Short-term Psychological Outcomes of Disclosing Amyloid Imaging Results to Research Participants Who Do Not Have Cognitive Impairment

Key Points

Question  Can Alzheimer disease biomarker results be safely shared with older research participants who do not have cognitive impairments?

Findings  In this observational study, disclosure of amyloid imaging results using a structured process in a clinical trial did not result in clinically meaningful short-term adverse psychological reactions but did change participants’ perceived risk of developing Alzheimer disease.

Meaning  In this study, in the short term, amyloid imaging results were safely disclosed to older adults who did not have cognitive impairment.

Importance  The goal of preclinical Alzheimer disease (AD) clinical trials is to move diagnosis and treatment to presymptomatic stages, which will require biomarker testing and disclosure.

Objective  To assess the short-term psychological outcomes of disclosing amyloid positron emission tomography results to older adults who did not have cognitive impairment.

Design, Setting, and Participants  This observational study included participants who were screening for a multisite randomized clinical trial that began on February 28, 2014, and is anticipated to be completed in 2022. Participants aged 65 to 85 years who had no known cognitive impairments underwent an amyloid positron emission tomography scan and learned their result from an investigator who used a protocol-specified process that included prescan education and psychological assessments. This report compares participants with elevated amyloid levels with at least 1 available outcome measure with participants who did not have elevated amyloid levels who enrolled in an observational cohort study and received further evaluations. Data were collected from April 2014 to December 2017 and analyzed from March 2019 to October 2019.

Exposures  A personal biomarker result described as either an elevated or not elevated amyloid level.

Main Outcomes and Measures  To assess the immediate and short-term psychological outcome of disclosure, the following validated measures were used: the Geriatric Depression Scale, the state items from the State-Trait Anxiety Inventory, and the Columbia Suicide Severity Rating Scale, as well as the Concerns About AD Scale and the Future Time Perspective Scale to assess changes in participants’ perceived risk for AD and perceived remaining life span, respectively.

Results  A total of 1167 participants with elevated amyloid levels and 538 participants with not elevated amyloid levels were included. Participants had a mean (SD) age of 71.5 (4.7) years, 1025 (60.1%) were women, and most were white (1611 [94.5%]) and non-Latino (1638 [96.1%]). Compared with participants who learned that they had a not elevated amyloid result, individuals who learned of an elevated amyloid result were no more likely to experience short-term increases in depression (mean [SD] change in the Geriatric Depression Scale score, 0.02 [1.3] vs 0.04 [1.3]; P = .90), anxiety (mean [SD] change in State-Trait Anxiety Inventory score, –0.02 [3.2] vs –0.15 [3.0]; P = .65), or suicidality (mean [SD] change in the Columbia Suicide Severity Rating Scale score, 0.0 [0.4] vs –0.01 [0.5]; P = .67). Participants with elevated amyloid levels had increased Concern About AD scores (raw change in scores: elevated amyloid group, 0.8 [3.9]; not elevated amyloid group, –0.4 [3.8]; P < .001). Participants with not elevated amyloid levels experienced a slight increase in Future Time Perspective score(mean [SD] score, 1.15 [7.4] points; P < .001); there was no change in time perspective among those receiving an elevated amyloid result (mean [SD] score, 0.33 [7.8] points).

Conclusions and Relevance  In this observational preclinical AD study, participants who learned they had elevated amyloid levels did not experience short-term negative psychological sequelae compared with persons who learned they did not have elevated amyloid levels.

Alzheimer disease (AD) is a progressive neurodegenerative condition that results in mild cognitive impairment, dementia, and death.^1-3 Alzheimer disease is diagnosed when patients demonstrate cognitive symptoms.⁴

Longitudinal studies using positron emission tomography (PET) and other biological markers (biomarkers) have revealed that AD pathology may be present in the brain for years before the onset of cognitive impairment.^5-7 The stage of AD in which biomarkers are present but cognitive impairment is absent has been termed preclinical AD. Criteria for preclinical AD were proposed for use in research to advance development of AD therapies.^8,9 Disclosure of biomarker results to older adults who do not have cognitive impairment is not currently recommended in clinical practice.¹⁰ Disclosure is justified in preclinical AD trials because of the need to ensure trial feasibility, because of the generalizability of these experiences to an eventual clinical practice, and to respect the self-determination of participants, who may wish to know their biomarker result before committing to take an investigational therapy.^11,12

If successful, preclinical AD trials will transform the diagnosis and treatment of AD. Biomarker test results will indicate treatment strategies for individuals who do not have cognitive impairment. Preclinical AD trials are therefore testing 2 clinically important questions: the safety and efficacy of potential disease-delaying treatments and the safety and outcome of disclosing AD biomarker results to older adults who do not have cognitive impairment. Here, we examine the second question, the short-term psychological sequelae of disclosing amyloid biomarker results to older participants who do not have cognitive impairment and were screened for the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study.¹³

The A4 Study is a phase 3 registration trial (NCT02008357) of the monoclonal antibody against monomeric amyloid β, solanezumab, in participants meeting criteria for preclinical AD. Written informed consent was provided by participants prior to any research activities being performed in the A4 study. Institutional review board approval was secured at the participating sites.

The design and preliminary biomarker results from the A4 screening process have been reported elsewhere.¹⁴ Here, we focus specifically on the disclosure of amyloid PET imaging results to participants, which occurred across screening and baseline visits (Figure 1). At visit 1, participants provided self-reported demographic characteristics, such as age, sex, education, family history of dementia, and the Cognitive Function Instrument (CFI),¹⁵ a subjective cognitive function scale. Participants completed predisclosure outcome measures, including the 15-item Geriatric Depression Scale (GDS; range, 0-15 points),¹⁶ the 6 state items of the State-Trait Anxiety Scale (STAI; each item was scored on a 4-point Likert scale, from not at all [1] to very much [4]; range, 6-24 points),^17,18 and the Columbia Suicide Severity Rating Scale (CSSRS).¹⁹ The CSSRS summary score was based on the highest level of suicidality reported (range, 0-9 points).²⁰ Additional instruments collected at visit 1 included an adapted Concerns About AD Scale, in which participants indicate their level of agreement (on a Likert scale from strongly disagree [1] to strongly agree [5]; range, 6-30 points) with 6 statements about their perceived probability of developing AD (eg, “I believe I will someday develop Alzheimer’s disease dementia”) and their level of concern for that outcome (eg, “My concern about developing Alzheimer’s disease dementia is greater than my concern about other medical problems”).²¹ The 10-item Future Time Perspective Scale assesses agreement (from very untrue [1] to very true [7]; range, 10-70 points) with perceptions of one’s future (eg, “I have the sense that time is running out”).

