intervention: 
No intervention 
Study Duration: 
5 years 
Participant Duration: 5 years 

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1.2 
SCHEMA 
 
 
 
Figure 1 Overall Schema of TRC-PAD Program (Feeder Registries, APT Webstudy and In-clinic TRC) 
 
No
No

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Figure 2 Participant Flow diagram: APT Webstudy and In-clinic TRC 
1 Optional remote APOE genotyping via mail-in saliva test and optional remote blood collection for 
plasma AD biomarkers subject to availability. 
2 ‘Known Amyloid +’ indicates prior confirmed biomarkers (PET or CSF) consistent with disease 
pathology or elevated or intermediate brain amyloid.  

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
The schedule below is for the In-Clinic TRC  
 
Procedures 
Screening 
(Stage 1-2 complete within 60-day window; 
Stage 3 complete within 84-day window) 
Follow-up 
Visits8 
Every 6 months 
+/-21 days 
Stage 1 
Stage 23 
Stage 3 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
  
 X 
Concomitant Medication 
X 
 
 
X 
Adverse events 
 
X 
 
X  
Vital Signs1 
X 
 
 
X 
Physical and Neurological exam 
X 
 
 
X 
PACC 
X 
 
 
 X 
CFI 
X*  
 
 
 X* 
CDR-SB 
X* 
 
 
 X* 
STAI and GDS 
X* 
 
 
X* 
Concerns about AD, Future Time 
Perspective Scale 
X* 
 
X6 
X* 
Blood and urine for clinical labs 
X 
 
  
  
Blood for Genomics2 and AD 
Biomarkers (fasted)10 
X 
 
 
  
Amyloid testing3 by CSF4,10 or PET 
 
X 
  
  
Wellness Telephone Check5 
 
X 
X 
 
Eligibility Discussion 
 
 
X 
 
Impact of Events Scale 
 
 
X7  
 
Global Unique Identifier (GUID) 
generation 
X9 
 
 
 
 
1 Vital signs include weight, plus height at screening visit only. 
2 DNA collection performed for APOE Genotyping and banking/future analyses.  
3 Previous amyloid testing from external study may be used with approval from the Coordinating Center and screening stage 2 
may be skipped. 
4 A coagulation panel and platelet count will be obtained either locally or centrally prior to the LP (within 3 months), in order to 
rule out a clotting disorder. Participants on anticoagulation are not eligible for LP.  
5 Post-LP/ post-PET, post-eligibility discussion telephone follow-up within 72 hours after procedure.  
6 Administered in-person after eligibility discussion. 
7 Administered by phone at the wellness telephone check following eligibility discussion. 
8 Screening visit procedures may be repeated at follow-up visits, with approval from the Coordinating Center, if needed to 
assess potential changes in eligibility for clinical trials, e.g. after participation in a clinical trial or prolonged enrollment in TRC 
without successful enrollment in a trial.  
9 GUID generation will occur at screening visit or at any visit thereafter once consent has been obtained 
10 CSF and Blood biomarker collection should occur after a minimum 8-hour fast 
 
*At the discretion of the PI, these assessments may be conducted over the phone.   
 
For those participants who are enrolled in the APT Webstudy, quarterly online participation will continue while screening for 
and enrolled in TRC.  
 
 
 
 
 

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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE AND BACKGROUND  
Alzheimer’s disease (AD) remains one of our greatest unmet medical needs, without any approved disease-
modifying therapies. Both animal data and recent clinical trial results with anti-amyloid agents suggest that our 
previous attempts to intervene may have been “too little, too late.”  Fortunately, a number of trials in both genetic 
and biomarker at-risk older individuals thought to be in the preclinical stages of AD, as well as trials in the clinical 
stage of mild cognitive impairment (MCI) or prodromal AD, are underway or currently being planned.  However, 
the timeframe, complexity and expense of the recruitment process and site activation for these secondary 
prevention trials are extremely challenging, and indeed site start-up and trial enrollment, in general, represent the 
greatest bottleneck for drug development for AD. Moreover, it is likely that future early-stage trials will move even 
earlier in the process of amyloid accumulation prior to the stage of “amyloid positivity”.  These prevention trials 
will increasingly rely on remote electronic contact and assessments due to the need to screen large number of 
individuals and follow participants over long periods of time. Thus, there is growing consensus that we must 
fundamentally overhaul the current clinical trial recruitment and assessment process for these early intervention 
trials. The overarching goal of this protocol is to accelerate current and future secondary prevention trial 
enrollment through an innovative, highly efficient approach to identify, evaluate, and enroll appropriate preclinical 
and prodromal trial candidates, supported by a new site network with enhanced capacities for more efficient and 
effective conduct of AD clinical trials.   
2.2 
OVERVIEW 
TRC-PAD is an ambitious program, addressing wide-ranging issues in trial recruitment and site management.  To 
succeed, it will build on existing efforts by expert collaborators in informatics, web-based consent, innovative 
cognitive assessments, biostatistics, and multiple existing registry programs.  
The feeder registries (Brain Health Registry, Alzheimer’s Prevention Registry, HealthyBrains.org, et al.) will filter 
participants based on age and cognitive status and invite older individuals not meeting criteria for dementia to 
enroll in the APT Webstudy, which in turn will conduct unsupervised, web-based capture of demographic, medical, 
lifestyle and genetic factors, as well as longitudinal web-based cognitive testing and symptom questionnaires, to 
assess their risk of elevated brain amyloid.  The initial risk algorithm is derived from analysis of an existing study 
data.  This algorithm is then iteratively updated through an appropriate regression-based statistical approach to 
biomarker testing results.   
The individuals at highest risk within the APT Webstudy pool of asymptomatic (preclinical) and very mildly 
symptomatic (prodromal) individuals will be referred for in-person clinical and biomarker assessments at select AD 
clinical trial sites.  Those who are identified with biomarker profiles indicative of AD pathology, including 
asymptomatic individuals with minimally elevated or “intermediate” levels of amyloid, will be eligible for the in-
clinic trial-ready cohort (TRC), where they will be followed at semi-annual in person visits until they are ready for 
enrollment in preclinical/prodromal therapeutic trials, while continuing quarterly, remote, web-based cognitive 
assessments in the APT Webstudy. Biomarker-negative individuals will continue remote web-based follow-up in 
the APT Webstudy; if longitudinal trajectories and changes to other risk factors indicate increasing risk, those 
participants will be eligible for repeat in-person clinical and biomarker assessment. Participants with known 

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biomarker status may have direct referral to the in-clinic TRC cohort and will be encouraged to participate in the 
APT Webstudy. 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
2.3.1.1 RISKS ASSOCIATED WITH POSITRON EMISSION TOMOGRAPHY (PET) 
The primary risk related to PET imaging is that of radiation exposure associated with the injected radiotracers and 
accompanying CT (if a PET/CT scanner is used). There is also minor risk associated with the venipuncture, 
placement of an intravenous catheter, and radioisotope injection (pain and bruising or painful infiltration of a 
failed injection).  
Any of the following radiotracers may be utilized for amyloid imaging in this study:   
• 
florbetaben (Neuraceq),  
• 
florbetapir (Amyvid)  
• 
flutemetamol (Vizamyl)  
• 
NAV-4694 (Flutafuranol) 
Specific risk information for florbetaben, florbetapir and flutemetamol can be found in their corresponding  
Package Insert.  Specific risk information for NAV-4694 can be found in the Investigator Brochure. 
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. If a female is not surgically sterile or post-menopausal by two 
years, a pregnancy test will be performed. Participants with positive pregnancy test will be ineligible for amyloid 
PET imaging.  
2.3.1.2 RISKS ASSOCIATED WITH LUMBAR PUNCTURE (LP) 
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 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. 
2.3.1.3 GENETIC RISKS 

