Cognitively unimpaired adults' reactions to disclosure of amyloid PET scan results.

IMPORTANCE: Clinical guidelines currently recommend against amyloid imaging for cognitively unimpaired persons. The goal of Alzheimer's disease (AD) prevention, together with advances in understanding the pathophysiology of AD, however, has led to trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Assuming the eventual success of such trials, millions of patients will be affected. There is a need to understand the effects of biomarker disclosure on those individuals.
DESIGN: The Study of Knowledge and Reactions to Amyloid Testing (SOKRATES) involved 2 semi-structured telephone interviews with individuals who received amyloid PET scan results as part of screening for research participation. Post-disclosure interviews were conducted at 4 to 12 weeks and again 1 year later. Data were collected from November 5, 2014 to November 30, 2016. Interviews were transcribed and coded in NVivo 12.0. PARTICIPANTS: 80 adults aged 65 and older: 50 who received "elevated" and 30 who received "not-elevated" amyloid PET scan results. MAIN OUTCOMES: Interviews examined four domains: (1) comprehension of the amyloid PET scan result; (2) implications of the result for sense of self, memory, and future; (3) sharing of results with others; and (4) AD risk-reduction behaviors.
RESULTS: Participants who received an elevated amyloid PET scan result viewed the result as more serious and sensitive than other medical test results given its unique implications for identity, self-determination, and stigma. In contrast, participants who received a not-elevated amyloid PET scan result described feeling relief and reinterpreted perceived memory impairments as normal aging. Participants with elevated amyloid reported contemplating and making more changes to health behaviors and future plans than their peers with not-elevated amyloid.
CONCLUSIONS: Clinical practice in the diagnosis and treatment of persons with preclinical AD, a stage of the disease defined by the presence of biomarkers in the absence of cognitive impairment, will need to address matters of identity, stigma, and life-planning.

Introduction

Alzheimer’s disease (AD) is being reconceptualized as a disease that begins in a preclinical stage characterized by the presence of AD biomarkers in the absence of cognitive impairment.[1][2] An estimated 46.7 million Americans have preclinical AD, though not all will progress to the clinical stages of mild cognitive impairment (MCI) or dementia.[3] At present, diagnostic guidelines recommend against imaging for the diagnosis of AD in cognitively unimpaired persons.[4,5] Should the preclinical AD construct be validated and become a target of therapeutic intervention, however, cognitively unimpaired older adults will likely be routinely screened for AD biomarkers.

Looking to the future, clinicians need to understand both how patients experience the emerging disease stage of preclinical AD and how best to talk about biomarker results in the pre- and post-test context. Anticipating these needs, the same studies designed to validate preclinical AD and to test novel interventions in the preclinical stage are an opportunity to understand the practical and ethical dimensions of biomarker disclosure to cognitively unimpaired persons.[6-8] Interest in learning biomarker results is high among at-risk individuals and is supported by investigators.[9-11] The extant empirical literature on disclosure of amyloid imaging results to cognitively unimpaired adults is, however, limited.[12,13] The more we understand their understanding of and reactions to biomarker disclosure, the better we can prepare for future clinical practice.[14]

Here, we report the results of the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES), a longitudinal qualitative study of cognitively unimpaired adults ages 65 to 85 who learned the result of an amyloid positron emission tomography (PET) scan in order to enroll in a clinical trial.

Methods

SOKRATES participants were recruited from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4) (NCT0200835)—a secondary prevention trial testing whether solanezumab can slow cognitive decline in persons with amyloid accumulation—and its companion longitudinal cohort study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (NCT02488720).[15] A4 participants had evidence of amyloid plaque build-up (i.e., an “elevated” amyloid PET scan result), while LEARN participants screen-failed for A4 solely on the basis of not having amyloid accumulation (i.e., a “not-elevated” amyloid PET scan result). Inclusion critera required that participants were cognitively unimpaired at baseline; they scored within normal limits on baseline cognitive testing and were rated a zero (no impairment) on the Clinical Dementia Rating (CDR) dementia-staging instrument.[16] Subjective cognitive complaints were permitted.

A4 and LEARN participants underwent a standardized amyloid disclosure process.[17] Participants were pre-screened for depression and anxiety, and completed an educational session with a comprehension check in which they received both verbal and written information about amyloid imaging, including possible results, their meaning, and their implications for risk of future cognitive decline. The study guide explains that elevated amyloid “does not necessarily mean you will develop AD-related memory loss” but can be associated with an increased risk; it further explains that “not elevated” does not mean you will never develop AD or “elevated amyloid” in the future. Amyloid imaging occurred on a separate day from the education session, and disclosure of the imaging results occurred on a separate day from imaging. Site investigators disclosed the amyloid PET scan results in-person using standardized talking points. Participants received a post-disclosure follow up phone call and regular monitoring of mood and well-being throughout the study.