At visit 2, eligible participants underwent amyloid imaging. Individuals determined by visual reading or standardized uptake value ratios to have elevated brain amyloid levels were eligible for randomization in the A4 trial. Among individuals determined to have not elevated amyloid levels, a subset were enrolled at sites participating in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort study (NCT02488720). Participants in LEARN otherwise met the same eligibility criteria for the A4 trial.

Participants received their amyloid imaging results at visit 3. They then completed postdisclosure Concerns About AD and Future Time Perspective scales. Sites performed telephone follow-up with participants 24 to 72 hours after disclosure and collected responses to the Impact of Events Scale (IES).²² The IES uses 15 items (range, 0-75 points) to assess intrusive thoughts and avoidance (eg, “I thought about it when I didn’t mean to”), specific to the person’s amyloid PET result.

Participants with elevated amyloid levels and participants in the LEARN trial with not elevated amyloid levels underwent visit 6, including the postdisclosure GDS, STAI, and CSSRS assessments. These analyses were limited to (1) participants who had elevated amyloid levels with at least 1 of CSSRS, STAI, or GDS at visit 6 and (2) participants who did not have elevated amyloid levels; enrolled in the observational LEARN cohort; and had at least 1 of the CSSRS, STAI, or GDS measures at visit 6.

The A4 study used a process to disclose amyloid PET results to participants²³ that began with education about preclinical AD. Education was initiated with the informed consent process (visit 1) and was aided by the A4 Study Brochure, which outlined the goals and procedures of the trial. Site investigators were trained and certified centrally prior to performing disclosure and used the teach-back method to confirm participant comprehension.²⁴ The disclosure process specified that imaging be performed on a separate day from consent and disclosure. Certified investigators performed in-person disclosures at visit 3 after reviewing psychological assessments from visit 1 and ensuring that the participant remained willing to learn their biomarker information.

The A4 disclosure process outlined additional monitoring for participants at increased risk (ie, GDS scores of 6 to 10, STAI scores of 17 to 19, or a history of suicidal ideations) and exclusion or consultation with study leadership for participants with higher scores (ie, GDS scores >10, STAI scores >19, or a history of suicidal behaviors). Exclusion was therefore ultimately based on site investigator discretion. The time allowed to complete the A4 screening process was 90 days.

The characteristics of the groups at screening visit 1 were compared using Fisher exact tests for categorical variables and 2-sample t tests for continuous variables. To assess whether amyloid status and other covariates were associated with psychological outcomes even before PET imaging and disclosure at visit 1, a rank regression analysis was conducted, controlling for age, sex, scores on the CFI, and a family history of dementia. To examine whether groups with vs without elevated amyloid levels differed in their psychological responses to disclosure, analysis of covariance (ANCOVA) models were used, with change in scores on the outcome measures (GDS and STAI) as the dependent variable and the amyloid group as the independent variable of interest, after adjusting for predetermined covariates, including age, sex, scores on the screening CFI, and family history of dementia. Secondary analyses compared the frequency with which participants experienced changes to predetermined scores on the GDS (>6), STAI (>17), or CSSRS (>0). These cutpoints are frequently used as exclusion criteria in clinical trials and to indicate clinically relevant severities. A small number of participants with elevated amyloid levels (n = 156) were not included in our analyses because they lacked all of the GDS, STAI, or CSSRS measurements at either the predisclosure or postdisclosure visit. The participants who were included and excluded from the elevated group were compared using Fisher exact tests and 2-sample t tests, as appropriate, to assess possible differences in these groups. For all models, we have reported the estimates, standard errors, and P values. For these analyses, a P < .05 was considered statistically significant. Because of the exploratory nature of these analyses, no adjustment for multiple comparisons were performed. All analyses were performed using the statistical software R version 3.6.1 (R Foundation for Statistical Computing). Data were collected from April 2014 to December 2017 and analyzed from March 2019 to October 2019.

A total of 1167 participants with elevated amyloid levels and 538 participants with not elevated amyloid levels were analyzed (mean [SD] age, 71.5 [4.7] years; 1025 women [60.1%]; and 1611 white individuals [94.5%] and 1638 individuals of non-Latino ethnicity [96.1%]). Table 1 describes demographic characteristics of individuals in the elevated amyloid vs not elevated amyloid groups. Expected differences between the groups were apparent. The participants with elevated amyloid levels, compared with those with not elevated levels, were slightly older (mean [SD] age, 71.9 [4.8] years vs 70.5 [4.3] years; P < .001), more often carried apolipoprotein E (APOE) ε4 (679 of 1167 [58.2%] vs 123 of 538 [22.0%]; P < .001), and more often reported a family history of dementia (878 of 1167 [75.2%] vs 355 of 538 [66.0%]; P < .001). The participants with elevated amyloid who were included vs excluded were similar, except that excluded participants were older (mean [SD] ages, 71.9 [4.8] vs 73.4 [5.2] years) (data not shown).

Prior to imaging and disclosure, no differences between the groups were apparent on the CSSRS, GDS, or STAI. After adjusting for covariates, the amyloid group was not associated with higher GDS or STAI scores, but higher CFI scores were associated with higher scores on both scales (estimate [SE], GDS, 74.4 [5.0]; P < .001; STAI, 46.4 [5.6]; P < .001), and female sex was associated with higher STAI scores (estimate [SE], −102.9 [23.8]; P < .001) (eTable 1 in the Supplement). Those who would later learn they had elevated amyloid levels showed higher predisclosure scores on the Concerns About AD Scale (mean [SD] scores, 21.7 [4.5] vs 20.6 [4.5]; P < .001) and the CFI (mean [SD] scores, 2.36 [2.2] vs 1.80 [1.0]; P < .001) and lower scores on the Future Time Perspective Scale (mean [SD] scores, 44.3 [10.4] vs 45.6 [10.6]; P = .02).