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NIH policy requires that de-identified genomic data is uploaded to a secure government sponsored health research 
database for broad sharing with approved investigators.  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. 
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. 
2.3.1.4 PSYCHOLOGICAL RISKS OF REFERRAL FROM THE APT WEBSTUDY 
When a participant is identified as having increased risk for future development of AD based on their profile and 
performance in the APT Webstudy, they will be contacted by email or phone to present for an in-clinic evaluation 
to have their increased risk explained and to consent for screening to join the in-clinic TRC-PAD cohort. Participants 
deemed ineligible at the in-clinic evaluation may be referred for further clinical evaluation of a non-AD diagnosis 
and/or returned to the APT Webstudy for continued tracking. Risks associated with this process include negative 
outlook based on the invitation for further evaluation of memory performance as part of the APT Webstudy. In the 
case of individuals referred from other studies where their amyloid status may be known, they might be referred 
to in-clinic evaluation to join the TRC-PAD cohort if eligible. These individuals may therefore bypass the APT 
Webstudy completely. 
2.3.1.5 PSYCHOLOGICAL RISKS FROM ELIGIBILITY RESULTS  
Once eligibility testing is performed there will be an eligibility discussion session where results about study 
eligibility and increased risk for future development of AD will be shared with participants. It is possible that some 
participants may be upset by learning the results of their TRC eligibility assessment which indicates an increased 
risk of developing AD in the future. However, in recent studies, there was no deleterious effect of learning about 
increased risk for AD by learning amyloid status on depression or anxiety scales (Pontecorvo, Avid A18 study, 
Dementia Ger Cog Disord 2017; Mozersky et al, 2018 Sokrates study, JAMA Neurology).  The Imaging Dementia – 
Evidence for Amyloid Scanning (IDEAS) study, led by Dr. Rabinovici, has scanned over 18,000 cognitively impaired 
patients with amyloid PET. The study is monitoring all known causes of death following amyloid PET disclosure, and 
thus far no suicides have been reported.   
2.3.1.6 RISK ASSOCIATED WITH LOSS OF PRIVACY 
In this study, a great deal of information about participant health status is collected. Study staff at the clinic sites 
will be collecting personal protected health information such as name, date of birth, address, phone number, and 
emails. All participants will be given a participant code number as part of the in-clinic TRC, and all data collected 
under this protocol will be associated with the code number. The data, associated with the code number, will be 
shared widely, but it will not be possible to identify an individual participant from the data. However, there is a 
very unlikely possibility that there will be a security failure, and that somehow the protected health information 
will be no longer protected. This is an extremely unlikely but possible occurrence and is a risk of this study. 

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2.3.2 KNOWN POTENTIAL BENEFITS  
By enrolling in the in-clinic TRC cohort, individuals with increased risk for developing AD will have the opportunity 
to participate in AD prevention clinical trials.  Volunteering for the study may be associated with a sense of 
altruism and helping the community to address a serious disease affecting many people. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Although there is some risk associated with PET imaging (e.g. radiation exposure) and lumbar puncture (pain), the 
benefits of enrolling in a prevention study for AD are far greater, as there are currently no treatments for the 
prevention of AD and the opportunity to have access to medications that slow the development of AD dementia 
outweighs these risks.  
 
3 
OBJECTIVES AND ENDPOINTS 
Aim 1: To build an efficient and sustainable recruitment system in order to enroll and retain an initial TRC-PAD 
Cohort. This approach will markedly accelerate recruitment timelines, shorten time to site activation for trials, and 
reduce unexplained variance in pre-trial cognitive testing, as compared to current recruitment approaches.   
Aim 2: To optimize an innovative, adaptive risk algorithm to efficiently identify the most appropriate trial 
participants. Once optimized, this algorithm will be able to select amyloid positive individuals (and eventually tau 
and other neurodegenerative biomarkers) with >75% accuracy, greatly reducing future costly biomarker screen 
fails.   
Aim 3: To develop and validate web-based cognitive and functional outcome measures for future clinical trials. 
Baseline and longitudinal cognitive performance (including lack of practice effect on repeated web-based cognitive 
tests), decline on performance based functional measures, and a combination of self- and study-partner report will 
predict and subsequently track with in-person measures of cognitive (PACC) and functional (CDR-SB) decline.  
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
This is a prospective, longitudinal observational study primarily aimed at enrolling well-characterized, AD 
biomarker-positive individuals into preclinical and prodromal AD clinical trials. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The rationale for the study design is to develop and utilize the APT Webstudy and the TRC cohort to accelerate AD 
prevention trial enrollment through an innovative, highly efficient approach to identify, evaluate, and enroll 
appropriate preclinical and prodromal trial candidates as the current methods of recruitment for prevention 
studies is slow and has extremely high screen fail rates (~80%) and adds years to the duration of such studies.  

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4.3 
END OF STUDY DEFINITION 
Given the overarching goal of the study to facilitate and accelerate enrollment of participants into clinical trials, 
there is no specific end point.  Study activities are anticipated to continue until funding is no longer available.     
 
5 
STUDY POPULATION FOR IN-CLINIC TRC 
5.1 
INCLUSION CRITERIA 
In order to be eligible, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated availability and willingness to comply with all study procedures until referred to a clinical trial  
3. Age 50-85 (inclusive) 
4. Global CDR score of 0 or 0.5 and no diagnosis of dementia 
5. Has a study partner that is willing to participate as a source of information and has at least weekly contact 
with the participant (contact can be in-person, via telephone or electronic communication). The study 
partner must have sufficient contact such that the investigator feels the study partner can provide 
meaningful information about the participant’s daily function. 
6. In good general health as evidenced by medical history 
7. Adequate visual and auditory acuity to allow neuropsychological testing 
8. Fluent in English or Spanish 
9. For females who are not surgically sterile or post-menopausal by two years, receiving a PET scan for 
amyloid biomarker confirmation: negative pregnancy test prior to amyloid PET scan 
10. Completed six grades of education or has a good work history 
11. Evidence of elevated or intermediate (subthreshold) levels brain amyloid as assessed by central review of 
amyloid PET or CSF data.  Prior amyloid testing results may be used with approval from the Coordinating 
Center.   
Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the Project Director 
and Coordinating Center. 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Treatment with an investigational anti-amyloid drug or other experimental intervention within 12 
months.  Use of aducanumab or other approved anti-amyloid treatments allowed if stable for at least 3 
months. 
2. Enrolled in another interventional clinical trial within the last 12 weeks  
3. Any significant neurologic disease such as Alzheimer’s disease dementia, 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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4. Major depression, bipolar disorder as described in DSM-V within the past 1 year or psychotic features, 
agitation or behavioral problems within 3 months, which could lead to difficulty complying with the 
protocol 
5. History of schizophrenia (DSM V criteria) 
6. History of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria) 
7. Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled 
diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the 
opinion of the Investigator, may either put the participant at risk because of participation in the study, or 
influence the results, or the participant’s ability to participate in the study. 
8. History within the last 3 years of a primary or recurrent malignant disease with the exception of non-
melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, 
cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen post-treatment 
9. 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. 
10. Clinically significant abnormalities in screening laboratories. 
11. For participants undergoing CSF collection: a current blood clotting or bleeding disorder, or significantly 
abnormal PT or PTT at screening or if on anti-coagulation (e.g. warfarin) 
12. Participants whom the Site PI deems to be otherwise ineligible. 
• 
Site PIs should consult with the Coordinating Center on any issues that may disqualify the 
participant from participation in future clinical trials to determine whether enrollment into TRC 
would be appropriate.  
Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the Project Director 
and Coordinating Center. 
5.3 
SCREEN FAILURES 
Screen failures are defined as participants who do not meet inclusion criteria or do meet exclusionary criteria and 
therefore are not entered in the TRC cohort. A minimal set of screen failure reasons is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities.  
Individuals who screen fail on the basis of amyloid results, may be rescreened in the future with approval by the 
Coordinating Center or, if cognitively impaired, may be referred by the clinic for evaluation of possible non-AD 
diagnosis.  
Screen fail participants may continue in the APT Webstudy for ongoing remote, longitudinal monitoring of their 
cognitive performance to assess for any increased risk of developing AD.  
5.4 
CLINICAL TRIAL PARTICIPATION AND TRC STATUS 
Individuals enrolled into TRC and then screened for clinical trials are placed on temporary inactive status at the 
time of consent for the clinical trial.  Data regarding clinical trial screening and participation will be reported in the 
eCRF.  Upon completion of trial activities, participants are reactivated in TRC, resuming 6 months visits as per the 
SOA.   

