Risk Evaluation and Education for Alzheimer's Disease - the Study of Communicating Amyloid Neuroimaging (REVEAL-SCAN)
Phase: NA
Conditions: Alzheimer Disease, Amyloid Beta-Peptides, Risk Assessment, Education, Neuropsychological Tests, Neuroimaging
Sponsor: Brigham and Women's Hospital

Risk Evaluation and Education for Alzheimer’s Disease – the Study of Communicating 
Amyloid Neuroimaging (the REVEAL-SCAN Study) 
Detailed Protocol  
November 8, 2019 
National Institutes of Health/National Institute on Aging: RF1 AG047866 
 
ClinicalTrials.gov Number: NCT02959489 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Coordinating Center Detailed Protocol 
 
PRINCIPAL/OVERALL INVESTIGATOR(S) 
 
Robert Green, MD, MPH  
 
PROTOCOL TITLE 
 
Risk Evaluation and Education for Alzheimer’s Disease – the Study of Communicating Amyloid 
Neuroimaging (the REVEAL-SCAN Study) 
 
FUNDING 
 
National Institutes of Health/National Institute on Aging: RF1 AG047866 
 
VERSION DATE 
 
08 NOV 2019 
 
 
I. Background and Significance 
 
Alzheimer’s disease (AD) clinical trials have traditionally tested potential treatments for 
individuals with symptoms of dementia, but the discovery of AD biomarkers has dramatically 
altered this approach. Trials such as the Anti-Amyloid in Asymptomatic Alzheimer’s Study, or 
A4 Study, are now focusing on enrolling cognitively normal participants who have biomarkers 
suggestive of “preclinical AD” in order to delay the onset of cognitive impairments. This goal 
presents two questions of critical importance to both the validity and safety of these trials, and 
the successful translation of their results into clinical practice: (1) Will individuals’ knowledge of 
their biomarker status bias cognitive outcomes? (2) Will such knowledge prompt beneficial 
behavior changes or cause adverse psychological and social consequences? The goal of this 
study is to answer these questions. 
 
The A4 Study is the first large-scale AD prevention trial to enroll cognitively normal persons 
who learn that they have elevated levels of brain amyloid. This trial is already underway, yet 
critical knowledge gaps exist: no studies describe the neuropsychological or behavioral effects of 
disclosing PET amyloid imaging results to cognitively normal individuals. If simply learning that 
one is biomarker positive causes a person to perform worse on cognitive testing, then primary 
outcomes data of AD trials may not be valid. Moreover, since amyloid imaging received FDA 
approval for use in cognitively impaired individuals, our preliminary studies show that clinical 
investigators want guidance on whether and how to disclose amyloid imaging results, not only to 
these individuals, but also to cognitively normal older individuals.   
 
Our randomized clinical trial aims to examine the impact of learning amyloid imaging results in 
cognitively normal individuals. Our sample will be drawn from a racially diverse population, 
allowing us to address the generalizability of results. The core team that will conduct this project 

has worked together for over ten years on the NIH-funded REVEAL (Risk Evaluation and 
Education of Alzheimer’s Disease) Study trials that have studied risk estimation, risk 
communication and the disclosure of apolipoprotein E (APOE) genotype for risk of AD. For this 
project, this core team is strengthened by additional collaborators with expertise in amyloid 
imaging, neuroethics, neuropsychological assessment, minority outreach and recruitment, and 
the impact of psychological expectations and cultural biases (stereotype threat) on cognitive 
performance, and a close integration with the A4 Study, including the use of the same primary 
endpoint, amyloid PET scan reading protocol, and disclosure process.  
 
Alzheimer’s disease (AD) is a continuum of cognitive decline caused by progressive 
neurodegeneration associated with accrual of amyloid plaque and tau tangle pathologies.  
New diagnostic guidelines prepared by the NIA and the Alzheimer’s Association recognize: a 
preclinical or asymptomatic stage, a mild cognitive impairment stage, and a dementia stage.1,2 
Across these stages, biomarkers are increasingly recognized as core diagnostic features critical to 
understanding the pathophysiology and ultimately, the treatment of AD.3 Perhaps the most 
advanced of the in vivo biomarkers is amyloid imaging.4-11 The 2012 FDA approval of 
florbetapir PET amyloid imaging for the detection of neuritic amyloid plaques (Aβ+ when 
present) paved the way for clinical use of this technology.12 
 
Converging data show that asymptomatic Aβ+ individuals already have “AD-like” changes in 
brain structure and function.13-16 When followed, persons who are Aβ+ decline cognitively and 
show accelerated brain atrophy in comparison to Aβ- persons.9,17-19 These data, along with 
similar data based on cerebrospinal fluid (CSF) biomarkers of AD pathology, have led to the 
concept of “preclinical AD” in which Aβ+ deposition is an early event in a pathophysiological 
cascade that includes neurofibrillary pathology, inflammation, synaptic dysfunction, neuronal 
loss, and, ultimately, cognitive decline and dementia. In most studies, 20%-40% of cognitively 
normal older individuals show high tracer binding.20 The prevalence of amyloid-positivity in 
cognitively normal individuals is age-dependent and correlates highly with the presence of 
apolipoprotein (APOE) e4, the major genetic risk factor for sporadic AD.21-23 
 
Secondary prevention trials planned or underway will enroll participants who are 
cognitively normal and have positive or “elevated” amyloid. Prospective cohort studies 
suggest that Aβ deposition takes place over decades, and that it may precede even mild clinical 
symptoms by 15 years or more.24,25 The long preclinical phase of AD is seen as a potential 
therapeutic window in which anti-amyloid therapies might be initiated before irreversible brain 
damage has occurred.26 Secondary prevention clinical trials of amyloid-focused therapies in 
asymptomatic individuals are being launched, two in familial AD and one (the A4 Study) in 
cognitively normal individuals who are Aβ+ by PET imaging.27-29 As a condition of enrollment, 
A4 Study participants are informed that they have elevated amyloid. “Elevated amyloid” is a 
term developed by the A4 Study to describe a result that combines a visual and quantitative read. 
It is conceptually analogous to a “positive amyloid PET scan,” and “not elevated” is analogous to 
a “negative scan.”  
 
The impact of disclosing amyloid status itself may affect key clinical trial outcomes. 
Learning that one has a neurocognitive diagnosis,30 or even that one is at risk for AD dementia31 
can have a deleterious effect neurocognitive performance. We do not know whether participants 

who learn that they have elevated amyloid will exhibit diminished neuropsychological 
performance, biasing cognitive outcomes in trials. There is also concern that these test results 
may cause psychological distress. For example, the Alzheimer’s Association and Society of 
Nuclear Medicine and Molecular Imaging report on Appropriate Use Criteria for Amyloid PET 
states that the clinical use of amyloid PET in asymptomatic individuals is “not appropriate…the 
potential harms outweigh the minimal benefits.”8 Yet, there has never been a careful assessment 
of the likelihood and extent of these potential harms. Although amyloid imaging has only been 
approved by the FDA for those with cognitive impairment, it will likely be used “off-label.” For 
example, in a recent survey of dementia specialists, 24% reported that they planned to use 
amyloid imaging to screen asymptomatic individuals,32 and in a separate survey of ADNI 
researchers that we conducted, over half of ADNI investigators supported the return of amyloid 
imaging to cognitively normal ADNI research participants.33   
 
African Americans (AAs) are historically underrepresented in clinical trials, including AD 
clinical trials. A significant challenge in conducting research has been in obtaining sufficient 
participation and retention among AAs in order to better understand health disparities and their 
impact.34-36 AD research studies typically do not include large numbers of AAs, a group that is at 
high risk for AD37 but also historically reluctant to participate in medical research.38 As clinical 
trials for AD are implemented, it is critically important to make sure that underrepresented 
minorities, particularly AAs, are included and that questions of potential bias in outcomes and 
risk-benefit balance be understood so that trial results in this population are equally valid. In this 
study, through a partnership with Duke,39 we will include at least 25% AAs. 
 
The team proposing this study has worked for many years on how to disclose the risk of 
AD. The organizing principle of this proposal is that amyloid burden is a risk factor similar to 
APOE genotype, but we recognize that we are studying a distinct and novel research question. 
REVEAL Study data are used in this proposal to demonstrate our capability to perform this type 
of research. Our prior experiences with the REVEAL Study are highly relevant to the 
methodology needed to conduct this research, and to the outcomes to be measured.  
 
Relevance to future decision-making in both clinical trials and clinical practice. The major 
relevance of this work will be to the design of future clinical trials that use AD biomarkers such 
as amyloid as part of the inclusion criteria and the translation of their results into clinical 
practice. If we demonstrate substantive cognitive bias, the sample size of future trials may need 
to be increased, and sub-analyses of our data (not described in this proposal) could guide us to 
select tests or batteries of tests that are less vulnerable to stereotype bias. If we demonstrate that 
there are individuals who become anxious or severely distressed in response to learning their 
amyloid status, future trials may require processes for recognition and treatment of such 
symptoms. While our recruitment procedures will not result in a subject pool that is 
representative of clinical practice, these insights will also be relevant to guide clinicians in 
ordering and communicating results of amyloid imaging to cognitively normal individuals. Our 
study is not designed to formally measure costs or resource utilization, but will measure the 
degree to which subjects seek consultation and order additional diagnostic tests after obtaining 
amyloid imaging. This information will help researchers and clinicians begin to understand the 
downstream implications of amyloid imaging as it becomes increasingly utilized. 
 