The mean (SD) times between disclosure and psychological assessments were 41.6 (23.2; range, 2-189) days and 56.6 (53.5; range, 0-391) days for the elevated amyloid and not elevated amyloid groups, respectively. Disclosure of elevated amyloid status was not associated with short-term adverse psychological reactions (Figure 2). Controlling for covariates, amyloid group was not associated with change on the GDS or STAI (Table 2). Age was associated with greater change in GDS score (estimate [SE], 0.02 [0.01]; P = .01), and a family history of AD was associated with greater change in STAI (estimate [SE], −0.34 [0.17]; P = .04) after disclosure.

Overall, the proportions of scores in the range of clinical significance were extremely low (eTable 2 in the Supplement). There were no suicide attempts or suicide behaviors. New-onset suicidal ideations were infrequent and not statistically different between the groups. Ten individuals (0.9%) in the elevated amyloid group, compared with 5 (0.9%) in the not elevated amyloid group, experienced an increase to a GDS score of more than 6. Seventeen individuals (1.5%) in the elevated amyloid group, compared with 10 (1.9%) in the not elevated amyloid group, experienced an increase to STAI scores of more than 17. Six of 9 participants with predisclosure GDS scores of more than 6 who learned that they had an elevated amyloid result and 7 of 8 who learned they had a not elevated amyloid result had GDS scores that declined to less than 6 after disclosure. Nineteen of 24 participants with STAI scores of more than 17 who learned they had an elevated amyloid result and 11 of 13 who learned they had a not elevated amyloid result had STAI scores that declined to less than 17 after disclosure.

Those with elevated amyloid levels demonstrated greater intrusive thoughts on the IES, compared with participants with not elevated amyloid levels (mean [SD] scores, 10.2 [10.8] vs 5.9 [7.6]; P < .001; Figure 2). The difference remained after controlling for prespecified covariates (Table 2). Younger age (estimate [SE], –0.17 [0.05]; P < .001), higher CFI score (estimate [SE], 0.33 [0.11]; P = .004), and female sex (estimate [SE], –3.32 [0.49]; P < .001) were also associated with greater IES scores after disclosure. The proportion of IES scores suggesting mild distress (score, 9-25: those with elevated amyloid levels, 407 of 1155 [35.3%]; not elevated amyloid levels, 119 of 534 [23.2%]) or moderate distress (score, >25: those with elevated amyloid levels, 114 [9.8%]; not elevated amyloid levels, 16 [3.1%]) were higher in the elevated amyloid group (eTable 2 in the Supplement).

Scores on the Concerns About AD Scale increased in participants with elevated amyloid and decreased in those with not elevated amyloid levels after disclosure (raw change in scores: elevated amyloid group, 0.8 [3.9]; not elevated amyloid group, –0.4 [3.8]; ANCOVA point estimate [SE], 1.28 [0.21]; P < .001). Figure 3 illustrates the group changes in the proportion of participants endorsing the highest levels of agreement on the individual scale items. Those with elevated amyloid levels did not demonstrate a change on the Future Time Perspective Scale after disclosure; those with not elevated amyloid levels increased in score (mean [SD] scores, elevated amyloid group, 0.33 [7.8] points; not elevated amyloid group, 1.15 [7.4] points; P < .001).

In a preclinical AD trial that used a process of education and assessment of pretest psychological well-being, we found that trial participants who did not have cognitive impairment and received an elevated amyloid result were no more likely than those receiving a not elevated amyloid result to experience depression, anxiety, or catastrophic reactions in the short term. This study, the largest experience in AD biomarker disclosure to date,²⁵ confirms and extends previous studies^26-29 and supports a process for future similar clinical trials, specifically education and psychological assessment prior to AD biomarker testing and disclosure.

In contrast with previous studies assessing the safety of AD risk factor disclosure (eg, APOE genotypes),³⁰ the A4 study protocol did not categorically exclude participants for specific scores on the CSSRS, GDS, or STAI. A small number of individuals with suicidal ideations, GDS scores of more than 6, or STAI scores of more than 17 prior to amyloid imaging were enrolled. Most of these individuals’ scores declined to scores less than these thresholds after disclosure.

These short-term results are encouraging, but studies with longer follow-up will be essential to confirm the safety of AD biomarker disclosure. Studies in smaller numbers of individuals with elevated amyloid levels support safety through 6 and 12 months.^26,28 In a nested qualitative study of a subset of participants in the A4 trial (50 with elevated amyloid levels and 30 with not elevated amyloid levels), however, approximately 20% of participants with elevated amyloid levels acknowledged considering suicide or physician-assisted death if they experience cognitive decline or become a burden to others.³¹ These experiences emphasize the importance of the longitudinal evaluation of psychological outcomes being gathered in the A4 study.

Although amyloid disclosure did not result in depression, anxiety, or suicidality, it did affect participants in the A4 trial in the short term. Individuals receiving a not elevated amyloid result had reduced concerns about AD. Postdisclosure changes on the Future Time Perspective Scale indicated that the not elevated amyloid group also increased their expected future time. These data support results from 2 qualitative studies^32,33 that a common emotional reaction to learning of a not elevated amyloid result was relief. Combined with the observation that those receiving an elevated amyloid result experienced no change in Future Time Perspective Scale scores, these results suggest that most participants in the A4 study were expecting to be eligible.

Individuals with elevated amyloid levels understood that their biomarker result conferred increased risk for AD dementia (Figure 3).^33,34 This perception of increased risk, perhaps notably, did not appear to be associated with adverse psychological reactions, namely anxiety or depression. Whether such associations develop over time will be a key area of future research.