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The Site PI may request from the Medical Monitor that he/she be provided amyloid testing results to inform pre-
screening for a specific trial protocol.  In some cases, certain screening procedures may need to be repeated at the 
time of re-entry into TRC.  Consult with the Coordinating Center for guidance on a case-by-case basis.     
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment will occur through a variety of mechanisms.  ATRI will use a coordinated recruitment plan to ensure 
that enrollment occurs in a timely fashion.  The overall goals of the plan are to raise awareness of AD trials among 
targeted populations to ensure rapid and adequate enrollment in prevention trials.  The study recruitment and 
retention team will develop materials specific to the APT Webstudy and the TRC-PAD Cohort for use by the sites, 
provide ongoing recruitment assistance and support, and develop tracking procedures to monitor effectiveness of 
recruitment efforts.  Efforts will be made to target at least 20% minority enrollment, through minority community 
outreach initiatives facilitated by the coordinating center. 
The study’s goal is to enroll at least 2,000 participants, however in support of the overarching goal to facilitate and 
accelerate enrollment of participants into clinical trials, enrollment into TRC is anticipated to continue over the 
entire study period and may exceed 2,000 participants.   
6 
  PET TRACERS 
Each participant receiving a PET scan for eligibility confirmation will be scanned with an Amyloid PET tracer – which 
tracer is used will be determined based on availability at the site for this study.  Amyloid PET results will be 
generated centrally using quantitative metrics to assess level of amyloidosis, and eligibility information for 
continuing in the TRC cohort will be returned to site. 
6.1 
DOSING AND ADMINISTRATION OF AMYLOID PET TRACERS 
Florbetaben (Neuraceq):   
Florbetaben will be provided by Piramal Imaging Ltd. One mL (1 mL) of the solution for each injection/vial contains 
300 MBq of florbetaben. The other ingredients are ascorbic acid, ethanol anhydrous, macrogol 400, sodium 
ascorbate, and water for injections.  Image acquisition should begin 90 minutes after injection.  The effective dose 
resulting from a 300 MBq (8.1 mCi) administration of Neuraceq in adult participants is 5.8 mSv. The use of a CT 
scan to calculate attenuation correction for reconstruction of Neuraceq images (as done in PET/CT imaging) will 
add radiation exposure. Diagnostic head CT scans using helical scanners administer an average of 2.2 ± 1.3 mSv 
effective dose (CRCPD Publication E-07-2, 2007). The actual radiation dose is operator and scanner dependent. 
Thus, the total combined radiation exposure from Neuraceq administration and subsequent scan on a PET/CT 
scanner is estimated to be 8 mSv.    
Florbetapir (Amyvid):   
Scanning entails 10mCi injection of tracer administered through an intravenous line and a 50-minute uptake until 
20-minute image acquisition begins. Image acquisition occurs over a 20-minute period. The effective dose resulting 
from a 370 MBq (10 mCi) dose of Amyvid is 7.0 mSv in an adult, (19 x 370 = 7030 μSv = 7.030 mSv). The use of a CT 
scan to calculate attenuation correction for reconstruction of Amyvid images (as done in PET/CT imaging) will add 
radiation exposure. Diagnostic head CT scans using helical scanners administer an average of 2.2 ± 1.3 mSv 
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total radiation exposure from Amyvid administration and subsequent scan on a PET/CT scanner is estimated to be 
9 mSv. 
Flutemetamol (Vizamyl):   
The recommended dose for Vizamyl is 185 megabecquerels (MBq) [5 millicuries (mCi)] in a maximum dose volume 
of 10 mL, administered as a single intravenous bolus within 40 seconds. The maximum mass dose is 20 
micrograms. Follow the injection with an intravenous flush of 5 to 15 mL of 0.9% sterile sodium chloride injection. 
NAV-4694 (Flutafuranol):   
The recommended dose is 8.1 mCi (300 MBq) (± 10%) of [18F]NAV-4694 will be injected intravenously followed by 
an infusion line flush of 15-20 mL of normal saline. The Investigator’s Brochure has additional details regarding this 
amyloid radiotracer.  
7 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE IN-CLINIC TRC STUDY 
Participants are free to withdraw from participation in the study at any time upon request. An investigator may 
discontinue or withdraw a participant from the study for any reason. Examples include: 
• 
Participant develops dementia: Any participant who develops dementia will be discontinued from the 
study at the next follow up visit. 
• 
Adverse experience:  The participant has experienced an adverse event that requires early termination. 
This may include abnormal laboratory values. 
• 
Death 
• 
Protocol violation:  The participant fails to meet protocol entry criteria or did not adhere to protocol 
requirements. 
• 
Non-compliance: The participant is non-compliant with completion of study-related evaluations. 
• 
In the investigator’s judgment, it is in the participant’s best interest to discontinue participation in the 
study. 
• 
Consent is withdrawn.  The participant wishes to withdraw from the study, or the legally authorized 
representative wish the participant to be withdrawn.  
• 
Lost to follow up.  Participant could not be recalled back to conduct follow up visits. 
• 
Loss of informed study partner.  The participant no longer has an informed study partner. 
7.1.1 CLINICAL TRIAL PARTICIPATION 
Participants who screen into clinical trials will be placed in temporary inactive status in TRC-PAD at the time of 
consent into the clinical trial, the participant would return to active status following completion of participation in 
the trial (see Section 5.4). 
7.2 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for two scheduled visits and is unable to 
be contacted by the study site staff.  

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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 30 days or at the 
discretion of the PI. The site will also counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 2 telephone calls and, if necessary, a certified letter 
to the participant’s last known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
CLINICAL AND COGNITIVE ASSESSMENTS  
 
8.1.1 PRESCREEN PHASE  
During the prescreen phase, participants will be enrolled in the APT Webstudy and once triggered for increased 
risk of developing AD, will be referred to in-person clinical evaluation. Participants for whom evidence of brain 
amyloid has already been confirmed, may be referred for in-person clinical evaluation to participate in TRC and 
bypass the APT Webstudy. 
Prior amyloid testing, when applicable, should be confirmed prior to screening. 
8.1.2 SCREENING  
The purpose of the Screening Visit is to further determine eligibility for the TRC cohort and to complete the 
informed consent. The screening procedures will be conducted as outlined in the Schedule of Activities (section 
1.3). 
Procedures may be performed on separate days as long as all procedures are conducted within the visit window.  
Screening Stages 1 and 2 must be completed within a 60-day window.  Screening stage 3 should be completed 
within 84 days of the start of screening activities. It is acceptable to delay some assessments if the study cannot be 
properly conducted due the COVID-19 pandemic. In these cases, reach out to the Coordinating Center for 
additional guidance. 
Screening Stage 1 data will be centrally reviewed prior to site being authorized to proceed with Stage 2 (amyloid 
testing via PET or CSF) and again prior to the site being authorized to proceed with Stage 3 (eligibility discussion).  
Sites may not proceed with Stages 2 or 3 of screening until authorized. 
If a female is not surgically sterile or post-menopausal by two years, a pregnancy test will be performed locally at 
the site prior to conducting the PET scan. Participants with positive pregnancy test will be ineligible for amyloid PET 
imaging. 
Screening visit procedures may be repeated if clinically necessary (e.g. to follow-up on an abnormality identified on 
clinical labs) or if data from the initial procedure is not analyzable (e.g. PET scan QC failure).   

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8.1.2.1 BIOMARKER CONFIRMATION USING SHARED IMAGES AND/OR RESULTS  
Participants who have previously undergone amyloid testing via PET or CSF under another research study may 
provide consent to have their PET scan, CSF sample, PET scan results and/or CSF results shared with the 
Coordinating Center for the purposes of biomarker confirmation at Screening Stage 2.   
In such instances, approval from the sponsor of the other research study may be required prior to sharing of data 
or images.   The Coordinating Center will work with the site and, if needed, the study sponsor on securely 
transferring the relevant data, ensuring that no identifiable information is shared with the Coordinating Center.  
The following are examples of how data may be shared with TRC: 
• 
PET scan or CSF sample – scan/sample will be submitted to the Coordinating Center using standard 
submission procedures for central analysis 
• 
PET or CSF analysis results (e.g. quantitative data) – data will be transmitted from the study sponsor or 
site to the Coordinating Center for review and evaluation against TRC entry requirements 
• 
A report indicating that the participant was deemed eligible for a particular study based on amyloid 
testing results – report will be transmitted from the study sponsor or site to the Coordinating Center for 
review and evaluation against TRC entry requirements 
To the extent possible, data will be incorporated into the TRC data sets and will be shared along with other TRC 
data as described in Section 10, however this may not be possible if the study sponsor requires restrictions on data 
sharing with the site or with other investigators.    
In the event that a participant consents to having prior results shared, but the study sponsor does not provide their 
approval for sharing, the site investigator will consult with the Coordinating Center to obtain approval prior to 
enrollment. 
8.1.2.2 WELLNESS TELEPHONE CHECK  
Telephone calls will be made to participants within 72 hours after amyloid PET tracer administration or lumbar 
puncture, and after an in-person eligibility discussion to ascertain if adverse events occurred post procedure.   The 
phone check following an in-person eligibility discussion will also include the administration of the Impact of 
Events Scale. 
Additional telephone visits may be conducted during the study period at the discretion of the Site PI.  
8.1.2.3 ELIGIBILITY DISCUSSION  
Participants deemed eligible for TRC enrollment following completion of all screening procedures, including 
amyloid testing, will meet with a licensed clinician (M.D., M.B.B.S., N.P., D.O., PA-C, A.P.R.N.) in person to discuss 
their eligibility for the study.  A telephone call rather than in-person discussion of eligibility results may be done at 
the discretion of the Site PI in the following scenarios:  
• 
For eligible participants who had previously been disclosed results of prior amyloid testing. 
• 
For ineligible participants.  
Participants who are ineligible for TRC may remain in the APT Webstudy.    