 
II. Specific Aims 
 
We will enroll 370 cognitively normal individuals, aged 65-80, using APOE genotyping with 
oversampling of e4+ individuals to enrich the enrollment sample such that roughly 30% of those 
scanned will be amyloid elevated (A+) and the remainder amyloid not elevated (A-). From this 
enriched sample, 370 participants (approximately 25% African American) will all receive their 
Alzheimer’s Disease Dementia Risk Disclosure and be randomized (50/50) to either receive their 
amyloid scan results (Disclosure or D+) at the disclosure visit or not at the disclosure visit (D-). 
Those in the D- group will receive their amyloid scan results at an additional visit at the end of 
the study. The primary cognitive outcome will be the A4 Study’s Preclinical Alzheimer 
Cognitive Composite and the primary outcome for psychological distress will be the Impact of 
Events Scale (IES). We plan the following analyses: 
 
Specific Aim #1: To determine whether disclosure of elevated brain amyloid will bias 
ADCS-Preclinical Alzheimer Cognitive Composite (ADCS-PACC) test results.  
At 6 months after disclosure… 
Primary Hypothesis 1.1:  ADCS-PACC scores will be lower among A+D+ participants than 
A+D- participants. 
Exploratory Hypothesis 1:2: African-Americans will demonstrate a higher level of 
neuropsychological bias in response to amyloid imaging results than other racial groups due to 
complex sociocultural reasons which can negatively influence cognitive testing outcomes.  
 
Specific Aim #2: To determine whether disclosure of elevated brain amyloid will cause 
psychological distress.  
At 6 months after disclosure… 
Secondary Hypothesis 2.1:  A+D+ participants will have greater IES scores than A-D+ or D- 
participants. 
Exploratory Hypothesis 2.2:  A+D+ participants will have higher scores on scales of subjective 
memory complaints than A+D- participants. 
Exploratory Hypothesis 2.3:  Comparison of outcomes at 6 weeks and 6 months after disclosure 
will show African-Americans to be equally vulnerable to psychological distress after amyloid 
imaging as other racial and ethnic groups.  
 
Specific Aim #3: To explore how learning amyloid imaging disclosure will impact 
preventative health behaviors, advance planning for health (e.g. long-term care insurance 
decisions) and well-being (e.g. stigma, quality of life and relationships).  
 
Specific Aim #4: To examine whether disclosure of amyloid levels affects performance by 
inducing 
stereotype threat. 
At 6 months after disclosure… 
Quaternary Hypothesis 4.1: The effects of disclosure on task performance will depend upon 
whether or not the 
test is described as assessing cognition. 
Quaternary Hypothesis 4.2: The effects of disclosure on pupil dilation (a measure of effort and 

arousal that is 
assumed to index stereotype threat) will depend upon whether or not the test is described as 
assessing cognition. 
 
 
III. Subject Selection 
 
Eligible participants will be cognitively and neuropsychiatrically normal, fluent English 
speakers, between the ages of 65-80, who have at least one first-degree relative with AD, are 
willing to undergo blinded (undisclosed) APOE genotyping, and are willing to participate in the 
randomized trial of amyloid imaging disclosure. Participants will be excluded if they have 
suffered a stroke or head trauma, have active medical or psychiatric illness that is unstable or 
progressive, or are taking acetylcholinesterase inhibitors or memantine. Participants with a 
history of anxiety or depression that has resolved or that has been treated and is stable will be 
enrolled. Formal documentation of AD family history will not be required as our previous 
REVEAL studies have demonstrated the reliability of self-reported family history of AD. 
 
The inclusion and exclusion criteria for this study include assessment of participants’ mood, 
especially symptoms of depression and anxiety, and persons who score above cut-off scores will 
be excluded. In addition, measures of depression and anxiety are endpoints of the study as well 
as measures of safety. We will decide participants’ eligibility based on conversations between 
the study staff (clinician judgment) and participant, as well as pre-specified cut-off scores in 
screening measures to identify persons in need of additional monitoring:  
 
-Geriatric Depression Scale (GDS) (range 0 to 15): > 10 exclude. 6-10 additional 
monitoring/use discretion on whether to enroll 
 
-State-Trait Anxiety Inventory (STAI) (range 6-24): > 19 exclude. 17-18 increased 
monitoring. 
 
 
-Columbia Suicide Severity Rating Scale (CSSRS): Exclude any serious suicidal risk 
(investigator judgment) 
 
 
To have a sufficient number of elevated amyloid participants for the planned analyses, we will 
enrich the participant pool with additional AD dementia risk factors. Age and having the APOE 
e4 genotype are robustly associated with amyloid positivity and approximately 24% of 
unselected individuals will be e4+. Our experience in the REVEAL Study has indicated that 
among persons who self-identify as having a first-degree family member with AD, the 
percentage of individuals who are e4+ increases to about 47%. Thus, we will restrict 
participation to those who have such a family history. 
 
In addition to enrichment with family history, we will perform APOE genotyping on potential 
participants. Although the REVEAL Study has focused on the disclosure of APOE, in this 
research project we do not want to conflate disclosure of an AD risk gene variant with the 
disclosure of an AD biomarker, so the results of APOE genotyping will not be returned to the 

participants. Instead, APOE genotyping will be used to increase the mix of participants who are 
e4+ to at least 50%. 
 
“We will not be sharing the results of subjects’ APOE genotyping because we, and each clinical 
study site, will be blinded to these results. APOE results will be only used to enrich our study 
sample to ensure we are effectively randomizing 50% elevated amyloid scans vs. not-elevated 
amyloid scans into each intervention arm. These APOE results will only be reported to the 
centralized data site, Boston University, but not the other clinical sites (Brigham and Women’s 
Hospital, University of Pennsylvania, University of Michigan, and Duke University.” 
 
Recruitment 
All four sites have extensive experience in recruiting participants for AD clinical trials, with 
access to research registries of cognitively normal older individuals willing to participate in AD-
related studies. Participants will be recruited using a variety of methods including interactions 
with family members of patients in memory clinics; review of research registries; clinical trials 
websites; direct referral from neurologists, geriatricians and local Alzheimer’s Association 
chapters; and talks in the community. We will post information about this study on our website, 
and on social media. We will use trifold brochures in clinician offices and at appropriate forums. 
The study will be mentioned in grand rounds, local clinic presentations on AD, and media 
interviews.  
 
No “cold calls” will be made directly to any potential participant, whether identified from a 
patient database or medical record, without the consent of the patient and the patient’s primary 
physician or specialist.   
 
We will include all ethnic groups and men and women equally as part of this study. The study 
population will include both male and female healthy participants, 65 to 80 years of age. There is 
an increased ratio of women to men in AD, and it is anticipated that our recruited sample will 
reflect this ratio. Since AD affects individuals from all ethnic and racial backgrounds, every 
effort will be made to ensure a representative sample of preclinical AD participants. African 
Americans are historically underrepresented in clinical trials, including AD clinical trials. For 
this study of amyloid imaging disclosure, we will aim to recruit at least 25% African Americans 
through a partnership with Duke University. We expect that half of the participants at the Duke 
site will be African Americans.  
 
 
IV. Subject Enrollment 
 
All individuals who contact our study coordinator will be given a brief overview of the study, 
including all potential risks and discomforts, and will be asked if they would like to participate. 
At this initial contact, they will be given the opportunity to ask any questions and to consider 
whether they wish to participate. They will be informed that refusal to participate will not 
interfere with their future medical care.  Whenever possible, the consent form will be given to 
them or mailed to the potential participant and study partner prior to the screening visit to allow 
the participant and study partner, as well as their family, to review the consent form in the 
privacy of their own home. 

 
Should the participant be interested in participating, the study coordinator will set up a time to 
complete a phone interview (Phone Call #1). During the phone interview, subjects will provide 
verbal consent by expressing their interest in participating in the study. The phone interview will 
also explain that our participants will be randomized to one of two groups (initial disclosure of 
amyloid status; or delayed disclosure of amyloid status) and both groups will receive education 
and risk information for developing Alzheimer's disease dementia by age 85 based on age, 
gender, race, and family history of Alzheimer's disease dementia. 
 
At the beginning of the participant's first in-person appointment (Visit #1), he/she will undergo 
an informed consent process and the consent form will be reviewed and signed by each 
participant and the study coordinator.  
 
We will take great care in the informed consent process of all participants. To ensure that the 
participants understand what is being requested and the implications of participation, the impact 
of an elevated amyloid PET scan will be discussed at great length during the consenting process. 
We will review the consent forms with the participants and they will be allowed to ask for 
clarification or questions at any point.  
 