For SOKRATES, 50 participants with “elevated” amyloid and 30 participants with “not-elevated” amyloid completed a semi-structured interview 4 to 12 weeks after disclosure of their amyloid PET scan results (T1); 47 and 30 of these individuals, respectively, completed a 12-month follow-up interview (T2). T1 interviews examined four domains: (1) comprehension of the amyloid result; (2) implications for sense of self, memory, and future; (3) sharing of results with others; and (4) risk-reduction behaviors. T2 interviews re-examined participants’ reports from the initial interview.

All interviews occurred between November 5, 2014 and November 30, 2016 and were conducted by one interviewer (KH). Interviews were recorded, transcribed, and analyzed in NVivo qualitative analysis software, version 11.0 (QSR International). The methods have previously been reported.[18] Briefly, the research team reviewed all transcripts to develop a coding scheme to reflect the four aforementioned domains and to capture themes that emerged during coding and analysis. This iterative process involved multiple consensus meetings to resolve coding discrepancies, regular checks on agreement using the Cohen coefficient for inter-coder reliability, and adjustments to the codebook with an audit trail of coding rules and decisions made. To allow comparisons between participants who received an “elevated” result and those who received a “not-elevated” result, we report the frequency of codes as a fraction of each group’s total members.

The University of Pennsylvania Institutional Review Board (IRB) approved this study. The IRB approved a waiver of documentation of consent. SOKRATES participants were mailed or emailed written information about the study; that information was reviewed with them over the phone. Only then were participants asked to give verbal consent to be interviewed. Participants received a $20 gift card (choice of CVS or Amazon) in exchange for their participation.

Results

Table 1 reports participant demographics. Analyses included searching for differences among groups based on demographic variables; no notable differences in results were observed by age or gender.

Table 1

Demographic characteristics of SOKRATES subjects by amyloid status at time of the initial interview,.

Characteristic	“Elevated” Amyloid (n = 50)c	“Not-Elevated” Amyloid (n = 30)
	N (%)	N (%)
Sex
Male	25 (50%)	13 (43%)
Female	25 (50%)	17 (57%)
Aged
65–74	35 (70%)	25 (83%)
≥ 75	15 (30%)	5 (17%)
Race/Ethnicity
Caucasian/non-Hispanic	49 (98%)	28 (93%)
Asian	1 (2%)	0
Caucasian/Hispanic	0	1 (3%)
Multiracial/Hispanic	0	1 (3%)
Education
High School	1 (2%)	0
Some College or College Degree	19 (38%)	11 (37%)
Post Graduate Education	30 (60%)	19 (63%)
Family history of Alzheimer’s disease
Yes	40 (80%)	21 (70%)
No	10 (20%)	8 (27%)
Unknowne		1 (3%)
Marital Status
Married/Living with Partner	36 (72%)	26 (83%)
Divorced/Separated	8 (16%)	2 (7%)
Widowed	4 (8%)	2 (7%)
Single	2 (4%)	1 (3%)
Employment Status
Retired	31 (62%)	20 (67%)
Part-Time	14 (28%)	7 (23%)
Full-Time	5 (10%)	3 (10%)

Participating sites (n = 10) provided between 0–12 participants with elevated amyloid and 0–12 participants with not elevated amyloid

bDistribution of demographic characteristics did not differ by amyloid status at p = 0.05 level, by Chi-Square or Fisher’s exact test

cThree elevated amyloid participants completed interview 1 and could not be reached for follow up

dOversampled for greater representation among subjects 65–74 years of age due to the potentially greater significance of an amyloid PET scan imaging result for younger individuals

eOne participant was adopted and unable to provide information on family history

Understanding of amyloid PET scan results

Most participants who received an “elevated” amyloid PET scan result (31 of 50 [62%]) understood that the result described an increased but uncertain risk of developing AD dementia.[18] Some (20 of 50 [40%]) felt it was ambiguous, and many of these participants wanted quantitative information about the amount of amyloid detected.

Half of the participants who received a “not-elevated” result (16 of 30 [53%]) understood their result to mean they were at decreased risk of developing AD dementia. Some (9 [30%]) emphasized that the result meant they did not presently have AD but acknowledged “it doesn’t mean that I won’t get it in the future.” Few (3 [10%]) described their result as ambiguous or expressed a desire for additional information.

Effect on perceptions of memory

A third of participants with elevated brain amyloid (18 of 50 [36%]) reported feeling that their memory was impaired prior to the amyloid PET scan. For them, receiving an “elevated” result validated their memory-related concerns. Another third (16 [32%]) reported becoming more aware of and more worried about memory issues after learning their result. One explained, “I’m starting to question more whether these ‘senior moments’ are related to amyloid plaques.” At T2, these participants’ perceptions of memory were largely unchanged.