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For participants having an in-person discussion of eligibility results, the Concerns about Alzheimer’s Disease 
Questionnaire and Future Time perspective Scale will be administered following the discussion and a 72-hour 
wellness telephone check will be conducted that includes administration of the Impact of Events Scale.   
8.1.3 ACTIVE STUDY PHASE (ONGOING 6-MONTH ASSESSMENTS)  
The remaining study procedures will be conducted as outlined in Schedule of Activities (section 1.3).  Timing of 
each follow-up visit is calculated from the start of screening.  Procedures for each visit may be completed over 
multiple days but must occur within the window of +/-21 days from the visit’s target date.   
Screening visit procedures may be repeated at follow-up visits, with approval from the Coordinating Center, if 
needed to assess potential changes in eligibility for clinical trials, e.g. after participation in a clinical trial or 
prolonged enrollment in TRC without successful enrollment in a trial.   
8.1.4 PHYSICAL AND NEUROLOGICAL EXAMINATION 
A physical and neurological examination will be performed at each visit as listed in SOA (section 1.3) by a medically 
qualified, licensed clinician.  The physical examination will consist of a review of the major body systems (i.e. skin, 
HEENT (head/ears/eyes/ nose/throat), cardiovascular, pulmonary, abdomen, musculoskeletal, and extremities).   
Neurological examination will include an assessment of cranial nerves, strength, coordination, reflexes, sensation, 
tremor, gait and mental status.  
8.1.5 VITAL SIGNS 
Vital signs will be collected at each visit as indicated in SOA (section 1.3) and include weight, systolic and diastolic 
blood pressure, pulse, temperature and respiration rate.  Height will be taken at the screening visit only. 
8.1.6 MEDICAL HISTORY 
The participant’s lifetime medical history will be collected as listed in SOA (section 1.3). Medical history includes 
previous and current diseases, psychiatric history, and substance use history.  
8.1.7 COGNITIVE, FUNCTIONAL, AND WELL-BEING ASSESSMENTS 
Study participants will undergo the following cognitive and functional assessments: 
• 
PACC (PACC):  The PACC is a composite measure that comprises the Total Recall score from the Free and 
Cued Selective Reminding Test (FCSRT), the Delayed Paragraph Recall score on the Logical Memory Iia test 
from the Wechsler Memory Scale, the Digit-Symbol Substitution test from the Wechsler Adult Intelligence 
Scale-Revised, and the MMSE total score (Mormino et al. 2017). Psychometrists administering the PACC 
are required to complete an PACC training and certification process. The administration of the PACC will 
be recorded (audio only) for quality review purposes and for additional analyses according to locally 
applicable laws and regulations. 
• 
COGNITIVE FUNCTION INDEX Index (CFI):  The CFI is a modified version of the Mail-in Cognitive Function 
Screening Instrument, a participant- and study partner-reported outcome (patient-reported outcome) 
measure. This assessment includes 15 questions that assess the participant’s perceived ability to perform 
high level functional tasks in daily-life and their sense of overall cognitive functional (Walsh et al. 2006; 
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• 
CLINICAL DEMENTIA RATING SCALE SUM OF BOXES (CDR-SB):  The CDR-SB37, 38 is a clinical scale that rates 
the severity of dementia as absent, questionable, mild, moderate, or severe (global CDR scores of 0, 0.5, 
1, 2, or 3, respectively). The score is based on interviews with the participant and study partner, using a 
structured interview that assesses six domains: memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care.  The Sum of Boxes score affords a more refined 
measure of change.  Reliability and validity of both global and SB scores have been established. 
• 
CONCERNS ABOUT ALZHEIMER’S DISEASE: Concerns about Alzheimer’s Disease is a short self-report 
instrument about one’s concern about developing Alzheimer’s disease dementia. It is adapted from 
Roberts and Connell 2000. 
• 
IMPACT OF EVENTS SCALE: The IES (Horowitz et al. 1979) is a 15-item self-report measure that assesses 
two common responses related to a specific stressful life event: intrusion and avoidance.  It is a reliable 
scale that can be anchored to any specific life event and permits the assessment of participants over time, 
comparison of the degree of distress among subgroups, and comparison of the impact of various events. 
The IES has been anchored to test-related distress in previous genetic testing studies and has been 
adapted for amyloid testing related distress.  
• 
FUTURE TIME PERSPECTIVE SCALE: The Future Time Perspective scale (Roberts 2000; Lang and 
Carstensen 2002) measures a person’s perception of his or her remaining time which in turn has been 
shown to explain the priority of specific goals. 
• 
ASSESSMENT OF PSYCHOLOGICAL WELL-BEING (STAI, GDS): The Assessment of Psychological Well Being 
is composed of questions from a validated shortened version (Marteau and Bekker 1992) of the “state 
anxiety” portion of the State-Trait Anxiety Inventory (STAI; Spielberger et al. 1983) and from the Geriatric 
Depression Scale (GDS; Sheikh and Yesavage 1986). It is a self-report assessment designed to identify 
symptoms of anxiety and depression in the elderly. The anxiety portion of the assessment consists of 6 
questions that the subject indicates on a scale from 1 (not at all) to 4 (very much) on how much of a given 
anxiety symptom they are currently experiencing to assess anxiety level. The depression portion of the 
assessment has 15 questions that the subject is asked to answer yes or no based on how they felt over 
the past week in an effort to assess depression symptoms. The more benign items are asked first. Answers 
to 5 of the items are negatively oriented for depression (for example, Do you feel full of energy?) and 10 
positively oriented (for example, Do you often feel helpless?).  
8.2 
LUMBAR PUNCTURE  
CSF samples will be collected in the morning after an 8-hour fast.  Consult with ATRI for guidance if adherence to 
this scheduling requirement is problematic, e.g. due to participant travel.  If the participant arrives for the 
procedure without having fasted as instructed, sites may still proceed with the procedure and record fasting status 
on the relevant eCRF.   
Prior to lumbar puncture (LP), a coagulation panel and platelet count will be obtained to rule out a clotting 
disorder.   Labs will be analyzed locally or centrally within 3 months prior to the LP.  Participants taking an anti-
platelet agent (e.g. aspirin) may be discontinued from that agent for a period of time before and after the LP at the 
discretion of the PI (or qualified designee). Participants who are taking anticoagulants (e.g. warfarin (Coumadin) 
and/or dabigatran (Pradaxa)) may not undergo an LP. 
An MRI or CT prior to LP and LP under fluoroscopy are permitted, if needed, with approval by the Medical Monitor 
on a case-by-case basis.  The participant should be appropriately consented prior to the additional procedure 
according to local site requirements.   