Consent of participants will be a requirement for participation in the research. Participants will 
have normal cognition and will have capacity to provide consent. No surrogates will be used. 
 
At the beginning of the second in-person appointment, the study partner will be consented to 
participate in his/her specific responsibilities, specifically participating in the CDR scale in Visit 
#2. The study partner’s consent form will include language for him/her to be re-contacted by the 
study coordinators to collect additional information from the study partner’s perspective.  
 
Should the participant want his/her study partner present at any visit, and the study partner is 
unable to accompany him/her, then a substitute study partner (a family member or a paid 
caregiver) can be sent.  
 
 
V. Study Procedures 
 
This clinical trial will randomize 370 cognitively normal participants enriched for their odds of 
having elevated amyloid by age, family history and APOE genotype. Written informed consent 
for the study will be sought from all participants. The site-PI or appropriate study staff at each 
site will obtain written consent through a standard informed consent document approved by their 
site’s Institutional Review Board. Informed consent processes are detailed in “Subject 
Enrollment” above. Participants who pass screening will undergo amyloid imaging and then be 
randomized to either (1) learn the results of their amyloid scans at the fourth visit, or (2) not 
learn their result at the fourth visit, though will receive a delayed scan result disclosure within 
approximately four weeks after their 6-month follow-up visit. All participants will receive an AD 
Dementia Risk Assessment based on individual risk factors including age, gender, family history 
and race/ethnicity, with intervention arm participants additionally receiving their amyloid 
imaging results. Follow-up after disclosure will occur via a phone call and up to three in-person 

visits.  
 
Step 1 – Recruitment:  
 
Recruitment will take place through many modalities, such as interactions with family 
members of patients in memory clinics; review of research registries; clinical trials 
websites; direct referral from neurologists, geriatricians and local Alzheimer’s 
Association chapters; news media coverage and talks in the community. Additionally, 
recruitment will rely on self-referral by interested individuals who learn of our study 
from our brochure or community outreach program. We will also be posting a description 
of our study on the Clinicaltrials.gov website.  
 
 
 
Step 2 – Phone Call #1: Initial Screening for Family, Medical, Medication History + 
Collect Demographic information + optional Telephone Interview of Cognitive 
Status (TICS) 
 
During this telephone interview, the study will be described, and a self-reported family 
history, and self-reported medical history will be obtained from the participant. Family 
history questions will include asking if the participant had or has a first degree relative 
with a known diagnosis of amyotrophic lateral sclerosis (ALS), Parkinson’s or 
Parkinsonian disease, Lewy Body disease, or known diagnosis beyond dementia. Formal 
documentation of having a positive family history of Alzheimer’s disease (AD) will not 
be required as past REVEAL trials have previously demonstrated the reliability of a self-
reported family history of AD. If the participant is unsure of his/her family history at the 
time of this phone call, the participant will be able to update the family history at the first 
in-person visit. Medical history questions include past history of stroke or head trauma, 
no active medical or psychiatric illness that is unstable or progressive. Medication history 
questions include taking acetycholinesterase (ACE) inhibitors or memantine. Formal 
documentation of medical and medication history is not needed. 
 
Demographic information will be elicited via a brief survey administered to the 
participant. In addition, information will be collected about previous outside scans, APOE 
testing, testing related to Alzheimer’s disease, and genetic counseling services the 
participant may have received prior to this study. If a participant seems eligible based on 
screening criteria and expresses interest in participating in this study, the study 
coordinator will mail or email the study guide and written consent form for the 
participant to review, and will schedule the in-person screening visit.  
 
If the participant has cognitive complaints, the participant will complete the TICS 
(telephone interview of cognitive status) assessment during this phone call in order to 
initially confirm normal cognitive function. If the participant does not express cognitive 
complaints, the TICS will be administered at the first in-person visit. Participants will be 
excluded on this phone call based on these initial screening criteria (see 
“Inclusion/Exclusion Criteria” section).  

 
Potential participants are asked to identify a study partner for support at this time. The 
participant is required to bring his/her study partner to the second in-person visit to obtain 
official written informed consent and to participate in an interview, and will have the 
option to bring his/her study partner to other study visits. The study coordinator will 
schedule a time for Step 3 – Visit #1 with the participant within approximately one month 
of this initial phone call. 
 
 
Step 3 – Visit #1: Informed Consent (participant) + TICS (if not done at Phone Call 
#1) or MMSE (if TICS done at Phone Call #1) + Measure Blood Pressure + Review 
eligibility criteria + Mood Scales + Buccal sample collection  
 
At the first in-person visit (Visit 1), written informed consent is obtained from the 
participant. The consent form includes information about Alzheimer’s disease dementia 
risk factors and amyloid imaging, how this information pertains to this study, and covers 
all procedures in Steps 4-12 detailed below. The informed consent will be signed by the 
participant, as well as the study coordinator performing the consent.  
 
If the TICS was not performed at Phone Call #1, the participant will complete the TICS 
at this visit. If the TICS was performed at Phone Call #1, the participant will complete the 
Mini-Mental State Exam (MMSE) for the study coordinator to confirm normal cognitive 
function.  
 
The participant’s family, medical, and medication history collected from Phone Call #1 
will be reviewed at this visit, in addition to the study’s eligibility criteria. 
 
Mood scales of the Geriatric Depression Scale (GDS),40 Mini-State Trait Anxiety 
Inventory (Mini-STAI),41 and Columbia Suicide Severity Rating Scale (CSSRS)42 are 
then administered to the participant to assess for signs of baseline depression and anxiety 
(see “Inclusion/Exclusion Criteria” section for cut-off scores).  
 
If the participant is not screened out due to deficiencies on the mood scales, he/she is 
eligible to continue with study participation. 
 
The study participant will have his/her blood pressure measured by a clinical nurse or 
trained clinical personnel. Participants with blood pressure greater than 140/90 will not 
be excluded from the study, but will be recommended to speak to their physician.  
 
Participants with blood pressure greater than 180/110 may be excluded and will be 
recommended to speak to their physician. The participant may choose return to have 
his/her blood pressure re-measured after seeking care from his/her physician. If his/her 
blood pressure is under 180/110 at this return visit, he/she may participate in the study at 
the discretion of the study team. If the participant chooses not to return or if his/her blood 
pressure still exceeds 180/110 at this return visit, the participant will be excluded. 
 

The study participant will have a buccal swab sample collected for genetic testing. Buccal 
swab samples will be sent to the designated CLIA-approved laboratory for genotyping, 
and results will be available in approximately 2 weeks. The consent obtained at the 
beginning of this visit explains that APOE results will not be disclosed as part of the 
study. 
 
If genotyping of the buccal swab sample fails, the study participant will be asked to 
return for a brief in-person visit to collect a new buccal swab sample. If the study 
participant is unable or unwilling to return to complete a second buccal swab sample, the 
study team may offer to mail a buccal swab collection kit, complete with sample 
collection and shipping directions, to their home. 
 
APOE genotyping will be used as part of our screening procedures to enrich our study 
sample with APOE e4+ participants. APOE statuses (labeled with study ID and de-
identified personal health information) will be reported to the centralized data site, 
Boston University.  
 
 
Step 4 – Phone Call #2: Confirm eligibility/ineligibility  
 
The study coordinator will call the participant after the respective site receives the 
participant’s eligibility status, which is based on both APOE status and the prior visit’s 
screening measure scores. Participants will not be told their specific reasons for being 
eligible or ineligible, but those found to be cognitively or emotionally impaired on their 
screening visit (based on the TICS, MMSE and other questionnaires) will be offered 
appropriate referral. If the participant is not screened out, he/she is eligible to continue 
with study participation and the coordinator will schedule Visit 2 within approximately 
six weeks of this phone call. 
 
 
Step 5 – Visit #2: Informed Consent (study partner) + Review Medical History + 
Collect vitals + Clinical Dementia Rating (CDR) Scale with Study Partner + Full 
Education + Pre-/Post-Education Checklists + Neuropsychiatric battery + Mood 
scales + Health Behavior Surveys 
 
The participant will have the option of having his/her study partner accompany him/her 
to any visit. The study partner is encouraged to attend Visit 2 to obtain his/her informed 
consent to be a study partner and to be interviewed for the Clinical Dementia Rating 
(CDR) scale.43 If the study partner is unable to attend in-person, the study team will ask 
the study partner to complete the informed consent process and interview over the phone 
or video call (via use of site-specific approved applications) during the visit. 
 
 
After informed consent of the study partner is obtained, the participant and study partner 
will be interviewed at this visit using a guided interview and worksheets for the CDR 
scale. The results of this brief assessment are intended to provide objective information to 

verify cognitive normal status at study start.  
 
Participants who score >0 on the CDR scale will be notified at this visit, excluded from 
the study at this point in time, and will be offered appropriate referral.  
 