Participants receiving an elevated amyloid result, compared with participants receiving a not elevated amyloid result, reported more intrusive thoughts and avoidance on the IES. Scores among those with elevated amyloid levels were similar to scores observed after disclosure of APOE genotypes and even autosomal-dominant AD gene sequence variation status.³⁵ The absolute difference in scores between the groups (approximately 4 points) was relatively small, given that the range of the IES is 0 to 75 points. Furthermore, IES scores were greater than 0 for most participants (eTable 2 in the Supplement), indicating that at least some aspect of the experience was derived from the process of learning any information about brain amyloid status, in addition to the specific result. In a qualitative study, participants in the A4 trial frequently acknowledged the unique sensitivity around amyloid imaging and disclosure, strongly distinguishing it from other medical tests. Specifically, participants explained that AD biomarker tests have a unique risk of stigma.³³

The precision afforded by the large sample sizes in the A4 study led to statistical significance for numerically small differences between the groups (eg, a 1-point difference on the Future Time Perspective Scale). Longitudinal analyses of the A4 data will reveal whether these outcomes are fleeting reactions or separation between groups that increases over time. It will be essential to assess in future preclinical AD trials whether these and other reactions to amyloid information are unique to the population enrolled in the A4 study, which is to our knowledge the first trial of its kind.

In the future, biomarker testing may be used to identify individuals with preclinical AD for targeted therapies. In this setting, efficient and safe disclosure methods will be necessary and must also prepare patients and their families for a potential disease course that includes cognitive decline and dementia. The current results, although not generalizable to diverse clinical settings or the general population, suggest that trial participants internalize biomarker information without experiencing immediate mental health sequelae. Whether this information may also be motivating—leading to changes in diet, exercise, and other lifestyle modifications, as well as important long-term decisions and life planning^33,36,37—will be another important area of future research.

As expected from previous population-based cohort studies, participants with elevated amyloid levels were older, more often carried APOE ε4, more frequently had a family history of dementia, and had greater subjective cognitive complaints at baseline.³⁸ There were no differences in depression and anxiety between the groups prior to imaging and disclosure, despite previous demonstrations of longitudinal associations of amyloid and neuropsychiatric symptoms in preclinical AD.^39,40 Notably, participants did differ in their Future Time Perspective Scale scores and level of concerns about AD prior to being told their amyloid status.

The A4 study is not a randomized study to test the safety of amyloid disclosure. Differences between the elevated and not elevated amyloid groups present prior to disclosure cannot be entirely accounted for when interpreting the results. Such differences contributed to some of the observed results (eg, those with higher CFI scores were more likely to demonstrate higher IES scores). Participants in the A4 trial may be unique compared with eventual clinical practice or even future preclinical AD trials in their demographics, motivation, altruism, risk tolerance, and psychological status associated with AD. The A4 study sample was primarily composed of non-Hispanic white participants. Given especially that underrepresented groups, such as African American and Latino individuals, are at increased risk for AD,⁴¹ there is an urgent need to understand whether disclosure is associated with similar outcomes, including safety measures, in these groups. The not elevated amyloid group in this study represented only a subset of those disclosed a not elevated amyloid result and were largely self-selected based on their willingness to participate (although available results in the larger not elevated amyloid population were highly consistent [data not shown]). There was a differential time between disclosure and data collection in the not elevated amyloid group compared with the elevated amyloid group. Addressing these limitations to generalizability will be critical to future preclinical AD trials, especially if disclosure is not implemented by the same rigorous, protocol-defined process performed by experts,¹⁰ as was the case in the A4 study. Similarly, the A4 study included only individuals willing to learn their amyloid imaging results, further limiting generalizability to the general population. Data were missing for approximately 9% of participants and were not missing at random. Finally, analyses focused exclusively on participants, but biomarker information may also affect family members. Understanding the psychological effects of disclosure on partners at the time of the study, who may eventually become caregivers,⁴² will require further research.

These results support the short-term safety of research disclosure of amyloid imaging results to participants who do not have cognitive impairments in the setting of preclinical AD trials. Research into the longitudinal outcomes of biomarker disclosure will be essential to guide future clinical trials and clinical practice.

Accepted for Publication: May 29, 2020.

Corresponding Author: Joshua D. Grill, PhD, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 3204 Biological Sciences III, Irvine, CA 92697 (jgrill@uci.edu).

Published Online: August 10, 2020. doi:10.1001/jamaneurol.2020.2734

Author Contributions: Dr Grill had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Grill, Johnson, Karlawish.

Acquisition, analysis, or interpretation of data: Grill, Raman, Ernstrom, Sultzer, Burns, Donohue, Johnson, Aisen, Sperling.

Drafting of the manuscript: Grill, Raman, Burns, Johnson.

Critical revision of the manuscript for important intellectual content: Grill, Ernstrom, Sultzer, Burns, Donohue, Johnson, Aisen, Sperling, Karlawish.

Statistical analysis: Raman, Ernstrom, Donohue, Karlawish.

Obtained funding: Johnson, Aisen, Sperling.

Administrative, technical, or material support: Grill, Johnson, Aisen.

Supervision: Johnson, Sperling.

Conflict of Interest Disclosures: Dr Grill reports research support from Biogen, Eli Lilly, Genentech, and the National Institutes of Health and consulting for Cogniciti. Dr Sultzer reports consulting for Acadia, Avanir, and Otsuka; employment by University of California and Department of Veterans Affairs; and grants from the National Institutes of Health. Dr Raman and Ms Ernstrom reports research support from the National Institute on Aging, Eli Lilly, and Janssen. Dr Donohue’s spouse is a fulltime employee of Janssen; he has also served on scientific advisory boards for Biogen and Eli Lilly, consulted for Roche, received grants from the National Institute on Aging and Eli Lilly during the conduct of the study, received grants from Janssen outside the submitted work, and received personal fees from Biogen, Neurotrack, Roche, and Eli Lilly outside the submitted work. Dr Johnson reports grants from the National Institutes of Health; personal fees from Biogen, Merck, Novartis, Takeda, Roche/Genentech, and Janssen; and grants from Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation during the conduct of the study. Dr Aisen reports grants from the National Institute on Aging, Foundation for the National Institutes of Health, the Alzheimer's Association, Janssen, Eli Lilly, and Eisai and personal fees from Merck, Roche, Biogen, ImmunoBrain Checkpoint, and Samus outside the submitted work. Dr Sperling’s institution has received research support from Eli Lilly, but she does not receive any personal income; she has also received research grants from the National Institute on Aging, Eli Lilly, GHR Foundation, Fidelity, Gates Ventures, and the Alzheimer’s Association; served as a consultant for AC Immune, Biogen, Eisai, Neurocentria, Roche, Novartis, and Takeda; received nonfinancial support from Cogstate and Mount Sinai during the conduct of the study; and received grants and personal fees from Janssen outside the submitted work. Dr Karlawish is a site investigator for clinical trials supported by Lilly Inc, including the A4 Study, and Novartis. Dr Burns reported grants from the National Institutes of Health and Eli Lilly during the conduct of the study and grants from Avid Radiopharmaceuticals outside the submitted work. No other disclosures were reported.