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A total volume of 20 mL of CSF should be collected for each LP. To clear blood associated with needle insertion, the 
first 1-2 mL (or more if needed) of CSF should be discarded.  1-2 mL CSF (or volume per local laboratory 
requirements) will be sent to the local laboratory for protein, glucose, and cell counts. Remaining CSF will be 
frozen on dry ice or in a -80 freezer and shipped overnight frozen to the ATRI Laboratory and Biorepository for 
processing and analysis.  Analyses will include AD biomarkers (e.g. Aβ and tau, exploratory biomarkers).  Amyloid 
CSF results will be generated centrally using quantitative metrics to assess level of amyloidosis, and eligibility 
information for continuing in the TRC cohort will be returned to site. 
Each study participant or a person designated to speak for them will be contacted by phone 72 hours after the LP 
to confirm participant well-being and to query about any adverse events. 
CSF samples will be shipped to the Alzheimer’s Therapeutic Research Institute (ATRI) Laboratory and Biorepository 
at the University of Southern California (USC).  Sample analysis will be performed by the ATRI Laboratory and 
Biorepository and laboratories they contract with. 
8.3 
GENOMIC AND PLASMA AD BIOMARKER SAMPLES 
Blood for genomic and plasma AD biomarker analyses will be collected after an 8-hour fast.  Consult with ATRI for 
guidance if adherence to this scheduling requirement is problematic, e.g. due to participant travel.  If the 
participant arrives for the procedure without having fasted as instructed, sites may still proceed with the 
procedure and record fasting status on the relevant eCRF. 
There is growing evidence that genomic characteristics may impact a participant’s response to therapy. Variable 
response to therapy may be due to genomic determinants that impact drug absorption, distribution, metabolism, 
and excretion, the mechanism of action of the drug, the disease etiology and/or the molecular subtype of the 
disease being treated. Therefore, blood samples will be collected for several types of genomic analysis. 
Apolipoprotein E (APOE) genotyping is a mandatory part of this study. Neither participants nor investigators will 
receive the genotyping results unless there is a country-specific law or regulation that requires notification of the 
results. The samples will be coded with the participant number and stored indefinitely for future analyses. The 
samples and any data generated from them can only be linked back to the participant by investigator site 
personnel.  
Whole blood samples will be shipped to the Alzheimer’s Therapeutic Research Institute (ATRI) Laboratory and 
Biorepository at the University of Southern California (USC) for extraction of genomic and plasma samples. At sites 
where the capabilities exist, additional blood will be collected and processed locally for plasma, then shipped to 
the ATRI Laboratory and Biorepository.  Genomic and biomarker analysis will be performed by the ATRI Laboratory 
and Biorepository and laboratories they contract with. 
Plasma concentrations of Aβ species and tau will be determined from processed blood samples using either 
validated or research grade immunoassay and/or mass spectrometry methods.  Analysis of Aβ species and tau is 
intended to understand these plasma-based biomarkers as compared to other clinical, cognitive, and imaging 
measures. Other sources of Aβ species, including plasma exosome-based amyloids thought to be associated with 
amyloid accumulation may also be analyzed. Our goal is to determine the optimal pre-processing pathway and 
analytical approach to measurement of plasma Aβ ratios to reduce negative amyloid PET scans and LP studies. 
Banked plasma specimens may also be used for other emerging biomarkers that may become available, including 
measures of Neurofilament Light chain (NfL), and specific tau fragments.  

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8.3.1 SAMPLES FOR BIOMARKER STORAGE AND FUTURE RESEARCH  
Collection of biomarker samples for long-term storage and future research is also part of this study.  Plasma, whole 
blood, and CSF samples will be shipped to the Alzheimer’s Therapeutic Research Institute (ATRI) Laboratory and 
Biorepository at the University of Southern California (USC) for long-term storage and future research.  Sample 
collection, handling, and shipment will occur according to the procedures described in the relevant ATRI Biomarker 
Procedures Manual. Analysis may be conducted on possible novel biomarkers  to evaluate their association with 
clinical outcomes. Analysis of these data could provide an important biomarker that would guide future decisions 
by clinicians and researchers. The stored samples will be coded with the participant number and stored indefinitely 
for future research.  The samples and any data generated from them can only be linked back to the participant by 
investigator site personnel.  Because of the exploratory nature of these analyses and because the results should 
not change medical management, neither participants nor investigators will receive the test results. 
8.4 
SAFETY AND OTHER ASSESSMENTS 
 
8.4.1 CONCOMITANT MEDICATION REVIEW  
Concomitant medications will be reviewed at every visit as indicated in SOA (section 1.3).  
8.4.2 CLINICAL LABORATORY ASSESSMENTS  
Clinical labs will be performed centrally as indicated in SOA (section 1.3) and will consist of Hematology, Chemistry 
Panel, TSH, Vitamin B12, and urinalysis.  Lab reports will be reviewed, signed and dated by the site Principal 
Investigator (or a medically-qualified individual delegated by the PI).  If a value is outside of the laboratory’s 
normal range, the clinician will indicate if it is clinically significant or not.  Those results that are deemed clinically 
significant may need to be repeated and follow up with the participant’s primary care physician for further 
evaluation should occur. 
If a participant is having lumbar puncture, a coagulation panel and platelet count will be obtained either locally or 
centrally prior to the LP (within 3 months), in order to rule out a clotting disorder.  
If a female is not surgically sterile or post-menopausal by two years, a pregnancy test will be performed locally at 
the site prior to conducting the PET scan. Participants with positive pregnancy test will be ineligible for amyloid PET 
imaging. 
8.5 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.5.1 DEFINITION OF ADVERSE EVENTS 
An adverse event (AE) is defined as any untoward medical occurrence.  Adverse events deemed related to the 
study compounds (e.g. PET tracers) or procedures by the site investigator and serious adverse events occurring 
within 2 days of PET tracer administration, regardless of causality, will be tracked during the study.  
The following events are considered adverse events: 
(1) worsening or change in nature, severity, or frequency of conditions or symptoms present at the start of 
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(2) participant deterioration due to primary illness 
(3) intercurrent illness  
(4) drug interaction  
Abnormal laboratory and imaging findings will only be reported as an AE if the PI or medical designee considers it 
to be clinically significant or if it leads to the participant being withdrawn from the study. 
The investigator should attempt to establish a diagnosis of the event based on signs, symptoms, and or other 
clinical information. In such cases, the diagnosis should be documented as the AE and not the individual signs or 
symptoms.  Symptoms and conditions present at the beginning of the study will be characterized, so that AEs can 
be defined as any new symptom, or any increase in frequency or severity of an existing symptom. Adverse events 
should be described with medical terminology so that the event can be matched against a medical coding 
dictionary, such as Medical Dictionary for Regulatory Activities (MedDRA).  
Investigators should report their assessment of the potential relatedness of each AE to the protocol compounds 
and procedures.  Following questioning and evaluation, only AEs, determined to be related to the protocol 
compounds or procedures by a medically qualified Site PI or medical designee or serious adverse events occurring 
within 2 days of PET tracer administration, regardless of causality, must be documented in the participant’s 
records, in accordance with the investigator’s normal clinical practice, and on the AE eCRF. 
8.5.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
A serious adverse event is defined as an adverse event or suspected adverse reaction that results in any of the 
following outcomes:  
1. 
Death 
2. 
A life-threatening adverse event 
3. 
In-patient hospitalization or prolongation of existing hospitalization (see below for more information 
regarding hospitalization) 
4. 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5. 
A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Hospitalizations that fulfill one of the following conditions will not have to be reported as SAE: 
• 
Admission for treatment of a pre-existing condition that is not associated with the development of a new 
AE or with a worsening of the pre-existing condition (i.e., work-up for persistent lab abnormality that 
occurred prior to the study) 
• 
Social admission (i.e., participant has no place to sleep) 
• 
Administrative admission (i.e., yearly physical exam) 
• 
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• 
Optional admission not associated with a precipitating clinical AE (i.e., pre-planned treatments, elective 
cosmetic surgery) 
For more detail, refer to the Code of Federal Regulation Title 21 Part 312: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32 
8.5.3 CLASSIFICATION OF AN ADVERSE EVENT (AE) 
Reporting standards for reporting AEs will be provided in the relevant procedures manual and must be followed 
regardless of applicable regulatory requirements that may be less stringent.  
8.5.3.1 
SEVERITY OF EVENT 
All AEs will be assessed by the study clinician using a protocol defined grading system. The following guidelines will 
be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious”. 
8.5.3.2 RELATIONSHIP TO STUDY COMPOUNDS OR PROCEDURES 
The investigator or designated, licensed clinician is responsible for determining whether or not an event is related 
to study compounds (e.g. PET radiotracer), specific study procedures or “other study procedure(s)”. “Other study 
procedure(s)” refers to any other procedure outside of those specified that may have a causal relationship to the 
AE. 
• 
Definitely Related – The event is clearly related to a study compound or procedure. There is clear 
evidence to suggest a causal relationship. The influence of other factors can be ruled out. 
• 
Probably Related – The event is likely related to a study compound or procedure. There is evidence to 
suggest a causal relationship, such as reasonable temporal sequence. The influence of other factors is 
unlikely. Suggest a causal relationship. The influence of other factors can be ruled out. 
• 
Possibly Related – suggest a causal relationship. The influence of other factors can be ruled out. 
• 
Unlikely Related – A poor temporal relationship exists between the event onset and study compound or 
procedure. The event could easily be explained by the participant’s clinical state, intercurrent illness, or 
concomitant therapies. 
• 
Not Related - There is no evidence of a causal relationship and a causal relationship cannot be reasonably 
attributed to the study compound or procedures. The event is clearly due to extraneous causes. 
8.5.3.3 EXPECTEDNESS  
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the IB, package insert, or 
device labeling or is not listed at the specificity or severity that has been observed; or, if an IB is not required or 
available, is not consistent with the risk information described in the protocol, as amended.  