Receiving a “not-elevated” result relieved participants’ memory-related anxiety. Roughly half of these individuals (16 of 30 [53%]) described re-interpreting memory lapses as normal aging. One explained that the result “made me think that any memory problems I was having was just normal age related rather than … Alzheimer’s.” At T2, most participants with not-elevated brain amyloid continued to describe minor memory lapses as “normal aging,” though several expressed frustration because they lacked an explanation for perceived memory issues. One explained, “[K]nowing that I don't have any amyloids, I'm saying, ‘Well, what can it be?‴

At T1, a notable minority of all participants (elevated brain amyloid: 16 of 50 [32%]; not-elevated brain amyloid: 12 of 30 [40%]) stated both that they had no concerns about their memory prior to the amyloid PET scan and that learning their result had no effect on their perceptions of memory. By T2, however, several participants with elevated brain amyloid expressed increased concern about their memory, while a few participants who had received a “not-elevated” imaging result noted memory issues but expressed “peace of mind” that these were not due to brain amyloid.

Comparing amyloid PET scan results to other medical test results

Most participants (elevated brain amyloid: 33 of 50 [66%]; not-elevated brain amyloid: 23 of 30 [77%]) reported that the amyloid PET scan result was unlike results from other medical tests.

Half of the participants with elevated brain amyloid who felt the amyloid imaging result was different than other medical tests (16 of 33 [48%]) described it using words such as sensitive, touchy, severe, and devastating. Several explained that the amyloid PET scan result had unique implications for their sense of self, stating for example that “a colonoscopy isn’t going to change who I am … this is my brain involved” or “[the result] speaks to who I am … my brain is a very critical part of me.” A quarter of participants with elevated brain amyloid who felt the amyloid imaging result was different than other medical tests (9 of 33 [27%]) expressed concern that the result could have social consequences because “[l]osing your mental faculties is regarded by people differently than eye sight or hearing or anything else because they are seeing that you’re less of a person” and “Alzheimer’s has a negative stigma to it.” Reasons for not sharing an “elevated” result with others mirrored these concerns and included desires “not to distress anyone,” to respect others’ desires not to know, to avoid negative social consequences such as being “shut out” or treated differently, and to prevent discrimination in employment, healthcare, or insurance.

Nearly half of participants who received a “not-elevated” result and reported that the amyloid PET scan result was different than other medical test results (11 of 23 [48%]) described it as a “research finding” rather than a clinical result.

Feelings about the future

Participants with elevated brain amyloid expressed diverse feelings about the future (Table 2). They variously described feeling that their future was bleak (12 of 50 [24%]), unknown (27 [54%]), or bright (14 [28%]). Reasons for feeling the future was bright included being optimistic by nature, hoping to “be one of the lucky ones” who escapes dementia, having faith in medical advances, and having family members who were healthy into their old age. No participants expressed relief after receiving an “elevated” result.

Table 2

Responses to the questions “How do you feel about your future?” and “Did you feel the same way before you learned your amyloid PET scan result?/ How did learning your result change how you feel about your future?”.

	“Elevated” Amyloid		Representative Quote	“Not-Elevated” Amyloid		Representative Quote
	Time 1 (N = 50)	Time 2 (N = 47)		Time 1 (N = 30)	Time 2 (N = 30)
Bright Future	14 (28%)	12 (25%)	“I'm convinced they'll find a cure for Alzheimer's, so I feel relieved that I have an advantage, that knowing I have it, I can be doing lifestyle things to help myself, and maybe really keep an eagle eye out for developments in the clinical world.”	19 (63%)	17 (57%)	“Now that the probability is lower that I'm going to have Alzheimer's that gives the longer term forecast a lot more positive look to it.”
Bleak Future	12 (24%)	6 (13%)	“Well, I'm less optimistic than I used to be about what my future would be like. I know over the years, several people who have had Alzheimer's. … They were more like vegetables. I don't look forward to that.”	2 (7%)	1 (3%)	“I feel like I'm almost 75 and that's sort of the way it's going to be. It's not going to get better.”
Future Unknown	27 (54%)	1 4 (30%)	“Well, I would say there are just a lot of question marks… just from the standpoint of not knowing whether I'm going to stay the same, get worse, and how soon that would happen… I have no information to guide me other than I had this elevated amyloids, it's not that much information to go on…”	6 (20%)	3 (10%)	“How do I feel about the future? It's an unknown. It's a big question mark, I guess.”
Not Thinking About Future	22 (44%)	21 (45%)	“I don't think that far ahead. My future right now is… I'm kind of in the present or trying to be. I'm not worried. I can't be thinking that, "You know, okay, I'm 66. When I'm 86, I'm going to be this or that or the other thing." I'm busy trying to enjoy being 66.”	12 (40%)	13 (43%)	“A lot of issues of the future are not things I really want to think about.… I'm just going with the flow, as it were.”

aCodes are not mutually exclusive. Responses were coded for whether each sentiment was expressed.

Participants who received a “not-elevated” amyloid PET scan result had more uniform feelings about the future. Two-thirds (19 of 30 [63%]) reported their future was bright, and two-thirds (19 [63%]) reported feeling relief. Nearly half [13 [43%]) reported both sentiments. One participant explained that he had been “living under this cloud that someday [AD] may get me. … [The amyloid PET scan result] took a lot off of my mind.”