Funding/Support: Individual researchers are supported by National Institutes on Aging (grants AG016573 [Dr Grill], P01AG036694 [Dr Sperling], K24 AG035007 [Dr Sperling], and AG010124 [Dr Karlawish]) and National Center for Advancing Translational Sciences (grant UL1 TR001414 [Dr Grill]). The A4 Study is funded by a public private partnership between the National Institute on Aging (grants U19AG010483, R01AG063689, and U24AG057437) and Eli Lilly, the Alzheimer’s Association (grant NIRG-12-243012), the GHR Foundation, and other philanthropic support.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: A4 Study Team: Leadership Team: Reisa Sperling, MD (Harvard Medical School, Brigham and Women’s Hospital, Massachusetts General Hospital); Paul Aisen, MD (University of Southern California, Alzheimer’s Therapeutic Research Institute); Roy Yaari, MD (Eli Lilly); Phyllis Barkman Ferrell, MBA (Eli Lilly); Eric Siemers, MD (Eli Lilly [Retired]); Team Leaders: Keith Johnson, MD (PET Imaging); Janice Hitchcock, PhD (Eli Lilly [Retired]); Karen Holdridge, MPH (Eli Lilly); Isabella Velona, MS (Eli Lilly); Jason Karlawish, MD (A4 Study Ethics Committee, University of Pennsylvania); Tiffany Chow, MD (University of Southern California, Alzheimer’s Therapeutic Research Institute); Veasna Tan, MA (University of Southern California, Alzheimer’s Therapeutic Research Institute); Clifford R. Jack, Jr., MD (MRI, Mayo Clinic); James B. Brewer, MD, PhD (Alzheimer’s Disease Cooperative Study [ADCS] Imaging); Paul Maruff, PhD (Cogstate); Alison Belsha, BS (University of Southern California, Alzheimer’s Therapeutic Research Institute); Gabriela Muranevici, MD (University of Southern California, Alzheimer’s Therapeutic Research Institute); Mike Rafii, MD, PhD (University of Southern California, Alzheimer’s Therapeutic Research Institute); Robert Rissman, PhD (ADCS Biomarker Core, University of California, San Diego); Cecily Jenkins, PhD (University of Southern California, Alzheimer’s Therapeutic Research Institute); Kenneth Marek, MD (Invicro); John Seibyl, MD (Invicro); Mark Mintun, MD (Avid/Eli Lilly); and Steve Bruno III, BA (University of Southern California, Alzheimer’s Therapeutic Research Institute); Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts: Kate Papp, PhD; Aaron Schultz, PhD; Beth Mormino, PhD; Justin Sanchez; Rebecca Amariglio, PhD; Gad Marshall, MD; Dylan Kirn; Dorene Rentz, PsyD; Michael Properzi; J. Alex Becker, PhD; and Matthew Scott; University of Southern California, Alzheimer’s Therapeutic Research Institute, Los Angeles: Devon Gessert, BS; Alison Belsha, BS; Jennifer Salazar, MBS; Kelly Harless, BA; Sarah Walter, MSc; Teresa Diaz, MS; Vianica Arguello, BS; Thea J. Morris, MA; Edna Stirewalt, BS, CRP, CPM; Robin Fluty, CRA, LPN; Alyssa Schmitt, MS; Renarda Jones, MS; Sarah L. Danowski, MA; Ryan Black, BS; Callyn Buchel, BS, CCRP; and Robyn Jucius, MPH; Gina Garcia-Camilo, MD; Viviana Messick, BS; Deborah Tobias; Jeremy Pizzola; Lindsey Earp, BA; Dan Abinsay; Karen Bowman, MCM; Shelley Moore, BA; Taylor Clanton, MPH, CHES; Gustavo Jimenez-Maggiora, MBA; Phuoc Hong, BA; Stefania Bruschi, MS, MBA; Hongmei Qiu, MS; Jia-shing So, BS; Elizabeth Shaffer, BS; and Emily Voeller, BA; Rema Raman, PhD; Michael Donohue, PhD; Chung-Kai Sun, MS; Karin Ernstrom, MS; Yanxin Jiang, MS; Cecily Jenkins, PhD; Xavier Salazar, PhD; Ryoko Ihara, MD, PhD; Barbara Bartocci, MPH; Kimberlee Eudy, JD; Quin Revel, JD; and Michael Selsnik, BS; Eli Lilly: Anne Micol, BS; Julie Bush, MS; Anita Suppiger, RN; Wendy Sorg; Traci Peddie, BA; AnnCatherine Downing, PhD; Brian Willis, PhD; Cheryl Brown, RPh, PMP; Russell Barton, MS (Retired); Cheryl Rumer, BSN (Retired); Connie Yan Tong, MD; James Senetar, PhD (Retired); Julie Chandler, PhD; Deanilee Deckard, MS, RN; Brandon Talkington; Shiloh Scott; Giedra Campbell, MA; Gopalan Sethuraman, PhD (Retired); Melissa Pugh, PhD; James David Barfield, MS; Hong Liu-Seifert, PhD; Holly Barce, MBA; Lynne Johnson, MSN; Kathryn Broderick, PhD; Keith Parson, BS, MBA; Brian Steuerwald; Lauren Brunke, PharmD; Lisa Ferguson-Sells, BSc; Kristina Dinkel, MS; Jane Njoroge; Michele Mancini, MD; Morris Bret Haisley; Leigh Cipriani, BS; Shamrock Garrett; Angela Corbly, RVT; Deborah Falk, RPh; Sheila Miller, PharmD; Adam Schwarz, PhD; Keita Asato; Tomomi Nakamura, MD; Diana Xiaoying Lau, BN, RN; Naohisa Hatakeyama; Mariela Gonzalez, BSc; Monica Tjan; John Holmes; and Sibyl Chauncy Materman, MA; MRI–Mayo Clinic: Jeffrey L. Gunter, PhD; Cory A. Johnson; Denise A. Reyes; Kejal Kantarci, MD; Leonard