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8.5.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Adverse events will be reported from the time of signing the TRC informed consent until signing an ICF for a clinical 
trial, and will resume following completion of the trial and reactivation in TRC.  
Following up on AEs:  The investigator is obliged to follow participants with AEs until the events have resolved, the 
conditions are considered medically stable, or the participants are no longer available for follow up. Participants 
who discontinue due to adverse experiences will be treated and followed according to established medical 
practice. All pertinent information will be entered into the eCRF. 
8.5.5 ADVERSE EVENT REPORTING  
Adverse events deemed related to the study compounds (e.g. PET tracers) or procedures by the Site PI will be 
tracked during the study. The principal investigators and ATRI staff will monitor the study procedures for this study 
for overall safety and scientific relevance on an ongoing basis. The local site PI (in conjunction with, as needed, the 
Medical Monitor and the data safety monitoring board (DSMB)) will evaluate each serious adverse event for safety 
and causality and will determine whether the adverse event affects the risk/benefit ratio of the study and whether 
modifications to the protocol or consent form are required. 
8.5.6 SERIOUS ADVERSE EVENT REPORTING  
Serious adverse events deemed related to the study compounds (e.g. PET tracers) or procedures by the Site PI or 
occurring within 2 days of PET tracer administration, regardless of causality, will be tracked during the study.  Any 
serious adverse event meeting either requirement which occurs during the course of the investigation (i.e. any 
time after informed consent) or within 30 days of last study visit must be reported to the Medical Monitor at ATRI 
within 24 hours of learning of the event.  ATRI Medical Safety team will generate an SAE report, which will be 
distributed to all participating sites and to the central IRB.    
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator deems 
the event to be chronic or the participant is stable. Other supporting documentation of the event may be 
requested by ATRI’s Medical Safety group and should be provided as soon as possible. 
8.5.7 REPORTING EVENTS TO PARTICIPANTS 
Study participants at an aggregate level will be informed by the Investigator or designated site clinician as deemed 
clinically necessary by ATRI.  
8.5.8 EVENTS OF SPECIAL INTEREST  
N/A 
8.5.9 REPORTING OF PREGNANCY  
Pregnancy is not an adverse event, but some studies will require unique considerations if pregnancy was to occur 
during the study. A participant who is enrolled in the TRC cohort who becomes pregnant can continue in the 
cohort but eligibility for enrollment in to a preclinical/prodromal AD trial will occur once pregnancy (and any 
interval of breast feeding) are complete. 

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8.6 
UNANTICIPATED PROBLEMS 
 
8.6.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections considers unanticipated problems involving risks to participants or 
others to include, in general, any incident, experience, or outcome that meets all of the following criteria:  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being studied  
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
the research).   
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
ATRI Coordinating Center staff will monitor the unanticipated problems for overall safety and scientific relevance 
on an ongoing basis and provide information to the Data Safety Monitoring Board.  
8.6.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board (IRB) and to 
the Coordinating Center via the AE eCRF. The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the Coordinating Center 
within 24 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the Coordinating Center within 24 hours of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported by the site to appropriate institutional officials (as required by an institution’s 
written reporting procedures), upon receipt of the report of the problem from the investigator.  
8.6.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Participants will be informed by the Investigator or designated site clinician as deemed clinically necessary by the 
Coordinating Center.  
8.7 
GLOBAL UNIQUE IDENTIFIER 

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A Global Unique identifier (GUID) will be generated for each participant if permissible based on local and regional 
laws/requirements. A GUID provides a method to link collections of research data and specimens, balancing the 
competing goals of distinguishing individuals, collecting accurate information for matching, and protecting 
confidentiality. Certain personal identifying information (PII) is collected by the site and submitted to an algorithm 
to create the GUID, which will then be recorded in the CRF.  The PII fields employed in this approach are invariant 
over the lifetime of the subject. This approach has proven to adequately discriminate individuals in both simulation 
and field studies (Johnson et al., 2010).  Software will be provided to sites to generate the GUID using a standard 
algorithm so that the PII itself will not be submitted or stored centrally.  
9 
STATISTICAL CONSIDERATIONS  
All statistical analyses will be based on a pre-specified statistical analysis plan (SAP). This plan will be informed by 
preliminary data analysis done mid-way during the study to identify the presence of potential sources of bias, 
including but not limited to the distribution and nature of the data, confounding effects, and amount and type of 
missing data.  Each metric of interest will be initially assessed descriptively. For categorical data, we will use rates 
as the outcome measures, excluding the missing and unknown cases. For continuous data, parametric (one-sample 
t-test), non-parametric (Wilcoxon signed rank test) or resampling approaches (bootstrap or jackknife techniques) 
will be used, as appropriate. Comparisons between metrics from recent, current-technology trials and the TRC-PAD 
metrics will be made using 95% confidence intervals. A p-value of 0.05 will be used to conclude significant 
differences between the two study groups. For comparisons of metrics across different sub-groups of interest, t-
tests, chi-square tests or resampling techniques will be used, as appropriate for the type (continuous, categorical) 
and distribution (normal, non-normal) of the data. Regression models (generalized linear models or generalized 
linear mixed models), as appropriate, will be used to examine associations of covariates of interest with the TRC-
PAD metrics. 
All statistical analyses will be conducted at the end of the grant cycle with all available data at the point of data 
cut-off date. Due to the exploratory nature of these aims, no adjustments will be made for multiple comparisons. 
However, data will be reported as point estimates and confidence intervals to provide the magnitude and 
variability around each of the estimates. All analyses will utilize R (www.r-project.org). 
Statistical Aim 1: This approach will markedly accelerate recruitment timelines, shorten time to site activation for 
trials, and reduce unexplained variance in cognitive testing. 
Analysis Plan: The use of adaptive approaches to participant selection, data capture and data monitoring will 
continually optimize the approach. At the end of the five years, formal tests of hypotheses will be conducted to 
assess the success of the web-based mechanisms by quantitative and qualitative analysis, in particular comparing 
timelines, cost, screen failure rates and the measured change and variance in cognitive scores to those in 
preclinical and prodromal studies for which similar data can be obtained. Two-sided, one-sample tests of means 
(recruitment timelines and time to site activation) or variances (variance in cognitive testing) or corresponding 
resampling techniques will be used to detect differences between the TRC-PAD sample and comparator data.  
Power Analysis: Power analyses for these hypotheses were done using a two-sided, one-sample t-test for means 
and a one-sample test of variance using the software PASS. A reduction of 10% in mean recruitment timeline, 
mean time to site activation and unexplained variance in cognitive testing is considered scientifically meaningful.  
While the sample size selected was based on the need for a Cohort sufficiently large to support an efficacy trial, we 
have examined the power of this sample to test our hypotheses.  1. A sample size of 2000 participants achieves 
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assuming current estimates of 120+/-40 days respectively.  2 Estimates of baseline variability from completed AD 
trials range between 4.5 and 10 points in ADASCog11 score within a site. A sample size of 2000 participants 
achieves 90% power to detect a difference of at least 0.4 points (5% change) in unexplained standard deviation of 
cognitive scores, assuming a type I error rate of 5%.  Thus, there is adequate power to detect very small 
differences and looking at multiple sub-groups of interest would not compromise power. 
Statistical Aim 2: Once optimized, this algorithm will be able to select amyloid positive individuals (and eventually 
tau and other neurodegenerative biomarkers) with >75% accuracy, greatly reducing future costly biomarker screen 
fails.  
Analysis Plan: Initial amyloid PET results will be compared to historical data from preclinical and prodromal studies 
for which similar data can be obtained and, for prodromal participants, published data from gantenerumab and 
avagacestat studies.  Standard statistical methods (t-tests for continuous measures and chi-square tests for 
categorical measures) will be used to compare the participants identified as biomarker positive and biomarker 
negative. Associations between an indicator of biomarker positivity and each of the potential risk factors will be 
assessed in a two-staged manner using a generalized linear model with a logit-link function or a generalized linear 
mixed model for binary data (to account for the measurements over time for an individual participant). Univariate 
associations deemed to be statistically significant (p <0.15) will be included in a multivariable logistic regression 
model. Potential confounding and effect-modifying variables will be included in the model as covariates, if 
necessary. The risk factors and the appropriate functional form of these factors that will be utilized in the model 
will be clearly stated in the SAP and will be based on the results of the preliminary analysis. An individual 
participant’s predicted risk of biomarker positivity will be calculated using the final multivariable risk prediction 
model and serve as a risk-algorithm.  The performance of this model will be assessed using four measures: the 
concordance index (c-index) to evaluate the discrimination ability, the calibration slope and calibration in the large 
to evaluate the model calibration, and decision-curve analysis to assess clinical usefulness. The model will be 
internally validated using 10-fold cross-validation and bootstrap sampling.   
Power Analysis: Power analysis was done using a comparison of the area under a ROC curve (AUC) with a null 
hypothesis value of 0.75. Assuming a total sample size of 2000 participants and a 60% amyloid expected positivity 
rate, we have 90% power to detect an AUC of at least 0.80 using a two-sided z-test and a level of significance of 
5%. 
Statistical Aim 3: Baseline and longitudinal cognitive performance, (including lack of practice effect on repeated 
web-based cognitive tests), decline on performance based functional measures, and a combination of self- and 
study-partner report will predict and subsequently track with in-person measures of cognitive (PACC) and 
functional (CDR-SB) decline.  
Analysis Plan: To assess the associations between web-based cognitive tests and in-person measures, linear mixed 
models will be used to accommodate the dependencies of scores over the follow-up time period. Such models 
accommodate different times of measurement, time varying and time invariant covariates as well as missed 
measurements and data from participants who are lost to follow-up. Permutation tests may be implemented to 
verify that valid p-values will be obtained even if model assumptions are not correct.  
Power Analysis: Assuming a correlation coefficient of 0.6 as the true correlation between these measures, we have 
90% power to observe a correlation as low as 0.67 with a sample size of 1000 participants and a type I error rate of 
5%. Hence, the sample size will have adequate power to detect clinically meaningful associations between the 
web-based and in-person measures of decline. 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Informed consent will be obtained in accordance with 45 CFR 46, 21CFR 50, 21 CFR Part 56 and in adherence to ICH 
GCP.  Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and/or legally authorized representative (LAR) and written documentation of informed consent is 
required prior to starting study procedures.  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that will be initiated prior to the individual’s agreeing to participate in the study and 
will continue throughout the individual’s study participation. Consent forms will be Institutional Review Board 
(IRB)-approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. A verbal explanation will be 
provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential risks of the 
study and of their rights as research participants.  Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants will have the opportunity to discuss the 
study with their family or surrogates or think about it prior to agreeing to participate if they wish. The participant 
will sign the informed consent document prior to any procedures being done specifically for the study. Participants 
must be informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records.  For 
participants with cognitive impairment, a legally authorized representative is allowed to provide consent on their 
behalf.  The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights and welfare 
of the participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
The informed consent will not only cover consent for the study itself, but broad sharing of all study data (including 
clinical, cognitive, imaging, biomarker and genetic data), as well as storage of biological samples for future 
research (genetic and biomarker samples). 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 not receive results.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause.    If the 
study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. 