For participants who do not screen out based on their CDR scores, medical history 
(medication and concurrent conditions) will be reviewed at this visit. 
 
The first neuropsychological test battery will be performed at this Visit #2. Baseline 
cognitive status will be ascertained using the Alzheimer’s Disease Cooperative Study 
Preclinical Alzheimer Cognitive Composite (ADCS-PACC) to ensure the participant is 
cognitively normal.44 The ADCS-PACC is comprised of measures of episodic memory 
(Buschke Selective Reminding Test, Logical Memory I, II), timed sensorimotor function 
(Digit Symbol Subtest from the WMS), and a global test of cognition (MMSE). Pre-
specified cut-off scores of safety screening measures are listed under the “Safety of 
Participants” section below.  
 
In addition to the ADCS-PACC, the neuropsychological test battery is also comprised of 
1) a test of effort: Test of Memory Malingering (TOMM)45, 2) a measure of attention and 
short-term memory capacity: Digit Span forward span test46 and 3) a test of premorbid 
function (TOPF)47  
 
After the neuropsychological battery is the full education session. To assess participants’ 
knowledge prior to the education session, we will ask the participant a list of questions on 
a “Pre-Education” checklist. Participants will then receive a full educational session 
about Alzheimer’s disease dementia risk factors, amyloid imaging, and the meaning of an 
elevated and not elevated result in an older adult with normal cognition. The content of 
this written description was generated using a modified Delphi consensus process that 
involved experts in human amyloid imaging and informed consent for genetic testing. It 
includes sections that describe what is amyloid, what is Alzheimer’s disease, how do we 
know whether someone has brain amyloid, what does having a brain amyloid scan 
involve, what does a positive brain amyloid scan mean, is a positive amyloid scan like 
other medical risks, and what a negative brain amyloid scan means. The participant is 
allowed to ask questions regarding the information just learned. After the educational 
session, the participant will complete a “Post-Education” checklist. 
 
The NEO personality index,48 Geriatric Depression Scale (GDS),40 Mini-State Trait 
Anxiety Inventory (Mini-STAI),41 and Columbia Suicide Severity Rating Scale 
(CSSRS),42 are then administered to the participant to assess for signs of depression and 
anxiety (see “Inclusion/Exclusion Criteria” section for cut-off scores).  
 
Subjective cognitive measures of the Metamemory in Adulthood (MIA),49 and Memory 
Function Questionnaire (MFQ),50 will be administered. The MIA 108-item test is used to 
describe memory issues and changes relevant to healthy aging, and assess impact of 
disclosure of perceived cognitive symptoms and abilities.49   The MFQ 64-item test 
reflects subjective appraisals of frequency of forgetting in different situations, the 

seriousness of the consequences of forgetting in these situations, comparison of present 
and past memory functioning, and frequency of memory strategy use; and assesses the 
impact of disclosure of perceived cognitive symptoms and abilities.50  
 
Behavioral health measures obtained at baseline also include: 1) a measure for quality of 
life, the SF-12 Physical and Mental Health Summary Scale – a 12-item multi-purpose 
short form (SF) generic measures of health status, and self-rated overall physical and 
mental health51; and 2) a measure of how individuals view their future with the Future 
Time Perspective Scale – a 10-item scale to assess future time perspective as a 
developmental construct in adults.52 
 
Measures of recall and comprehension, behavioral changes, information sharing and 
interpersonal relationships, willingness and effort to participate, and cognitive symptoms 
will be created for this study. Participants will take these created health behavior surveys 
at baseline and at the 6-week and 6-month follow-up visits (Visits #5 and Visits #6, 
respectively) to determine the type and frequency of behavior changes in response to 
learning risk information. Information collected will include assessing health behavior 
changes, advanced planning, insurance changes (i.e. purchasing or altering long-term care 
policies), medication changes, willingness to enroll in clinical research, stigma, and 
tolerance of research risk. 
 
An Emergency Contact Information sheet will be completed by the participant, including 
two personal emergency contacts and one physician contact. In the event that the 
participant experiences significant study-related distress, the study team may disclose to 
an emergency contact that the participant is enrolled in the study. Amyloid status will not 
be disclosed by the study team. 
 
In addition, Dynamic Experiments for Estimating Preference (DEEP)61 behavioral 
assessments will measure participant risk and time preference as presented electronically 
through various decision-making scenarios. 
 
Finally, the Everyday Discrimination Scale62 has been developed and will be used to 
assess perceived discrimination. 
 
 
Step 6 – Phone call #3: Confirm eligibility/ineligibility + Schedule Scan 
 
The study coordinator will call the participant within two weeks of Visit #2. If the 
participant is not screened out, he/she is eligible to continue with study participation. If 
eligible, the study coordinator will schedule the participant’s PET scan at their site’s 
imaging center, This visit should happen within approximately one month of Visit #2. A 
study coordinator will also call to schedule the disclosure session (Visit #4) within 
approximately two weeks from when the scan results are returned to Boston University. 
 
 
Step 7 – Visit #3: Amyloid Neuroimaging Scan + Randomization 

 
At this third in-person visit, participants who pass the above listed screening measures 
will undergo amyloid imaging via a scheduled PET scan at each site’s respective imaging 
center. Participants will receive a single intravenous administration of approximately 370 
MBq (10 mCi) of florbetapir F 18 amyloid imaging agent. Participants will be positioned 
in the PET scanner and at 50 ± minutes after injection. 
 
Imaging data from this scan visit will be sent to Molecular NeuroImaging (MNI) 
electronically through a secure, already existing Web upload process. The imaging data 
will undergo a comprehensive quality control process consisting of both a technical and 
scientific quality control. MNI has already worked with, and received images from, all of 
the imaging centers in this study and has experience with all study site cameras. Imaging 
interpretations from MNI will be sent directly to our centralized data site, Boston 
University, labeled with study ID and de-identified personal health information.  
 
Boston University will randomize the participants into either (1) Comparison/non-
disclosure arm (D+): participants will learn the results of their amyloid scans at Visit #4 
or (2) Intervention/disclosure arm (D-): participants will not learn their scan results at 
Visit #4, but will return for another in-person visit (Visit #7) after the completion of their 
6-month follow-up (Visit #6) for a delayed disclosure visit.  Participants are randomized 
with a 1:1 randomization for non-disclosure arm: disclosure arm. For participants who 
are randomized in the disclosure arm, their amyloid imaging results of “elevated” or “not 
elevated” amyloid will be returned to their respective sites. 
 
 
Step 8 – Visit #4: Alzheimer’s Disease Dementia Risk Disclosure with (D+)/without 
(D-) Amyloid Scan results (in-person) 
 
All participants will return to the study site for their fourth in-person visit to receive their 
Alzheimer’s Disease Dementia Risk Assessment either with or without their amyloid 
imaging result, as determined by random assignment. At each site, a trained disclosure 
provider will present the participant with generalized reference curves of Alzheimer’s 
disease risk based on age, gender, family history, and race/ethnicity. If the participant is 
randomized to receive their amyloid imaging result, the disclosure provider will 
communicate whether they have elevated or not elevated amyloid and present his/her AD 
dementia risk estimate compared to the general population. 
 
If the participant is randomized to not receive their amyloid imaging result at this visit, 
but will receive their scan result at the end of the study, the disclosure provider will only 
present the participant’s AD dementia risk estimate based on age, gender, family history, 
and race/ethnicity.   
 
The participant will have the opportunity to ask questions.  
 
 
Step 9 – Phone Call #4: 1-3 Day Safety Check  

 
The study coordinator will call the participant in 1-3 days to assess the participant’s status 
as a safety check to assess any psychological impact of the disclosure visit, regardless if 
they are in the immediate scan disclosure group or delayed scan disclosure group. 
Psychological impact of the disclosure visit will be measured by using the Impact of 
NeuroImaging for Alzheimer’s Disease (INI-AD) scale adapted to this study to measure 
the impact of amyloid imaging for AD53 and using the intrusion subscale of the Impact of 
Event Scale (IES). The INI-AD scale is a 16-item multi-dimensional assessment of risk 
disclosure across distress, uncertainty, and positive experience.  
 
The INI-AD was developed and validated in our prior REVEAL trials, and will be 
adapted for this safety check by phone to allow for differentiation of the emotional effects 
of risk disclosure from more general distress or worry. 
 
The IES-intrusion subscale, a 7-item self-reported measure,54 assesses response related to 
a specific stressful life event, and has been specifically anchored to test-related distress in 
studies of the impact of health risk information, including all previous REVEAL Study 
trials. 
 
Pre-specified cut-off scores of safety screening measures are listed under the “Safety of 
Participants” section below. Those found to be cognitively or emotionally impaired will 
be offered appropriate referral. Should safety be a concern, the disclosure provider or 
study coordinator will schedule additional in-person visits or phone calls as needed or 
make a referral to a mental health professional as indicated. 
 