C. Matoush, Jr; Greg M. Preboske, MS; Bret J. Borowski, RT(R); Samantha M. Zuk; and Kaely B. Thostenson, RT(R); A4 Study Ethics Committee: Jeffrey M. Burns, MD, MS (University of Kansas Alzheimer’s Disease Center); Joshua D. Grill, PhD (University of California, Irvine); and David Sultzer, MD (UCLA and VA Greater Los Angeles Healthcare System); and Jason Karlawish, MD (University of Pennsylvania, Philadelphia); Alzheimer’s Disease Cooperative Study [ADCS] Biomarker Core, University of California, San Diego, San Diego: Louise Monte, MS; Sarah Abdel-Latin, BS; Natalie Abu Hamden, BS; Nicholas Monte, BS; Howard Feldman, MD (Director, Team Leader); Genny Matthews (Recruitment); Stephanie Parks (Clinical Operations); Jen Mason, MPH (Data Management); Jason Young, PhD (Informatics); Ashlee Heldreth, BA (Monitor); Renarda Jones, MPH (Monitor); Janet Kastelan, BA (Monitor); Lindsay Cotton, MPH (Monitor); Maria Bulger Lennox, RN (Monitor); Ronelyn Chavez, BA (Monitor); Tilman Oltersdorf, MD (MedSafety); Curtis Taylor, PhD (MedSafety); Barbara LaPlante, MA (Transition Team); Meghan Stirn, MBA (Transition Team); Joanne Brechlin, MBA, MPH (Transition Team); Gina Varner, MPH (Transition Team); Carol Evans, BA (U19 Grant Administration); Karim Hussein, JD (U19 Grant Administration); Erika Wilson (Finance); Ronald Thomas, PhD (Biostatistics); Rebecca Ryan-Jones, PhD (Monitor); and Sheila Jin, PhD (Biostatistics); ADCS Neuroimaging, University of California, San Diego, San Diego: John R. Hesselink, MD; Nichol Ferng, BS; Robin Jennings, BS, MS; and Leonardino Digma, BA; PET Imaging, Massachusetts General Hospital, Boston, Massachusetts: Heidi Jacobs, PhD; Justin Sanchez; Aaron Schultz, PhD; Jorge Sepulcre, MD; Matthew Scott; J. Alex Becker, PhD; and Michael Properzi; Avid: Stephen Truocchio, MS; Myrellen Merry; Michael Pontecorvo, PhD; Alexander Pratt; Andrea Abram, MBA; Michael Devous, PhD; Marybeth Howlett, MEM; and Robert Purtle; Invicro: Reneé Tschopp, MS, PMP; and Donna Miles; Cogstate, Melbourne, Australia: Ariel Matasci, BA; and Pawel Kalinowski, BBSC (Hons), PhD; Cogstate, New York, New York: Tanya O’Connor, BA; Patrick Brennan, BA; and Emina Behlic, BS; McCabe Message Partners: Patrick McCabe, BA; Becky Watt Knight, MA; Amy Martin Vogt, BA; Rachel Griffith, BA; Camille Ahearn, BA; and Melissa McGue, BSBA, BA; University of Alabama, Birmingham: Marissa C. Natelson Love, MD; David S. Geldmacher, MD; P. Denise Ledlow, RN; and Jacqueline Vaughn, RN; Banner Alzheimer’s Institute, Phoenix, Arizona: William J. Burke, MD; Roma Patel, MS, MBA; Daniel Viramontes Apodaca; Sachin Y. Pandya; and Anna D. Burke, MD; Banner Sun Health Research Institute, Sun City, Arizona: Edward Zamrini, MD; Zoran Obradov, CRC; Christine M. Beldan, PsyD; Carol Cline, MSW, LMSW, CSP (Psychometrist); Margaret Rich, CSP (Psychometrist); Lisa Roye, MS (Psychometrist); and Marwan Sabbagh, MD (Past Investigator); Stanford University School of Medicine, VA Aging Clinical Research Center, Stanford, California: Jerome Yesavage, MD; Steven Z. Chao, MD, PhD; Karlos E. Zepeda, BS; Tamara Beales, MA; and Vivian Q. Chu, BA; Sutter Institute for Medical Research, Sacramento, California: Shawn Kile, MD; William Au, MD; Yvonne Au, LCSW, PACC; Mary Vaughn, RN; Sampreet Kaur, CRC; Tammy Donnell, CCRC; and Dawn Lenakakis, CRC; Syrentis Clinical Research, Santa Ana, California: John Gregory Duffy, MD; Lorrie Bisesi, PhD; Poonam Nina Banerjee, PhD; Eloisa Vasquez, BSc; and Rebecca Sanchez; University of California, Davis, Alzheimer’s Disease Center East Bay, Walnut Creek, California: John Olichney, MD; Charles DeCarli, MD; Hongzheng Zhang, PhD; Antoinette Lopez, MD; and Mary McPhail-Ciufo, MD; University of California, Irvine BIC, Irvine: Adrian Preda, MD; Andrea Weideman; and Steven Potkin, MD (Past Investigator); University of California, Irvine, MIND, Irvine: Aimee L. Pierce, MD; Joshua D. Grill, PhD; Malcolm B. Dick, PhD; Gaby T. Thai, MD; and Steven Tam, MD; University of California, Los Angeles, Los Angeles: Joshua Grill, PhD (Past Investigator); Sarah Kremen, MD; Maryam Beigi, MD; Celine Ossinalde, MA; Michelle Craig, MA, LMFT; and Michelle Torreliza; University of California, San Diego, San Diego: Douglas Galasko, MD; Helen Vanderswag, RNC, BSN; Asmaa Al Hamdani, MBChB, MAS; Chi Kim, BS; and Shawnees Peacock, BS; University of California, San Francisco, Memory and Aging Center, San Francisco: Adam L. Boxer, MD, PhD; Gil Rabinovici, MD; Richard M. Tsai, MD; Peter Ljubenkov, MD; and Julio C. Rojas, MD, PhD; University of