Nearly half of participants with elevated amyloid (T1: 22 of 50 [44%], T2: 21 of 47 [45%]) and also with not-elevated amyloid (T1: 12 of 30 [40%], T2: 13 of 30 [43%]) were present-focused. When asked directly about their future, some persisted in talking only about the present, while others described deliberately not thinking about the future.

Health behaviors

Across T1 and T2, participants who received “elevated” and “not-elevated” results reported changing health behaviors, though change was more common among participants with elevated brain amyloid. Common health behavior changes are reported in Table 3. Many participants who had received an “elevated” result reported undertaking health behavior changes specifically to remain cognitively healthy and to delay or prevent cognitive symptoms. Representative explanations included: “I’m trying to eat more berries and nuts ‘cause that can be healthy for the brain” or “I started running again … I read that that helps, maybe, possibly, helps reverse some of the effects of Alzheimer’s” or “[an article] said that one way that could conceivably reduce your chances of suffering memory problem later on is to keep your brain active.”

Table 3

Health behavior: Material derived from responses to the questions: “Have you made any changes in your daily life based on knowing your amyloid scan result?/ Have you started/stopped doing anything?/Are you spending time differently?” As well as queries about specific health behaviors: Diet, exercise, medications/vitamins/supplements, stress reduction, mental/cognitive activities.

		“Elevated” Amyloid (N = 50)	“Not-Elevated” Amyloid (N = 30)
	Made No Change	11 (22%)	10 (33%)
	Made Any Change	39 (78%)	20 (67%)
Changes by Domaina	Preventive	36 (72%)	16 (53%)
	Exercise	22	8
	Diet	17	13
	Cognitive Activity	23	5
	Medication/Vitamins/Supplements	9	0
	Sleep	3	0
	Quit/reduce alcohol, smoking, marijuana	4	0
	Quality of Life	17 (34%)	6 (20%)
	Socializing	5	2
	Adopting a Positive Outlook	5	1
	Practicing Religion/Spirituality	3	1
	Volunteering	4	0
	Meditating	8	1
	Playing Music	2	0
	Adopting a Pet	2	2
	Other	18 (36%)	1 (3%)
	Reading and Learning about AD Research	11	1
	Adopting Strategies to Compensate	9	0

aCodes are not mutually exclusive. Responses were coded for whether a change in each domain was mentioned.

Future plans

As shown in Table 4, nearly three-quarters of participants who received an “elevated” amyloid PET scan result (36 of 50 [72%]) described contemplating or making changes to their future plans. Across T1 and T2, the most common changes were in the domains of planning for use of leisure time (19 of 50 [38%]), financial planning (15 [30%]), medical, legal, or general planning (14 [28%]), and adjustment of living arrangements (13 [26%]).

Table 4

Future planning: Material derived from responses to the questions: “How did learning your result change how you feel about your future? Are you changing or reassessing any plans in your life since learning the result?”.

		“Elevated” Amyloid (N = 50)	“Not-Elevated” Amyloid (N = 30)
	Made No Change	14 (28%)	17 (57%)
	Made Any Change	36 (72%)	13 (43%)
Changes by Domaina	Leisure Time & Activities E.g., traveling, checking items off “bucket list,” doing enjoyable activities now rather than putting them off for later	19 (38%)	4 (13%)
	Financial Planning E.g., “getting finances in order,” meeting with financial planner, reviewing/updating accounts and investments, considering/purchasing insurance, spending more, saving more	15 (30%)	4 (13%)
	Medico-Legal Planning E.g., “getting affairs in order,” meeting with lawyer, reviewing/updating will, other estate planning, power of attorney, conversations with loved ones about medical and end of life wishes	14 (28%)	3 (10%)
	Living Arrangements E.g., downsizing or selling properties, considering long-term care facilities or continuing care retirement communities, moving closer to or in with family, home repairs/renovations to accommodate aging and changing abilities, organizing/decluttering	13 (26%)	5 (17%)
	Employment E.g., balancing work and leisure, retiring, reducing workload, considering when/if to retire, switching careers, considering whether to take new job	6 (12%)	1 (3%)
	Activities of Daily Living E.g., considering/making plans related to potential changes in capabilities such as home maintenance, cleaning, and yard work, taking care of loved ones, driving	4 (8%)	0 (0%)

aCodes are not mutually exclusive. Responses were coded for whether a change in each domain was mentioned.

When asked directly, most participants who had received an “elevated” result denied that changes in their future plans were due to their amyloid imaging result. Instead they attributed the changes to their age or life-stage, or to changes in their family situation. For instance, one woman explained that her decision to “clear out the crap” in her house was “[n]ot as a result of the PET scan” but because family members were “all aging, and … all in various degrees of decrepitude, so that makes me face my future more.” Another reported that “establishing trusts or investments” had “nothing to do with memory. It's just got to [do] with common sense.” Several did acknowledge, however, that the “elevated” result might be an extra push to engage in planning. A number discussed making changes to avoid “becom[ing] a burden to any of my family.”