 
Step 10 – Visit #5: 6-Week Follow-Up + Neuropsychological test battery + 
Secondary Outcome Measures + Cognitive Measures + Health Behavior Surveys  
 
Participants will return in-person six weeks (Visit 5) post-disclosure. The 
neuropsychological battery, consisting of the 1) ADCS-PACC as our primary outcome 
measure to assess neuropsychological status,44 2) TOMM,55 3) Digit span forward test 46 
TOPF47 will be administered. 
 
The secondary outcomes measures at six weeks will measure anxiety and depression with 
the GDS,40 mini-STAI,41 and CSSRS measures42; test-specific distress with the Impact of 
Events Scale (IES)54; psychological impact of risk disclosure with the adapted INI-AD; 
quality of life with the SF-12 measure51; and perceived time with the Future Time 
Perspective scale.52  
 
Subjective cognitive measures of the Metamemory in Adulthood (MIA),49 Memory 
Function Questionnaire (MFQ),50 and Cognitive Function Instrument (CFI)56 will be 
administered. 
 
Participants will also take the follow-up health behavior surveys to determine the type 
and frequency of behavior changes in response to learning risk information. Information 

collected will include assessing health behavior changes, advanced planning, insurance 
changes (i.e. purchasing or altering long-term care policies), medication changes, 
willingness to enroll in clinical research, stigma, and tolerance of research risk. 
 
In addition, Dynamic Experiments for Estimating Preference (DEEP)61 behavioral 
assessments will measure participant risk and time preference as presented electronically 
through various decision-making scenarios. 
 
Step 11 – Visit #6: 6-Month Follow-Up + Neuropsychological test battery + 
Secondary Outcome Measures + Cognitive Measures + Health Behavior Surveys + 
Additional Stereotype Threat Measures  
 
Participants will return in person six months (Visit 6) post-disclosure. The 
neuropsychological battery, consisting of the 1) ADCS-PACC as our primary outcome 
measure to assess neuropsychological status,44 2) TOMM,55 3) TOPF47 (4) a non-standard 
Digit span forward test46 under low and high threat will be performed. Pupil dilation, 
which indexes arousal and effort, will be measured by a portable eye-tracking device 
while participants complete the two digit span task sequences. 
 
The first Digit span test46 will be done under low-threat instructions.  Participants will be 
told that the purpose of this test is to calibrate the eye-tracking equipment.  This is mild 
deception.  No calibration will be conducted, but this instruction will reduce any 
evaluative concerns that may be felt by the participants.  It will also provide a reasonable 
explanation for doing the Digit span test twice without revealing the stereotype threat 
manipulation or hypotheses to the participant. The second Digit span test will be done 
after giving high-threat instructions, where the participants will be told that the purpose 
of the test is to assess how memory is affected by levels of amyloid, and that the eye 
tracker measures how difficult the tasks are for them. Of note, this second set of 
instructions contains no deception. We will be analyzing the relationship between 
amyloid levels, memory performance, and pupil responses. Although making clear the 
purpose of the task may cause participants to feel evaluative pressure, this is precisely the 
response that we are interested in measuring. It is worth noting that lab studies 
investigating stereotype threat have often used similar instructional manipulations. In the 
consent form, we have also noted as a risk that distress could be caused by thinking about 
how amyloid status might affect cognitive performance. At the end of the study, 
participants will also be fully debriefed about the full purpose of the experiment.  We will 
explain the full purpose of varying the instructional manipulation.   
 
If a participant’s eyes cannot be tracked for some reason, they will complete the test 
anyway (i.e., they will hear the same instructions and complete the digit span tasks while 
the eye-tracker is on, even if it is not able to calibrate to their eyes). We will administer a 
Vision Questionnaire in order to later determine whether we need to exclude any 
participants from pupil dilation analyses due to vision issues that would impede data 
quality. 
 
The secondary outcomes measures at six months will measure anxiety and depression 

with the GDS,40 mini-STAI,41 and CSSRS measures42; test-specific distress with the 
Impact of Events Scale (IES)54; psychological impact of risk disclosure with the adapted 
INI-AD; quality of life with the SF-12 measure51; perceived time with the Future Time 
Perspective scale52, Essentialist Beliefs about Aging Question63, and a question about 
feelings of stereotype threat about Alzheimer’s disease risk..  
 
Subjective cognitive measures of the Metamemory in Adulthood (MIA),49 Memory 
Function Questionnaire (MFQ),50 and Cognitive Function Instrument (CFI)56 will be 
administered. 
 
Participants will also take the follow-up health behavior surveys to determine the type 
and frequency of behavior changes in response to learning risk information. Information 
collected will include assessing health behavior changes, advanced planning, insurance 
changes (i.e. purchasing or altering long-term care policies), medication changes, 
willingness to enroll in clinical research, stigma, and tolerance of research risk. 
 
In addition, Dynamic Experiments for Estimating Preference (DEEP)61 behavioral 
assessments will measure participant risk and time preference as presented electronically 
through various decision-making scenarios. 
 
 
Finally, the Everyday Discrimination Scale62 has been developed and will be used to 
assess perceived discrimination at Visit 6. 
 
 
Step 12 – Visit #7: Delayed Amyloid Scan Disclosure for Initial D- Group 
 
At the end of study data collection, participants in the control arm will return in-person 
(Visit 7) within approximately four weeks after their 6-month follow-up to learn their 
amyloid imaging results.  
 
 
Step 13 – Phone Call #5 for initial D- Group after delayed disclosure: 1-3 Day Safety 
Check 
Participants initially randomized to be in the delayed non-disclosure (D-) group, who 
later learn their amyloid imaging scan results at Visit #7 will be called by the study 
coordinator in 1-3 days to assess the participant’s status as a safety check. Psychological 
impact of the disclosure visit will be measured by using the adapted Impact of 
NeuroImaging for Alzheimer’s Disease (INI-AD) scale.53 
 
 
VI. Biostatistical Analysis 
 
Data Collection 
 

Data will be collected by the study coordinator and project manager, and monitored by the PI. 
The PI will be responsible for monitoring and assuring the validity and integrity of all data and 
adherence to the IRB approved protocol. 
 
De-identified study data will be collected and managed using REDCap electronic data capture 
tools hosted at Boston University. REDCap (Research Electronic Data Capture) is a secure, web-
based application designed to support data capture for research studies, providing 1) an intuitive 
interface for validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common statistical 
packages; and 4) procedures for importing data from external sources.  
 
Data Coordination 
 
De-identified data is coordinated by Boston University (BU). Subjects will be identified only by 
their assigned randomization number, initials, sex, and year of birth. No names will be used on 
buccal samples or PET scans that will be sent to diagnostic laboratories to link information to a 
specific person. If medically necessary to patient care, information or laboratory results of a 
research participant may be placed in the medical record (i.e., unexpected abnormality found on 
PET scan). No information will ever be released or published in a way that will identify a 
specific individual. 
 
Buccal samples collected for this study will be sent directly to the CLIA-approved laboratory for 
genotyping and will not be shared with research collaborators. Samples sent to the lab will be 
labeled with the participant’s unique study ID, gender and sample collection date. We will not 
label the buccal samples using names or other identifiers. Buccal samples collected for this study 
will not be stored. Subjects’ APOE results will be returned to BU, and BU will report 
participants eligibility results to each of the clinical sites such that our study sample overall will 
be enriched for APOE e4+ participants. 
 
Molecular NeuroImaging (MNI) will ensure standardized acquisition of 18F-amyvid (AV-45) 
PET data at each of the study sites. MNI has developed a comprehensive setup procedure to 
reduce variance in the imaging outcome among sites that has been used in numerous multicenter 
amyloid PET imaging studies.  MNI has already worked with, and received images from, all of 
the imaging centers in this study and has experience with all study site cameras. MNI’s setup 
includes review of the imaging protocol with site personnel, set-up of the imaging acquisition 
protocol on the site camera. Following MNI site approval, each site will acquire 18F-amyvid 
(AV-45) PET imaging using the protocol currently in use in both ADNI and the A4 study. 
Imaging data will be sent to MNI electronically through an already existing secure Web upload 
process.  The imaging data will contain the subjects’ assigned study number, and will not contain 
personal identifiable information. The imaging site will send the subjects’ PET image to MNI 
and undergo a comprehensive quality control (QC) process consisting of both a technical 
(documenting receipt, naming convention, assessing for camera artifacts, etc) and scientific 
quality control (review by an imaging expert to ensure adequate for analysis).  Imaging sites will 
provide scan transfer data and ongoing camera log information with each scan. Sites will be 
queried if data does not meet the study standards. Typically data quality control processes are 
completed within 3-5 days to enable the scans to continue data analysis. MNI will return the scan 

results to BU, and BU will randomize and return the results to each of the clinical sites such that 
50% are in the initial amyloid scan disclosure group and 50% are in the delayed disclosure group 
at the end of the study. 
 
To minimize the risk of disclosing amyloid PET results in the EPIC record, scan results will be 
classified as a “PET research exam entry” that discloses that a research study was conducted and 
will not include the study name or any interpretable images for incidental findings. Scan orders 
and results will only be viewable by designated research staff (i.e., study coordinator, site PI and 
PET imaging center staff).  
 