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Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, 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 sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review 
Board (IRB), regulatory agencies or pharmaceutical company supplying study product may inspect all documents 
and records required to be maintained by the investigator, 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. 
The study participant’s contact information will be securely stored at each clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the ATRI. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by clinical sites and by ATRI research staff will be 
secured and password protected. At the end of the study, all study databases will be archived at the ATRI. 
CERTIFICATE OF CONFIDENTIALITY  
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the National 
Institutes of Health (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. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study, including audio recordings, will be analyzed and stored at the ATRI. After the study is 
completed, the archived study data will be transmitted to and stored at the ATRI, for use by other researchers 
including those outside of the study. Transition of all study data to the ATRI will be included in the informed 
consent.  

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With the participant’s consent, biological samples will be stored at the ATRI Biospecimen Repository with the same 
goal as the sharing of data by the ATRI. These samples could be used to research the causes of AD and related 
neurodegenerative diseases, and its complications. The ATRI Biospecimen Repository will also be provided with a 
code-link that will allow linking the biological specimens with the phenotypic data from each participant, 
maintaining the blinding of the identity of the participant. 
During the conduct of the study, an individual participant can choose to withdraw consent to have biological 
specimens stored for future research. However, withdrawal of consent with regard to biospecimen storage may 
not be possible after the study is completed or if the biological specimen has already been shared.  
When the study is completed, access to study data and/or samples will be provided through the ATRI and the ATRI 
Biospecimen Repository. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator  
Project Director 
Principal Investigator 
Principal Investigator 
Medical Monitor 
Paul Aisen, MD  
Reisa Sperling, MD 
Jeffrey Cummings, MD 
Michael Rafii, MD 
ATRI USC  
Brigham and Women’s 
Hospital 
University of Nevada Las 
Vegas 
ATRI USC 
9860 Mesa Rim Road  
San Diego, CA 92121  
USA 
60 Fenwood Road 
Boston, MA 02115 
USA 
4505 S Maryland 
Parkway 
Las Vegas, NV 89154-
4022 
USA 
9860 Mesa Rim Road 
San Diego, CA 92121 
USA 
 
 
 
 
  
  
 
  
 
10.1.6 SAFETY OVERSIGHT 
The Data Safety Monitoring Board (DSMB) is an independent group providing recommendations to the ATRI 
Director, study leadership and the NIA.  No investigator involved in the study is a member of the DSMB.  
The initial task of the DSMB will be to review the protocol to identify any necessary modifications. If modifications 
are necessary, revisions will be reviewed by the DSMB prior to its recommendation on initiation of the project. The 
DSMB, based on its review of the protocol, will work with the Coordinating Center personnel to identify the study-
specific data parameters and format of the information to be regularly reported.  All adverse events and serious 
adverse events will be reported to the DSMB.  The DSMB and NIA representative will meet in person or by 
conference call on an annual basis.  The DSMB may at any time request additional information from ATRI.  
Based on the review of safety data, the DSMB will make recommendations regarding the conduct of the study. 
These may include amending safety monitoring procedures, modifying the protocol or consent, terminating the 
study or continuing the study as designed.  Details of the process will be clearly described in the DSMB charter, 
finalized prior to study start. 
10.1.7 CLINICAL MONITORING 

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The ATRI 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 (as described in 
the monitoring plan) must be conducted according to the applicable ICH and GCP guidelines to ensure protocol 
adherence, quality of data, drug accountability (if needed), compliance with regulatory requirements and 
continued adequacy of the investigational site and its facilities.  The Site Investigator 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 Investigator will promptly address any matters brought to his/her attention 
by the monitor. The Site Investigator may also be asked to meet in-person with the site monitor during certain 
visits. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control (QC) procedures will be implemented beginning with the data entry system.  Data QC checks that 
will be run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical study is 
conducted, data are generated and biological specimens are collected, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
In accordance with ICH GCP, representatives of the Coordinating Center and/or regulatory agency may select this 
study for audit.  The Investigator and study staff are responsible for maintaining the site master file containing all 
study-related regulatory documentation as outlined by Regulatory Affairs that will be suitable for inspection at any 
time by ATRI, its designees, and/or regulatory agencies. Inspection of site facilities (e.g., pharmacy, laboratories) to 
evaluate the study conduct and compliance with the protocol may also occur.  
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
ATRI is responsible for overseeing research clinical data collection and standardization, data management, data 
transfer, and quality control. 
STUDY DATA COLLECTION AND STORAGE 
Study data will be collected in the following ways: 
• 
the Principal Investigator or designee will record data collected (either written or electronic record of 
data) 
• 
the participant or study partner will complete assessments on paper 
Written or electronic data of record must be entered on the electronic Case Report Form (eCRF) provided for that 
purpose, except where instructed to use only the computerized system for capture of a particular assessment.  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 other computerized systems 