Southern California Alzheimer’s Disease Research Center, Los Angeles: Mauricio Becerra; Liberty Teodoro, RN; Sonia Pawluczyk, MD; Karen Dagerman, MS; and Lon Schneider, MD; Yale Alzheimer’s Disease Research Unit, New Haven, Connecticut: Christopher H. van Dyck, MD; Julia W. McDonald, BA; Joanna E. Harris, BA; Srinath Ramanan, BS; and Erika A. Pugh, MA; Georgetown University, Washington, DC: Raymond Scott Turner, MD, PhD; Melanie Chadwick, RN, MS, NP; Kathleen Johnson, RN, MSN, NP; Brigid Reynolds, RN, MSN, NP; and Kelly McCann, BA; Howard University, Washington, DC: Thomas O. Obisesan, MD, MPH; Oyonumo E. Ntekim, MD, PhD; Sheeba R. Nadarajah, PhD; Sharlene Leong, MSc; and Saba Wolday, MSc; Bioclinica Research, North: David C. Subich, MD, FAPCR, CPI; Steph Krauchunas, PA; Ruth Paiano, ARNP; Ayesha Lall, MD; Randall Braddom, MD; Bioclinica Research, Orlando, Florida: Esteban Olivera, MD; Craig Curtis, MD; Jennifer West, PAC; Maria A. Edridge, L-CRC; and Shayna Carter, CRNI; Brain Matters Research: Mark Brody, MD; Paayal Patel, MD; Elizabeth Diebel, CCRC; Daisy Acevedo; and Cynthia Stimeck, PA-C; Mayo Clinic, Jacksonville, Florida: Neill R. Graff-Radford, MD (); Rita M. Fletcher, RN, BSN; and Dana L. Haley, MPH; Premiere Research Institute: Carl Sadowsky, MD; Teresa Villena, MD; and Alfonso Moreno, MD; USF Health Byrd Alzheimer’s Institute, San Francisco, California: Amanda G. Smith, MD; Kelly Rodrigo, BA, CCRC; Beth Major, LPN, CCRC; Ijeoma Mba, MBBS; and Juris Janavs, MD; Wien Center for Alzheimer’s Disease and Dementia, Miami, Florida: Ranjan Duara, MD; Maria T. Greig Custo, MD; Rosemarie A. Rodriguez, PhD; Huston Powell, PharmD, MBA; Warren Barker, MA; and Florencia Tocasuche, AS; Emory University, Atlanta, Georgia: James J. Lah, MD, PhD; Allan I. Levey, MD, PhD; Deborah Westover, BSN, RN; and Sarah Evans, BS; Great Lakes Clinical Trials: Jeffrey Ross, MD; and Linda Rice, PhD; Northwestern University, Chicago, Illinois: Sandra Weintraub, PhD; Ian Grant, MD; Borna Bonakdarpour, MD; Kristine Lipowski, MA, CCRC; and Jordan Robson, BS; Rush University Medical Center, Chicago, Illinois: Neelum T. Aggarwal, MD; Raj C. Shah, MD; Mary Schum, MA, PA-C; and Amelia Williams; Indiana University, Indianapolis: Martin Farlow, MD; Jared Brosch, MD; Nancy McClaskey, RN; Gena Antonopoulos, RN; and Lizeth Achury, BS; University of Iowa, Iowa City: Del D. Miller, PharmD, MD; Hristina K. Koleva, MD; Karen Ekstam Smith, RN; Laura Temple, MS; and Susan Schultz, MD (Past Investigator); University of Kansas Medical Center Alzheimer’s Disease Center, Kansas City: Anne Arthur, APRN; Rebecca Bothwell, MS, CCRP; Aiden Bondurant, CCRP; and Phyllis Switzer; University of Kentucky, Lexington, Kentucky: Gregory A. Jicha, MD, PhD; Kendra Bates, BA; Shoshana Bardach, PhD; Molly Harper, MA; and Kelly Parsons, MSW; Pennington Biomedical Research Center, Baton Rouge, Louisiana: Jeffrey N. Keller; William P. Gahan, MD; Robert Brouillette, MS; Heather Foil, MS; and Owen Carmichael, PhD; Johns Hopkins University, Baltimore, Maryland: Paul B. Rosenberg, MD; Meghan Schultz, RN, MSN; Sarah Lawrence, MS; and Caitlin Romano, BS; Boston University School of Medicine, Boston, Massachusetts: Robert A. Stern, PhD; Jane Mwicigi, MBChB, MPH; Dawn Jacobs, BSN, MPH; Jesse Mez, MD, MS; Wendy Qiu, MD, PhD; and Eric Steinberg, MSN, RN, CS, CANP; Brigham and Women’s Hospital, Boston, Massachusetts: Gad A. Marshall, MD; Kirsten A. Glennon, RN; Nancy Coppelman, BA; Martha Vander Vliet, RN; and Dorene Rentz, PsyD; University of Michigan, Ann Arbor: Judith L. Heidebrink, MD, MS; and Jaimie Ziolkowski, MA, BS, TLLP; Mayo Clinic, Rochester, Minnesota: David S. Knopman, MD; Jon Graf Radford, MD; Sara Mason, RN; Karen Kuntz; and Kari Baxter, ACRC; Washington University School of Medicine, St Louis: Randall Bateman, MD; Joy Snider, MD, PhD; Gregory Day, MD; Nupur Ghoshal, MD, PhD; Erik Musiek, MD, PhD; John Morris, MD; and Tammie Benzinger, MD, PhD; University of Nebraska Medical Center, Omaha: Daniel L. Murman, MD, MS; Mary Horrum, RN; Renee Hogue, RN; Deb Heimes, BS; and Nick Miller, BS; Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada: Charles Bernick, MD, MPH; Donna Munic-Miller, PhD; Samuel Hickson, LSW, MSSA; Garam Lee, PharmD, RPh; and Milagros Formoso, BS, CCRP; Columbia University Medical Center, New York, New York: Karen L. Bell, MD; Ruth Tejeda, MD, MS; Betina Idnay, RN; Lawrence Honig, MD, PhD; and Evelyn Dominguez, MD, MS; Dent Neurologic Institute: Horacio A. Capote, MD; Caroline Kumm, MS, CRC; and Michelle Rainka, PharmD; Icahn