Eyetracking data and questionnaire data from the 6-month follow-up visit related to stereotype 
threat and the digit span task will be analyzed by the University of Southern California (USC) 
team. All data will be de-identified before being sent to USC for analysis. Each site will upload 
their de-identified, raw pupillometry data (labeled with subject ID#) to the BU secure Web data 
repository and from there it will be sent to USC. 
 
Data Analysis 
 
The analytical strategy will focus on comparing A+D+ and A+D- groups on the ADCS-PACC 
score at 6 months to better identify if non-disclosure itself had an effect on ADCS-PACC 
performance. Although the primary comparison is not based on the fully randomized groups, it is 
a comparison of randomized groups in the pre-specified subgroup of A+ subjects, thus 
controlling for type 1 error. The power calculation is based on the comparison within the 
subgroup of A+ subjects, so type 2 error is also controlled. Our primary analysis will use a 
mixed-effects model repeated measures (MMRM)57 approach to evaluate the three repeated 
measures over time. This Intention-to-Treat (ITT) analysis will incorporate information from 
those who drop out over the 6 months, assuming missing at random, and have better control of 
type 1 error and power. We will model time as a categorical measure, and the primary outcome 
will be the estimated difference (contrast) between the two groups at 6 months. As 
randomization may not be fully successful in balancing confounding factors between the groups 
(subgroups of the randomized groups), the analysis will also adjust for potentially confounding 
measures such as sex, age and APOE genotype. We will also include the baseline measure of the 
ADCS-PACC score in one regression model (using the two repeated measures at 6 weeks and 6 
months) to allow for differences in cognitive functioning at baseline. We will also consider 
models that examine change from baseline, with and without adjustment for the baseline 
measure.   
 
Analyses of IES as the main secondary outcome and of other measures, will be conducted in a 
similar fashion. While our main focus for the IES will be upon the contrast between the A+D+ 
and A-D+ groups, we will also contrast the A+D+ and the D- groups (as long as the A+D- and 
A-D- exhibit similar outcomes). The D- group may experience increased distress waiting for the 
disclosure of their imaging, which could reduce our power to explore comparisons between 
A+D+ and D- groups, although we did not see this occurring in our prior REVEAL studies when 
participants in the non-disclosure arms were waiting for their genotype data at the end of the 
study. It will also be of interest to compare the difference between A+D- and A-D- groups, 
because this comparison would reveal any differences in cognition due to the amyloid burden 

itself among participants who do not learn their amyloid status at the fourth visit.  We do not 
expect to find any difference here in only 6 months of follow-up. For Exploratory Aims 1.2 and 
2.3, we will examine regression models or MMRM models with interaction terms for race and 
group to evaluate whether the differences at 6 months between the groups (e.g. A+D+ vs A+D-) 
are similar for AAs and non-AAs. Point estimates will be considered in addition to confidence 
intervals and p-values. 
 
For the 6-month follow-up visit digit-span task, we will examine whether working memory 
performance and 
pupil dilation responses differ when under high than low threat differentially depending on both 
disclosure 
status and amyloid levels. 
 
For the 6-month visit digit-span task, we will examine whether working memory performance 
and pupil dilation responses differ when under high than low threat differentially depending on 
both disclosure status and amyloid levels. 
 
Power Calculation 
 
Our objective is to achieve 80% power to detect a difference of moderate effect size (0.4-0.6 SD 
units) on the primary outcome of ADCS-PACC mean score between the A+D- and A+D+ groups 
at 6 months. 
 
Assuming a PACC standard deviation of 2.244, 50 individuals per group would provide 80% 
power to detect a difference of 1.25 PACC units (0.52 SD units) between A+D- and A+D+ at 6 
months. 
 
Based on this calculation, we have set a target to enroll n=50 in each of the 2 elevated amyloid 
groups (A+D-, A+D+). Due to a much lower than anticipated rate of amyloid positivity and a 
dropout rate of approximately 10%, we plan to enroll 370 total participants and achieve 100 
completed 6 month visits to reach our group enrollment targets of n=50 for each elevated 
amyloid group. 
 
VII. Risks and Discomforts 
 
Psychological risks: We recognize that persons with normal cognition who learn they have 
elevated amyloid and an increased risk of developing AD dementia could experience 
psychological distress. We will monitor psychological well-being in our participants by pre-
screening potential participants for anxiety and depression and administering standardized rating 
scales with pre-specified cut-off scores for affect and anxiety at scheduled follow-up visits after 
disclosure of PET amyloid imaging results. Additional monitoring and appropriate actions will 
be taken based on conversations between the study staff (clinician judgment) and participant. 
 
For the 6-month visit digit-span task, we will examine how memory performance is affected by 
task instructions. Although the purpose of all the included cognitive measures is to assess the 
link between amyloid status and performance, during this task we will explicitly state this 

relationship.  Although we expect this to increase concerns about task performance, we do not 
expect this to create emotional distress.  However, we will monitor responses. This will be done 
via conversations between the study staff (clinician judgment) and participant. 
  
Deception: Mild deception will be used during the 6-month visit digit-span task.  More 
specifically, during the initial trials of this task participants will be told that the purpose is to 
calibrate the equipment.  No calibration will be conducted, but this instruction will reduce any 
evaluative concerns that may be felt by the participants.  We do not anticipate this mild 
deception to create any distress.  However, participants will be fully debriefed about this at the 
end of the study and their questions will be answered. 
 
Breach of privacy risks: Violations of confidentiality are unlikely given well-established 
procedures to protect participant privacy that will be carried out by experienced study 
investigators. We have disclosed genetic testing results to over 1100 REVEAL Study 
participants to date, and we have received no reports of insurance or employment bias. 
Participants have the alternative of refusing the study intervention and can discontinue the study 
at any time. 
 
PET imaging risks: The primary risk related to PET is that of radiation exposure associated 
with the CT scan or transmission scan and the injected radiotracers. We use a minimal dose of 
radiopharmaceuticals to permit high quality images with low exposure. These doses have been 
approved by the FDA in previous studies, and combined doses will fall within ranges approved 
by the Radiation Safety Committee or the Radioactive Drug Research Committees (RDRC). This 
radiation dose is not 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 every day risks.   
 
Current or recent participation in any procedures involving radioactive agents such that the total 
radiation dose exposure to the participant in any given year would exceed the limits of annual 
and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 
Section 361.1 is an exclusion for amyloid imaging (when amyloid imaging is employed). 
 
There is also minor risk associated with the venipuncture and radioisotope injection (pain and 
bruising or painful infiltration of a failed injection). 
 
 
 
 
 
Minimizing Risks 
 
Risks to participants include the possibility of psychological distress, social stigmatization, 
violations of confidentiality, and insurance or employment bias. In many ways, our study is 
designed to identify and quantify these risks. Our prior studies show that severe or long-term 
distress from learning APOE genetic risk information has been rare. However, we are prepared 

for monitoring psychological well-being in our participants, and each site will be prepared to 
refer participants to appropriate mental-health professionals in the event that distress reaches 
clinical levels.  
 
Should a serious adverse event (e.g., self-inflicted physical harm due to receipt of test results, 
severe acute depression or anxiety attributed to receipt of test results, etc.) occur, the investigator 
at that site would notify the co-PIs and the multidisciplinary Data Safety and Monitoring Board 
via email immediately following the event. They would review the case in question and 
additional study data as needed to make recommendations as to how we can improve the safety 
of the study, or if the study needs to be halted. 
 
 
Ensuring Safety of Human Subjects 
 
In previous REVEAL Study clinical trials that have involved disclosure of AD dementia genetic 
risk information, we have developed the following detailed and documented procedures for 
reducing risks to participants that we have adapted for this study that will involve the disclosure 
of amyloid imaging.  
 
In addition to careful and thorough communication with potential participants around the consent 
process, we have several layers of protection built into this protocol that have adequately 
guarded against any adverse consequences to date. These include: 
 
A. Pre-screening of all participants for clinically significant depression and anxiety.  
 
B. Careful education defining amyloid imaging and the meaning of amyloid imaging 
results.  
 
C. Scheduled follow-up visits after disclosure of PET amyloid imaging result with 
standardized rating scales for affect and anxiety. Additional monitoring and appropriate 
actions will be taken based on conversations between the study staff (clinician judgment) 
and participant, as well as pre-specified cut-off scores in screening measures:  
 
-Impact of Events Scale (IES): >25 increase monitoring  
 
-Geriatric Depression Scale (GDS) (range 0 to 15): >10 exclude. 6-10: Increase 
monitoring at investigator discretion and look at change from previous score  
 
-State-Trait Anxiety Inventory (STAI) (range 6-24): > 19 exclude. 17-18 Increase 
monitoring at investigator discretion and look at change from previous score  
 
-Columbia Suicide Severity Rating Scale (CSSRS): Exclude any serious suicidal 
risk, based on investigator’s judgment, can be followed up by site designated mental 
health professional and increase monitoring  
 

D. On-going phone contact and follow-up as needed with the participant through study 
staff, with referral to the site clinician who has experience in dealing with older adults 
who have cognitive impairment and mood disorders (a neurologist, geriatrician or 
psychiatrist). We have identified clinicians at each site who will rapidly respond to 
distress in any participant if referred by the study team. 
 