More than half of the participants who received a “not-elevated” result (17 of 30 [57%]) reported that they were not contemplating or making changes to their future plans across T1 and T2. Some explained that, after getting the “not-elevated” result, “[f]or better or worse, I don't feel as compelled to make long term plans.” Participants were asked to consider the counterfactual—that is, what they would have done had their amyloid imaging result been “elevated.” Most (86% across T1 and T2) stated that they would have changed their future plans. Their hypothesized changes were consistent with the actual changes that participants who received an “elevated result” reported contemplating or making.

Among participants still working, a third of those who received an “elevated” result (6 of 19 [32%]) reported making or contemplating changes to their employment status, whereas only one individual who received a “not-elevated” result (1 of 10 [10%]) described making or contemplating such a change. Participants with elevated brain amyloid spoke to the potential for changes in job performance due to cognitive decline. One participant explained, “[A] factor…that I have in the back of my mind, is whether [the amyloid] will affect my teaching ability, whether I should do that [continue teaching] or not.” Participants with elevated brain amyloid also perceived tradeoffs between work and leisure. One participant explained, “Now I'm thinking, ‘Oh, gosh. Maybe I should cut back on my working. Maybe I should live life now while I have a chance and spend all my retirement money traveling among other things.’ … I need to think more carefully about if my time is limited how much time do I want to spend working?”

Discussion

SOKRATES studied how cognitively unimpaired older adults react to learning the result of a PET scan measuring brain amyloid, an AD biomarker. Though conducted in a research context rather than a clinical one, A4’s screening process of assessment and testing, disclosure of test results, and if indicated, provision of therapy closely mirrors clinical practice in the context of other serious diseases. Thus, SOKRATES participants’ experiences provide important insights into the future experience of living with a preclinical AD diagnosis. In particular, comparing the results of participants who received an “elevated” amyloid PET scan result to the results of participants who received a “not-elevated” result informs our understanding of how clinicians should talk about amyloid PET scans with patients in the pre- and post-scan context.

SOKRATES participants generally understood the key point of the A4 amyloid imaging disclosure process: an “elevated” amyloid PET scan result means a person has an increased but presently unquantifiable risk of developing AD dementia.[18] Notably, participants differed in their interest in further details about the amyloid PET scan result. Participants who received an “elevated” result often wanted more information, whereas those who received a “not-elevated” result were generally satisfied with detail they received. Participants with elevated amyloid viewed the result as providing an explanation for perceived memory impairments. In contrast, as seen in prior work, participants who received a “not-elevated” result reinterpreted perceived memory impairments as normal aging.[19]

Consistent with prior work on disclosure of risk for AD, receipt of an “elevated” result sparked negative emotions but did not lead to extreme distress.[20] These negative emotions decreased but did not entirely dissipate with time. Our findings support the emerging consensus on the safety of disclosing amyloid imaging results to cognitively unimpaired persons following pre-test assessments of knowledge and psychological well-being.[21-24] Further, they are consistent with studies concluding that it is safe to disclose amyloid imaging results to adults with MCI and dementia.[25,26]

Post-disclosure, participants who received an “elevated” result reported contemplating and making changes to health behaviors and future plans to a greater extent than participants who received a “not-elevated” results. Participants with elevated brain amyloid did not uniformly ascribe these changes to their amyloid PET scan result. Yet, given both the relatively higher frequency of changes reported by those with elevated brain amyloid and the responses of participants who did not have elevated brain amyloid to a counterfactual question about what changes they would make had their result been “elevated,” we infer that the “elevated” amyloid imaging result was a key driver of change. Further supporting this inference, our findings are consistent with changes seen in APOE ε4 carriers who receive information about their risk of AD dementia.[27,28] Of particular interest, we found that disclosure of an “elevated” amyloid PET scan result brings into sharp relief tradeoffs related to time and money. Participants reflected on spending money for pleasure versus saving money in anticipation of future care expenses and, similarly, on working to save money versus retiring to enjoy life while still cognitively unimpaired.

Participants with elevated brain amyloid viewed the amyloid PET scan result as a serious, sensitive piece of health information. They highlighted its unique implications for identity, self-determination, and social interactions. Public stigma of AD—the attitudes and beliefs of the general public towards persons with AD—and self-stigma—which occurs when people internalize negative public attitudes—provide important context to our findings.[29,30] Stigma was reflected in participants’ circumspect approaches to sharing an “elevated” amyloid PET scan result with others and also their concerns about how the “elevated” result would change how they are perceived and treated by others. Further research is needed to understand how advances in AD diagnosis, testing, and treatment may alter the experience of AD stigma. Participants with elevated brain amyloid expressed concerns about discrimination in the contexts of employment and insurance that highlight the limited ability of current laws and policies to protect those with preclinical AD. The Genetic Information Nondiscrimination Act, for example, does not provide meaningful protections against discrimination based on AD biomarkers for Americans.[31] Advances in the diagnosis and treatment of AD will need to be matched with policy innovations to protect proactive patients.