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used for data collection and appropriate site personnel will be authorized to provide electronic signatures. The 
Principal Investigator is responsible to verify the integrity of the data and acknowledge as such by signature. 
All data will be collected in secure web sites or computer systems and the Principal Investigator will review the 
records for completeness.  If corrections are necessary to the eCRFs or data collected via other systems, the 
Principal Investigator or designee will correct the data and provide documentation for the reason for change.  
Sites will complete eCRFs and administer and submit data from computerized assessments according to ATRI’s 
instructions.  ATRI will review all data to determine their acceptability.  If necessary, data correction requests will 
be generated for resolution by the study site.    
STUDY FILES AND PARTICIPANT SOURCE DOCUMENTS 
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 Investigator, 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, PID) to maintain confidentiality.  
All physical records will be kept in a locked file cabinet.  All computer entry and networking programs will be done 
using PIDs only. Information will not be released without written permission of the participant, except as necessary 
for monitoring by IRB, 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 investigator, 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. 
RESEARCH BIOSPECIMENS AND GENETIC MATERIAL STORAGE 
All research biospecimens, including DNA and other residual samples and derivatives from processing and analysis, 
will be coded and stored securely by the central research laboratories.  Sample tubes will be identified only by a 
code number and descriptive data (such as the participant’s age and gender). No other personal identifying 
information will be attached to the samples.  
Samples collected from participants who do not consent to banking of those samples for future analysis will be 
destroyed after all protocol-related analyses are completed. 
PET IMAGING DATA STORAGE   

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PET scans will be labeled according to each site’s imaging machine capabilities using Participant ID and scanner 
specific series descriptions as detailed in the Technical Manual. All imaging data will be coded using participant 
identifiers as detailed in the Technical Manual and checked centrally to confirm the absence of participant 
identifying information.  
10.1.9.2 STUDY RECORDS RETENTION  
The investigator, institution or designated representative is responsible for retaining all study documents 
(including but not limited to essential documents and study records).  Refer to your contract and institution for 
guidelines on duration of time study records should be retained.  Coordinating Center approval is required prior to 
destruction of study records or offsite storage. 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical study protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the participant, 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
The investigator may not implement any protocol deviation without prior notification to the 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 study (ICH 4.5.4).  
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
The results of this study will be published.  To coordinate dissemination of data from this study, a publication 
committee will be formed.  The committee will consist of the study PIs, the study biostatisticians, and others at the 
discretion of the ATRI Director.  
SHARING OF STUDY DATA 
Data from this research will be shared with other researchers pursuant to the 02/26/2003 “NIH Final Statement on 
Sharing Research Data” and pursuant to the 8/24/2014 “NIH Genomic Data Sharing Policy”. The NIH policies can be 
found at:   
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html and 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html.  
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.  To protect participants’ rights and confidentiality, identifiers will be removed 
from the data before they are shared. 

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SHARING OF BIOSPECIMENS AND GENETIC MATERIAL   
Research biospecimens and DNA from consenting participants will be banked and may be shared with other 
researchers studying AD, aging, or other health conditions to facilitate future research.  Banking of these samples 
will permit qualified investigators to probe candidate biomarkers and genetic polymorphisms as predictors of 
outcome in future studies.   
Genetics, genomics, and related data will be shared with other researchers pursuant to the NIA Alzheimer’s 
Disease Genetics sharing Policy: http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan. 
National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), along with other NIA-
approved sites, will make genetic, genomic and related data and associated phenotypic data available to qualified 
investigators in the scientific community for secondary analysis in accordance with standards established by NIA. 
These data repositories are under strict security provisions, including multiple firewalls, separate servers, and data 
encryption protocols. Investigators and their sponsoring institutions seeking access to data from the NIA-approved 
data repository must submit a data access request (that specifies both the data to which access is sought and the 
planned research use) and agree to the terms of access set forth in the Data Use Certification. Investigators are 
approved by a Data Access Committee for access to specific datasets for a specific use(s).  
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical.  Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this study will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this study.   
10.1.13 
DATA AND COORDINATING CENTER 
The USC Alzheimer’s Therapeutic Research Center (ATRI) will serve as the Data and Coordinating Center. No 
human subjects will be enrolled at USC ATRI. Under the direction of Dr. Paul Aisen, ATRI will provide 
comprehensive data management, clinical operations, clinical monitoring and regulatory oversight for this study.  
All user and study data are stored and maintained on servers hosted on Amazon Web Services under an Enterprise 
Agreement with USC which stipulates rights and responsibilities between both parties. AWS implements 
sophisticated technical and physical controls designed to prevent unauthorized access to or disclosure of customer 
content which have been independently validated to meet or exceed ISO 27018 (Information technology --Security 
techniques --Code of practice for protection of personally identifiable information (PII) in public clouds acting as PII 
processors).  
All communication to and from the data system is encrypted. All user and study data transmissions occur through a 
secure internet connection-HTTPS over TLS 1.0 and higher (Hypertext Transfer Protocol within a connection 
encrypted by Transport Layer Security) using secure 128 bit and stronger ciphers. 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. Each user of the system has an individual account with a 
password which is required to be reset at set intervals to comply with USC ATRI password requirements. Users are 
logged out of the system after a period of inactivity. 

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10.2 ADDITIONAL CONSIDERATIONS 
Not applicable. 
 
 

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10.3 ABBREVIATIONS 
AD 
Alzheimer’s Disease 
AE 
Adverse Event 
APOE/APOE4 
Apolipoprotein E (APOE) epsilon 4 (APOE4) 
APT 
TRC-PAD Program:  Alzheimer Prevention Trials Webstudy 
ATRI 
Alzheimer’s Therapeutic Research Institute 
CDR/CDR-SOB 
Clinical Dementia Rating (CDR) Sum of Boxes (CDR-SOB) 
CFI 
Cognitive Function Index 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CSF 
Cerebrospinal Fluid 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GUID 
Global Unique Identifier 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
LAR 
Legally Authorized Representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR/MRI 
Magnetic Resonance / Magnetic Resonance Imaging 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
SAE 
Serious Adverse Event 

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SUSAR 
Suspected Unanticipated Serious Adverse Reaction 
T 
Tesla 
TRC 
TRC-PAD Program:  In-Clinic Trial-Ready Cohort Study 
TRC-PAD 
Trial-Ready Cohort for Preclinical/Prodromal AD Trials Program 
TSH 
Thyroid Stimulating Hormone 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Overview of Changes  
Brief Rationale 
1.0 
26NOV2018 
Original 
 
2.0 
14MAR2019 
Revised screening and baseline procedures, 
including visit schedule, eligibility 
requirements, and options for use of prior 
testing for eligibility; clarified participant 
status while involved in a clinical trial; 
adjusted the definition of reportable AEs and 
SAEs; revised lab collection procedures and 
added location of central research specimen 
storage facility; added allowance for LAR to 
consent; updated information about 
coordinating center and data security; 
updated the name of the Medical Monitor 
Study procedures being refined 
prior to study start. 
3.0 
15SEP2020 
Allowing NAV-4694 tracer; Adding GUID; 
Removing C-SSRS; Removing ECG; 
Increase Sites to 50; Flexibility on out-of-
window visits and phone visits due to 
COVID 
Allowing a new tracer for 
amyloid PET scans for sites. 
Adding GUID for future linkage 
of participants in treatment 
trials, C-SSRS not required for 
this assessment, removing ECG 
and COVID disruptions increase 
need for out-of-window 
flexibility 
4.0 
14SEP2021 
Typos and Formatting throughout 
document; Exclusion Criteria #1 was 
modified to include aducanumab; Change 
to screening visit window: Screening 
Stages 1 and 2 must be completed within 
a 60-day window and Screening stage 3 
should be completed within 84 days of 
the start of screening activities 
This will allow for central 
authorization to review blood 
plasma analysis 
4.1 
11NOV2022 
Change to Navidea Dose from 8.1 mCi 
(300 MBq) (± 20%) to 8.1 mCi (300 MBq) 
(± 10%) 
Providing a target dose of a 
single specified value  
 
 
 
 
 
 
 
 
 
 

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