E. Secure maintenance of participant research records: All written records are kept in 
locked files within locked offices, separate in every sense from the medical records of the 
participants. Whenever possible, electronic documents that are used to store important 
information related to research projects are password-protected so that a password must 
be entered before the document can be opened and before it can be modified. To 
minimize the risk of disclosing amyloid PET results in the EPIC record, scan results will 
be classified as a “PET research exam entry” that discloses that a research study was 
conducted and will not include the study name or any interpretable images for incidental 
findings. Scan orders and results will only be viewable by designated research staff (i.e., 
study coordinator, site PI and PET imaging center staff). 
 
F. Obtaining an NIH Certificate of Confidentiality: We are applying for a Certificate of 
Confidentiality and have included appropriate language in the informed consent form.  
 
G. Oversight of the entire project by an independent Data Safety and Monitoring Board 
(see below) 
 
H. We will require participants to have a study partner and require emergency contacts. 
Participants will be asked if they would like to have a close friend or family member 
(such as an adult child, spouse or partner) accompany them to study visits. We will also 
collect the name and contact information for two participant-designated emergency 
contacts described as “(1) a person who we can contact in the event you experience a 
problem that in our judgment requires the assistance of a close friend or family member 
(such as an adult child, spouse or partner), and (2) a physician such as an internist, 
neurologist or family practitioner who we can contact in the event you experience a 
problem that in our judgment requires medical assistance.” Participants will be told that 
this contact may require disclosure of their amyloid imaging result to this provider 
contact. 
 
 
VIII. Potential Benefits 
 
There is no direct benefit from participating in this study. This is not a treatment study, and 
participants will not receive any medication. By participating REVEAL-SCAN, participants may 
be eligible to participate in other research studies.  
 
Trials that require disclosing AD biomarker results to cognitively normal older adults may 
present the prospect of empowering people to action beyond research participation, such as 
adopting healthy behaviors and lifestyle changes, but they may also cause harm to both 
perceived and actual cognitive performance, mood, and social and personal well-being. Prior 

data from the REVEAL Study suggests that the information that subjects learn may decrease 
their anxiety about developing AD (or about their close friend, relative or spouse’ chance of 
developing AD) or may allow individuals to make long-term decisions for the future.53,58-60 
 
The results of our study will be first-of-their kind data to measure whether such harms are real, 
and, if they are, their magnitude and severity. This knowledge will be of substantial importance 
to AD investigators, clinicians and healthcare policy makers, and, therefore, we believe the risks 
to the participants are reasonable and justified. 
 
 
 
 
IX. Monitoring and Quality Assurance 
 
The risks of the study are outlined above. The study clinician/project manager will be 
responsible for the monitoring of participant outcomes, under the supervision of the PI. Frequent 
contact with the study clinician, both by phone and in person at the designated follow-up 
sessions, will be our primary source of clinical participant monitoring. Participants will be 
contacted by phone within 1-3 days of receiving their AD risk assessment in order to check in on 
their emotional state and answer any questions regarding the information or the study itself. At 
minimum, the study clinician will also meet with each participant for in-person follow-ups 6 
weeks and 6 months after receiving their risk assessment. At each of these follow-up 
appointments, the study clinician will also review participants' mood screening measures and 
other survey responses in real time in order to help look for possible adverse psychological 
reactions. 
 
Additionally, at minimum, the study clinician will monitor safety through the completion of 
mood scales, review participants' mood screening measures and other responses in real time in 
order to help look for possible adverse psychological reactions. 
 
Quality control for standardized ADCS-PACC administration via audio recordings will be shared 
with Duke University via secure file sharing. Sites will only provide the study personnel’s name 
performing the ADCS-PACC, and label the recording with subject ID numbers, not with names 
or any other identifiable information. 
 
Non-serious Adverse Events will mostly include events in which participants exceed thresholds 
on the anxiety or depression scales (GDS > 12; Mini-STAI > 19), and will be recorded and 
reported within 1 week to the PI for review and appropriate follow-up, and reported to the IRB 
and Data Safety and Monitoring Board annually. 
 
An interim analysis may be conducted by the Data Safety Monitoring Board (DSMB). They will 
review the study on an annual basis.  
 
Review of Adverse Events 
 

Study site personnel must report immediately to the principal investigator any adverse events 
from this study. Should a serious adverse event (e.g., self-inflicted physical harm due to receipt 
of test results, severe acute depression or anxiety attributed to receipt of test results, etc.) occur, 
the investigator at that site would notify the co-PIs and the multidisciplinary DSMB via email 
immediately following the event. They would review the case in question and additional study 
data as needed to make recommendations as to how we can improve the safety of the study, or if 
the study needs to be halted. 
 
If, for some reason, a participant withdraws or is unable to complete cognitive assessments, the 
Investigators will discontinue him or her undergoing detailed cognitive batteries. Where 
possible, safety monitoring procedures will be conducted until the end of the study.  
 
During all portions of this research study, the privacy and confidentiality of all participants will 
be maintained at all times. All hard copies of research data will be kept in the study clinician’s 
locked office. Data will be stored in locked filing cabinets, in binders, and on the study staff 
members' computers. Digital files of audio recordings will be labeled only with subject ID 
numbers, not with names or any other identifiable information. This data is accessible only by 
research staff, primarily the PI and study staff. The code linking the study ID with the identifiers 
will be stored on the study clinician’s computer in a password protected computer file. Only the 
password protected file will contain the link between the identifiers and the study ID.  
 
Any information obtained from a potential participant who chooses not to participate in 
the study will be destroyed unless they choose to participate in another study, in which 
case the information will be stored as part of the other study. All research and imaging 
data will be assigned a code with the participants’ initials and study number. The data 
will be blinded in all data analyses. 
 
No one other than the PI and the study staff will have access to identifiable research data. De-
identified data may be shared with collaborating institutions (University of Pennsylvania, 
University of Michigan, Duke University) and investigators, as well as with the NIH and public 
data repositories upon request. 
 
Confidentiality will be ensured by keeping all subject records in a locked file cabinet in a locked 
office and by using subject identification numbers (as opposed to names) in all databases created 
during this research. If any data are used for publication, it will be done so without any 
identifying information. Audio tapes will treated with the same level of protections by using 
subject identification numbers and storing all tapes in a locked file cabinet.  
 
A certificate of confidentiality has been obtained for this study.  
 
 
 
REFERENCES 
 
1. 
Sperling RA, Aisen P, Beckett L, et al. Toward defining the preclinical stages of Alzheimer's disease: 
recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic 
guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:280-92. 