Finally, irrespective of their brain amyloid status, SOKRATES participants were mindful that their amyloid PET scan result had implications for themselves and also for others. Participants with elevated brain amyloid expressed concern that they might burden their families if they developed AD, while others reported changing their living situation—for example, moving closer to an adult child—to facilitate future caregiving. More than 16 million adults across the United States currently provide informal dementia care and serve as the backbone of the nation’s long-term care system for persons with dementia.[32,33] Future studies should examine the effects of biomarker disclosure on study partners or “pre-caregivers” asked to monitor the cognition, function, and well-being of individuals with preclinical AD.[25,34] Monitoring a cognitively unimpaired adult with elevated biomarkers is different work than being a caregiver for a person with dementia. Pre-caregivers’ reactions to biomarker results will likely differ from caregivers’ reactions because pre-caregivers are not performing the physical and emotional labor of caregiving, but instead, anticipating it.

Limitations

This is a small sample, and SOKRATES participants—though reflective of A4 and LEARN participants—are homogeneous. Further, SOKRATES participants all passed assessments of psychological well-being and agreed to learn their amyloid PET scan result in order to determine eligibility to participate in A4. Individuals who might have had adverse responses to the information or who were not interested in enrolling in A4 were excluded. This limits generalizability. SOKRATES was a qualitative study and therefore did not measure quantitative psychometrics for comparisons of mood pre- and post-disclosure.[25] The A4 Study Team did gather psychological measures, which are reported elsewhere.[35] All SOKRATES participants underwent a standardized disclosure process; while that is a strength of the present study, we note that our findings may be contingent on the disclosure process. There was no pre-disclosure interview to understand baseline self-perceptions or expectations about the amyloid PET scan result. This is a direction for future research. We suggest additional research to examine AD biomarker disclosure across a larger, more diverse sample (e.g., age, race/ethnicity, family history of AD) to more fully understand the experience of receiving an AD biomarker result and how those experiences might vary across groups.

Conclusion

These findings demonstrate the need for additional research on the effect on patients and their families of learning information about preclinical AD to accompany along with research to understand the pathophysiological changes occurring in the brain.

(DOCX)

Click here for additional data file.

(DOCX)

Click here for additional data file.

13 Nov 2019

PONE-D-19-22767

Cognitively Unimpaired Adults’ Reactions to Amyloid Disclosure

PLOS ONE

Dear Dr. Largent,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please consider all of the reviewer's suggestions, particularly those that advise adding more details about the methods and renaming groups. Also, please assure that you have referenced all pertinent literature on the topic (the reviewers provide some citations).

We would appreciate receiving your revised manuscript by Dec 28 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Erin Bouldin, MPH, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

1. Please include a copy of the topic/interview guide used in the study, in both the original language and English, as Supporting Information, or include a citation if it has been published previously.

2. Please provide additional details regarding participant consent. In the Methods section, please state why it was not possible to obtain written consent, how verbal consent was recorded and whether the ethics committee approved this consent procedure. If your study included minors, state whether you obtained consent from parents or guardians.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: N/A

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Submitted article does not identify/clarify whether or not intended for special issue on "reward and decision making", so general submission to PLOS ONE assumed without consideration for special issue.

Title: "Cognitively Unimpaired Adults’ Reactions to Amyloid Disclosure"

There is a problem with use of the phrase "amyloid disclosure" in the title. Why not use the full phrase "amyloid imaging results disclosure"? What is the meaning of the shortened phrase "amyloid disclosure"? Does it refer to which testing or imaging of which kind of amyloid? Is it possible to "disclose amyloid"? Or is that a non-sensical phrase for which example precedents do not exist in published medical science? Certainly, we do not publish medical scientific reports on "blood disclosure" or "bone disclosure" or any other kind of bio-tissue or bio-molecule!!!

Abstract contains other shortened phrases such as "elevated participants" and "not-elevated participants" that also result in potentially confusing and/or non-sensical abuses of English language. Again, this reviewer objects to these misuses of the English language. Presumably, the research participants are neither elevated nor not-elevated! Rather, their amyloid imaging results have been interpreted as elevated or not-elevated.

Abstract contains the phrase "urgent need to understand the effects of biomarker disclosure on this population" which raises the question: what is the "urgency"? In clinical medical contexts, use of the words "emergent" or "urgent" do have relevant and important meanings. However, majority of evidence published so far on amyloid imaging results disclosure suggests that the risks if any are minimal, and certainly do not rise to the level or either emergent or urgent. So what is the rationale or justification for use of the word "urgent"? Why over-dramatize and raise an alarm with the word "urgent" if minimal if any harm will occur? And if the authors do believe that harm will occur then they should provide the explanation, rationale and evidence for the harm that they fear will occur with probability estimates for the numbers of potential patients impacted. How do these predicted numbers compare to the numbers of persons involved in the current opiates drug overdose epidemic plaguing America today? And what constitutes an emergency or urgency? The authors should be careful before using language that creates drama frightening people unnecessarily.

Data availability reported as "fully available without restriction" with additional statement that "All relevant data are within the manuscript and its Supporting Information files." However, this reviewer did not find any relevant raw data in either the manuscript or supporting information. There are no tables or URL links to repositories of raw data found anywhere in the manuscript or supporting information files. The manuscript contains only tables of analyzed results.