School of Medicine at Mount Sinai, New York, New York: Mary Sano, MD; Judith Neugroschl, MD; Kelly Pun, BA; Hillel Grossman, MD; and Amy Aloyisi, MD; New York University Langone Medical Center, New York, New York: Melanie Shulman, MD; Anaztasia Ulysse, BA, CRC; Jamika Singleton-Garvin, CCRC; Mohammed Sheikh, BS, CCRC; and Mrunaliniash Gaikwad, BS, CRC; University of Rochester, Rochester, New York: Anton P. Porsteinsson, MD; Audrey Rice, RN, ANP; Susan Salem- Spencer, RN, MSN; Kaitlyn Lane, BA; and Asa Widman, BA; Weill Cornell Medical Center, New York, New York: Michael Lin, MD; and Norman Relkin, MD, PhD; Wake Forest University School of Medicine, Winston-Salem, North Carolina: Suzanne Craft, PhD; Patricia Wittmer (Wake Forest University School of Medicine); Mary Hayworth Troncale, PA; Alexis Webb, MS; and Deborah Dahl, RN, MSN; University Hospitals Cleveland, Case Western Reserve University, Cleveland, Ohio: Alan J. Lerner, MD; Maria Gross, RN; Parianne Fatica, CCRC; Susie Sami, MA, CCRC; Paula Ogrocki, PhD; and Marianne Sanders, RN; Tulsa Clinical Research, LLC, Tulsa, Oklahoma: Ralph W. Richter, MD; Christy Lisenbee, BS; John Parsons, BS; Sarah Fowler, CPhbT; and Carmen Toegel, LPN; Oregon Health and Science University, Portland: Lisa C. Silbert, MD; Chad Sorenson, BS; Betty Lind, BS; Jeffrey Kaye, MD; and Jason David, BA; Drexel University, Philadelphia, Pennsylvania: G. Peter Gliebus, MD; Katherine Rife, BS; Melinda Webster, BS; Christine Barr, RN; and Monica Mazurek; University of Pennsylvania, Philadelphia: Sanjeev N. Vaishnavi, MD, PhD (Past Investigator); Martha Combs, BS, MS; and Jessica Nunez; Loren Terrill; University of Pittsburgh, Alzheimer’s Disease Research Center, Pittsburgh, Pennsylvania: Oscar Lopez, MD; Thomas Baumgartner, LSW, MPH; Sara Goldberg, MS; and Donna Simpson, CRNP, MSN, MPH; Butler Hospital Memory and Aging Program, Providence, Rhode Island: Stephen P. Salloway, MD, MS; Vanessa Rua, BSN, RN; Diane Monast, RN, MSN, CNS; Athene K.W. Lee, PhD; and Jessica Alber, PhD; Rhode Island Hospital, Providence: Brain R. Ott, MD; Lori A. Daiello, PharmD, ScM; Jonathan D. Drake, MD; and Alisa Omert, RN; Roper St. Francis, Charleston, South Carolina: Jacobo Mintzer, MD; Sheila Howland, RN, BSN; Allison Lapp, MS, CHES; Abigail O’Connell, MS, APRN, FNP-C; and Arthur Williams, BS, BA; Baylor College of Medicine, Houston, Texas: Sydney O’Connor, BA, MA; Valory Pavlik, PhD; Joseph Kass, JD, MD; Rachelle Doody, MD, PhD (Past Investigator); Nantz National Alzheimer Center, Houston Methodist, Houston, Texas: Joseph C. Masdeu, MD, PhD; Belen Pascual, PhD; Jennifer M. Garrett, RN; University of Texas Southwestern Medical Center, Houston: Brendan Kelley, MD; Kyle Womack, MD; Roger Rosenberg, MD; Trung Nguyen, MD; and Mary Quiceno, MD (Past Investigator); Seattle Institute for Biomedical & Clinical Research, Seattle, Washington: Elaine Peskind, MD; James O’Connell, MSW; Robert Turner, PA-C; Murray A. Raskind, MD, PhD; Debra Burges, BSN, RN; and Anita Ranta, BS; University of Wisconsin, Madison: Cynthia M. Carlsson, MD, MS; Benjamin Farral, BS; and Karen K. Lazar, MS; Sandra Harding, MS; and Aleshia Cole, RN, APNP; Parkwood Institute, London, Ontario, Canada: Sarah Best, BSc, CCRP, MHM; Abigail Korczak, BScN, RN; Kayla VanderPloeg, BScN; Elsa Mann, BScN; and Julia Truemner, BA, CCRP; Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada: Sandra Black, OC, OOnt, MD; Benjamin Lam, MD, MSc: Chinthaka Heyn, PhD, MD: Samantha Paul-Stotz, RN, BSc; and Maryna Butenko, MSc; Toronto Memory Program, Toronto, Ontario, Canada: Sharon Cohen, MD; C. Ian Cohen, MD, CCFP; Ellen Buchman, MD; Atif Shaikh, MBBS, RPN; and Linda Schlesinger, BA, CCRP; University of British Columbia, Clinic for Alzheimer Disease and Related Disorders, British Columbia, Vancouver, Canada: Robin Hsiung, MD, MHSc; Benita Mudge, BSc; Eloise Nicklin, MSc; Michele Assaly, MA; and Haakon Nygaard, MD, PhD; The University of Melbourne, Melbourne, Australia: Colin L. Masters, MD; Maree Mastwyk, PhD; Paul Yates, MBBS, PhD; Anne Buckland, RN; and David Darby, MBBS, PhD (Past Investigator); The University of Tokyo School of Medicine, Tokyo, Japan: Takeshi Iwatsubo, MD; Atushi Iwata, MD, PhD; Kazushi Suzuki, MD, PhD; Ryoko Ihara, MD, PhD; and Chie Sakanaka, MD, PhD. Updated as of August 2018.

Additional Contributions: We would like to thank the participants and study partners of the A4 study.

Additional Information: For more information on the the Anti-Amyloid Treatment in Asymptomatic AD Study, please see a4study.org.