2. 
Jack CR, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute 
on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement 2011;7:257-62. 
3. 
Bonnefoy J. The biomarker revolution: a step toward personalized medicine. Pers Med 2008;5:553-6. 
4. 
Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh 
Compound-B. Ann Neurol 2004;55:306-19. 
5. 
Nordberg A. PET imaging of amyloid in Alzheimer's disease. Lancet Neurol 2004;3:519-27. 
6. 
Ramanan B, Risacher S, Nho K, et al. APOE and BCHE as modulators of cerebral amyloid deposition: a 
florbetapir 1 PET genome-wide association study. Mol Psychiatry 2013;19:351-7. 
7. 
Johnson K, Minoshima S, Bohnen N, et al. Update on appropriate use criteria for amyloid PET imaging: 
dementia experts, mild cognitive impairment and education. Alzheimers Dement 2013;9:e106-9. 
8. 
Johnson K, Minoshima S, Bohnen N, et al. Appropriate use criteria for amyloid PET: a report of the 
amyloid imaging task force, the society of nuclear medicine and molecular imaging, and the alzheimer's association 
J Nucl Med 2013;54:14. 
9. 
Doraiswamy PM, Sperling RA, Coleman RE, et al. Amyloid-beta assessed by florbetapir F 18 PET and 18-
month cognitive decline: a multicenter study. Neurology 2012;79:1636-44. 
10. 
Clark CM, Pontecorvo MJ, Beach TG, et al. Cerebral PET with florbetapir compared with neuropathology 
at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 2012;11:669-
78. 
11. 
Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. 
JAMA 2011;305:275-83. 
12. 
Yang L, Rieves D, Ganley C. Brain amyloid imaging--FDA approval of florbetapir F18 injection. N Engl J 
Med 2012;367:885-7. 
13. 
Pike K, Savage G, Villemagne V, et al. Beta-amyloid imaging and memory in non-demented individuals: 
evidence for preclinical Alzheimer's disease. Brain 2007;130:2837-44. 
14. 
Mormino E, Brandel M, Madison C. Not quite PIB-positive, not quite PIB-negative: slight PIB elevations 
in elderly normal control subjects are biologically relevant. NeuroImage 2012;59:1152-60. 
15. 
Mormino E, Smilijic A, Hayenga A, et al. Relationships between beta-amyloid and functional connectivity 
in different components of the default mode network in aging. Cereb Cortex 2011;21:2399-407. 
16. 
Mormino E, Kluth J, Madison C, et al. Episodic memory loss is related to hippocampal-mediated beta-
amyloid deposition in elderly subjects. Brain 2009;132:1310-23. 
17. 
Landau S, Mintun M, Joshi A, et al. Amyloid deposition, hypometabolism, and longitudinal cognitive 
decline. Ann Neurol 2012;72:578-86. 
18. 
Chetelat G, La Joie R, Villain N, et al. Amyloid imaging in cognitively normal individuals, at-risk 
populations and preclinical Alzheimer's disease. Neuroimage Clin 2013;2:356-65. 
19. 
Storandt M, Mintun M, Head D, Morris J. Cognitive decline and brain volume loss as signatures of cerebral 
amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta 
deposition. Arch Neurol 2009;66:1476-484. 
20. 
Rabinovici G, Jagust W. Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. 
Behav Neurol 2009;21:117-28. 
21. 
Morris J, Roe C, Xiong C, et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in 
cognitively normal aging. Ann Neurol 2010;67:122-31. 
22. 
Rowe C, Ellis K, Rimajova M, et al. Amyloid imaging results from the Australian Imaging, Biomarkers 
and Lifestyle (AIBL) study of aging. Neurobiol Aging 2010;31:1275-83. 
23. 
Fleisher A, Chen K, Liu X, et al. Apolipoprotein E epsilon4 and age effects on florbetapir positron 
emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging 2013;34:1-12. 
24. 
Jack C, Knopman D, Jagust W, et al. Tracking pathophysiological processes in Alzheimer's disease: an 
updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013;12:207-16. 
25. 
Villemagne V, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive 
decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 2013;12:357-67. 
26. 
Sperling R, Karlawish J, Johnson K. Preclinical Alzheimer disease - the challenge ahead. Nat Rev Neurol 
2012;9:54-8. 
27. 
Aisen P, Vellas B, Hempel H. Moving towards early clinical trials for amyloid-targeted therapy in 
Alzheimer's disease. Nat Rev Drug Discov 2013;12:324. 
28. 
Reiman E, Langbaum J, Fleisher A. Alzheimer's prevention initiative: a plan to accelerate the evaluation of 
presymptomatic treatments. J Alzheimers Dis 2011;26:321-9. 

29. 
Sperling RA, Donohoe M, Aisen PS. The A4 trial: anti-amyloid treatment of asymptomatic Alzheimer's 
disease. Alzheimers Dement 2012;8:P425-P6. 
30. 
Suhr J, Gunstad J. 'Diagnosis threat': the effect of negative expectations on cognitive performance in head 
injury. J Clin Exp Neuropsychol 2002;24:448-57. 
31. 
Lineweaver T, Bondi M, Galasko D, Salmon D. Knowledge of APOE genotype affects subjective and 
objective memory performance in healthy older adults. Am J Psychiatry 2013;171:201-8. 
32. 
Klein EP, Kaye J. Dementia specialists and early adoption of amyloid imaging. J Alzheimers Dis 
2013;33:445-50. 
33. 
Shulman MB, Harkins K, Green RC, Karlawish J. Using AD biomarker research results for clinical care: a 
survey of ADNI investigators. Neurology 2013;81:1114-21. 
34. 
Whitfield K, Aiken A. Minority populations and cognitive aging. In: Hofer S, Alwin D, eds. Handbook of 
Cognitive Aging: Sage Publications; 2008:384-96. 
35. 
Whitfield K, Angel J, Burton L, Hayward M. Diversity, disparities and inequalities in aging: implications 
for policy. Public Policy and Aging Report 2006;16:16-22. 
36. 
Whitfield K, Hayward M. The landscape of health disparities in older adults. Public Policy and Aging 
Report 2003;13:1-7. 
37. 
Green RC, Cupples LA, Go R, et al. Risk of dementia among white and African American relatives of 
patients with Alzheimer disease. JAMA 2002;287:329-36. 
38. 
Whitbourne S, Bringle J, Yee B, Chiriboga D, Whitfield K. Ethical research dilemmas with minority elders. 
In: Trimble J, Fisher C, eds. The Handbook of Ethical Research with Ethnocultural Populations and Communities. 
Thousand Oaks, CA: Sage; 2005:217-40. 
39. 
Romero HR, Welsh-Bohmer KA, Gwyther KA, et al. Community engagement in diverse populations for 
Alzheimer disease prevention trials. Alzheimer Dis Assoc Disord 2014;28:269-74. 
40. 
Brown LM, Schinka JA. Development and initial validation of a 15-item informant version of the Geriatric 
Depression Scale. Int J Geriatr Psychiatry 2005;20:911-8. 
41. 
Marteau TM, Bekker H. The development of a six-item short-form of the state scale of the Spielberger 
State-Trait Anxiety Inventory (STAI). Br J Clin Psychol 1992;31 ( Pt 3):301-6. 
42. 
Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K. Prediction of suicidal behavior in 
clinical research by lifetime suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity 
Rating Scale. J Clin Psychiatry 2013;74:887-93. 
43. 
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 
1993;43:2412-4. 
44. 
Donohue MC, Sperling RA, Salmon DP, et al. The Preclinical Alzheimer Cognitive Composite: Measuring 
Amyloid-Related Decline. JAMA Neurol 2014. 
45. 
Tombaugh T. The Test of Memory Malingering (TOMM): normative data from cognitively intact and 
cognitively impaired individuals. Psychol Assessment 1997;9:260-68. 
46. 
Wechsler D. Wechsler Adult Intelligence Scale-Revised. San Antonio: Psychological Corporation; 1981. 
47. 
Duff K, Chelune GJ, Dennett K. Predicting estimates of premorbid memory functioning: validation in a 
dementia sample. Arch Clin Neuropsychol 2011;26:701-5. 
48. 
Costa P, MCCrae R. Normal personality assessment in clinical practice: the NEO Personality Inventory. 
Psychol Assessment 1992;4:5-13. 
49. 
Dixon R, Hultsch D, Hertzog C. The Metamemory in Adulthood (MIA) Questionnaire. Psychopharmacol 
Bull 1988;24:671-88. 
50. 
Gilewski M, Zelinski E, Schaie K. Memory Functioning Questionnaire (MFQ). Psychopharmacol Bull 
1988;24:665-70. 
51. 
Stewart AL, Ware JE, eds. Measuring Functioning and Well-being: The Medical Outcomes Study 
Approach. Durham: Duke University Press; 1992. 
52. 
Lang FR, Carstensen LL. Time counts: Future time perspective, goals and social relationships. Psychol 
Aging 2002;17:125-39. 
53. 
Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic 
susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord 2009;23:50-6. 
54. 
Horowitz M, Wilner N, Alvarez W. Impact of event scale: A measure of subjective stress. Psychosom Med 
1979;41:209-18. 
55. 
Tombaugh TN, Kozak J, Rees L. Normative data stratified by age and education for two measures of verbal 
fluency: FAS and animal naming. Arch Clin Neuropsychol 1999;14:167-77. 

56. 
Walsh SP, Raman R, Jones KB, Aisen PS, Alzheimer's Disease Cooperative Study G. ADCS Prevention 
Instrument Project: the Mail-In Cognitive Function Screening Instrument (MCFSI). Alzheimer Dis Assoc Disord 
2006;20:S170-8. 
57. 
Mallinckrodt CH, Watkin JG, Molenberghs G, Carroll RJ. Choice of the primary analysis in longitudinal 
clinical trials. Pharm Stat 2004;3:161-9. 
58. 
Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer's disease. N 
Engl J Med 2009;361:245-54. 
59. 
Green RC, Roberts J, Chen CM, et al. Comparing the impact of a condensed vs. extended protocol for 
disclosure of APOE to relatives of patients with AD: the REVEAL Study. Alzheimers Dement 2007;3:S184-S. 
60. 
Lerner B, Roberts JS, Shwartz M, Clark J. Identifying different patterns of patient-provider communication 
during the disclosure of susceptibility test results for Alzheimer’s disease. J Genet Couns 2009;18:626-7. 
61. 
Li Y, Baldassi M, Johnson E, Weber E. Complementary cognitive capabilities, economic decision-making, 
and aging. Psychol Assessment 2014;28:595-613. 
62.  
Barnes LL, Lewis TT, et al. Perceived Discrimination and Cognition in Older African Americans. J Int 
Neuropsychol Soc. 2012;18(5):856-865. 
63.  
Weiss D. On the Inevitability of Aging: Essentialist Beliefs Moderate the Impact of Negative Age 
Stereotypes on Older Adults’ Memory Performance and Physiological Reactivity. J Gerontol B Psychol Sci Soc Sci 
2016;gbw087.