Introduction contains the statement "The extant empirical literature on such disclosure is extremely limited.(11),(12)" However, this statement is neither correct nor current and up-to-date. Despite presence of bibliography with a total of 30 references, some important literature has been omitted. If the total number of references must be constrained, then would not some of these missing references be more important than some of those that were mentioned? Criteria for inclusion of literature citations should be relevance to discussion and argument of issues and claims in the submitted manuscript.

Missing literature:

https://www.alz.org/aaic/program/education-workshop-neuroimaging.asp

Book chapter associated with talk and slide presentation at AAIC 2019 Los Angeles on Fri Jul 12 at 11:30 AM

"Disclosure of Amyloid Imaging Results" 2019 by Jennifer H. Lingler.

This work important as a recent comprehensive survey that should be up to date for amyloid imaging results disclosure studies as of the AAIC conference in July 2019; it appears that none of the papers by Lingler, neither recent nor past, have been discussed by the authors of the manuscript submitted to PLOS ONE.

http://mhfmjournal.com/pdf/MHFM-120.pdf

"Safety of Disclosing Amyloid Imaging Results to MCI and AD Patients" 2018 Taswell et al

This work important as the largest size study to date of amyloid imaging results disclosure, also important for the careful use of robust statistical methods in the data analysis. This important clinical trial has not been cited and discussed by the authors of the manuscript submitted to PLOS ONE.

Methods contains the statement "Psychological measures of well-being are collected for all A4 and LEARN participants and are not reported here." Why not?!? What is the rationale and justification for NOT reporting and analyzing the results from the psychological measures of well-being for the research participants? If the data are available and analyzed correctly, then they should be reported.

Results contain the statement "No notable differences in results were observed by age or gender." However, there are no group-wise results based on age group based analysis presented in the manuscript with evidence to support this claim which contradicts intuition and common life experience. The authors should either present the data and results to substantiate their claims, or at least, offer a hypothetical explanation for their failure to find differences between age groups. What about younger age groups in their 50s, 40s or 30s? This reviewer remains skeptical that there would be no differences between age groups. It's just a matter of clarifying the specific ages of the age groups over the life span.

Reviewer #2: Largent et al performed qualitatitive research to assess the reaction to a positive/negative amyloid PET result in cognitively normal individuals. This is an important topic as increasing numbers of cognitively healthy persons are undergoing amyloid PET for research and the return of study results is very much wanted by study participants a priori.

The number of participants is high, with a high proportion of persons (50 out of 80) with an elevated amyloid PET result. Overall the study appears to confirm that knowledge of an elevated amyloid PET may have negative consequences, mainly because of stigma associated with the disease.

Major comments:

1. On several occasions (e.g. p 6) the authors allude to the fact that the participants perceived memory problems beforehand. It would be of interest to better describe the cognitive complaints/status of the participants prior to disclosure: what was their motivation for enrolling in the study, did they fulfill criteria for subjective cognitive decline, was there a difference in test scores between those who had a positive versus a negative amyloid PET? If a person has subjective memory complaints, the elevated amyloid PET result may have a very different meaning than when no complaints existed beforehand and cognition was intact. The authors acknowledge in the Limitations section that an interview prior to disclosure could have resolved some of these questions.

Minor comments

1. The disclosure process is described in a previous paper. This essential information may be summarized in a few sentences also in the current paper: which information was disclosed, e.g. in terms of positive and negative predictive value. By whom (physician, same researcher across all participants etc). Did the authors also use written information prior to or during the disclosure? It may be worthwile mentioning in the discussion that some of the reactions may be contingent on these factors.

2. I suggest the authors find a better term for ‘elevated participants’.

3. An analogous qualitative research study was performed in amnestic MCI and disclosure of amyloid PET in a research context by Vanderschaeghe et al. Since the research method is similar and several elements in the participants’ reactions are similar, the authors may consider to refer to this study.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

18 Nov 2019

Reviewer #1:

Submitted article does not identify/clarify whether or not intended for special issue on "reward and decision making", so general submission to PLOS ONE assumed without consideration for special issue.

• We apologize for any confusion; the cover letter noted that this paper was submitted to the “Early Diagnosis and Treatment of Alzheimer’s Disease” Call for Papers.

Title: "Cognitively Unimpaired Adults’ Reactions to Amyloid Disclosure." There is a problem with use of the phrase "amyloid disclosure" in the title. Why not use the full phrase "amyloid imaging results disclosure"? What is the meaning of the shortened phrase "amyloid disclosure"? Does it refer to which testing or imaging of which kind of amyloid? Is it possible to "disclose amyloid"? Or is that a non-sensical phrase for which example precedents do not exist in published medical science? Certainly, we do not publish medical scientific reports on "blood disclosure" or "bone disclosure" or any other kind of bio-tissue or bio-molecule!!!

• We have changed the title to: Cognitively Unimpaired Adults’ Reactions to Disclosure of Amyloid PET Scan Results.

Abstract contains other shortened phrases such as "elevated participants" and "not-elevated participants" that also result in potentially confusing and/or non-sensical abuses of English language. Again, this reviewer objects to these misuses of the English language. Presumably, the research participants are neither elevated nor not-elevated! Rather, their amyloid imaging results have been interpreted as elevated or not-elevated.

• We note that Reviewer 2 also shared this concern about use of “elevated” and “not-elevated.” We have made responsive edits throughout the manuscript to reflect that we are discussing “elevated” and “not-elevated” amyloid PET scan result.

Abstract contains the phrase "urgent need to understand the effects of biomarker disclosure on this population" which raises the question: what is the "urgency"? In clinical medical contexts, use of the words "emergent" or "urgent" do have relevant and important meanings. However, majority of evidence published so far on amyloid imaging results disclosure suggests that the risks if any are minimal, and certainly do not rise to the level or either emergent or urgent. So what is the rationale or justification for use of the word "urgent"? Why over-dramatize and raise an alarm with the word "urgent" if minimal if any harm will occur? And if the authors do believe that harm will occur then they should provide the explanation, rationale and evidence for the harm that they fear will occur with probability estimates for the numbers of potential patients impacted. How do these predicted numbers compare to the numbers of persons involved in the current opiates drug overdose epidemic plaguing America today? And what constitutes an emergency or urgency? The authors should be careful before using language that creates drama frightening people unnecessarily.

• We have deleted the word “urgent” from the abstract as it was not our intention to unnecessarily frighten anyone.

Data availability reported as "fully available without restriction" with additional statement that "All relevant data are within the manuscript and its Supporting Information files." However, this reviewer did not find any relevant raw data in either the manuscript or supporting information. There are no tables or URL links to repositories of raw data found anywhere in the manuscript or supporting information files. The manuscript contains only tables of analyzed results.

• This was in error. The transcripts are not fully available without restriction as they contain identifiable information.

Introduction contains the statement "The extant empirical literature on such disclosure is extremely limited.(11),(12)" However, this statement is neither correct nor current and up-to-date. Despite presence of bibliography with a total of 30 references, some important literature has been omitted. If the total number of references must be constrained, then would not some of these missing references be more important than some of those that were mentioned? Criteria for inclusion of literature citations should be relevance to discussion and argument of issues and claims in the submitted manuscript.

• Reviewer 1’s point that there is a literature on AD biomarker disclosure is well taken. We have revised the sentence as follows: “The extant empirical literature on disclosure of amyloid PET scan results to cognitive unimpaired adults is, however, limited.”

Missing literature:

Book chapter associated with talk and slide presentation at AAIC 2019 Los Angeles on Fri Jul 12 at 11:30 AM. "Disclosure of Amyloid Imaging Results" 2019 by Jennifer H. Lingler (https://www.alz.org/aaic/program/education-workshop-neuroimaging.asp). This work important as a recent comprehensive survey that should be up to date for amyloid imaging results disclosure studies as of the AAIC conference in July 2019; it appears that none of the papers by Lingler, neither recent nor past, have been discussed by the authors of the manuscript submitted to PLOS ONE.

• We have added a citation to Lingler & Klunk (2013) as that paper specifically recommends against disclosure of amyloid imaging results to cognitively normal research participants.

• We have also added a citation to Kim and Lingler (2019).

"Safety of Disclosing Amyloid Imaging Results to MCI and AD Patients" 2018 Taswell et al (http://mhfmjournal.com/pdf/MHFM-120.pdf). This work important as the largest size study to date of amyloid imaging results disclosure, also important for the careful use of robust statistical methods in the data analysis. This important clinical trial has not been cited and discussed by the authors of the manuscript submitted to PLOS ONE.

• We have added a citation to Taswell et al (2018). We note, however, that this study looked at disclosure of results to adults with MCI and dementia rather than to cognitively unimpaired adults.

Methods contains the statement "Psychological measures of well-being are collected for all A4 and LEARN participants and are not reported here." Why not?!? What is the rationale and justification for NOT reporting and analyzing the results from the psychological measures of well-being for the research participants? If the data are available and analyzed correctly, then they should be reported.

• The psychological measures are proprietary to the A4 and LEARN studies and are not presently available for analysis or for publication by the SOKRATES team. We have deleted this sentence as unnecessary.

Results contain the statement "No notable differences in results were observed by age or gender." However, there are no group-wise results based on age group based analysis presented in the manuscript with evidence to support this claim which contradicts intuition and common life experience. The authors should either present the data and results to substantiate their claims, or at least, offer a hypothetical explanation for their failure to find differences between age groups. What about younger age groups in their 50s, 40s or 30s? This reviewer remains skeptical that there would be no differences between age groups. It's just a matter of clarifying the specific ages of the age groups over the life span.

• We have added a sentence explaining that Analyses included searching for differences among groups based on demographic variables.

• SOKRATES enrolled only participants aged 65 to 85 – because one eligibility criterion for the parent A4 and LEARN studies was being 65 to 85 years old. In our analyses, we looked at two age groups: 65 to 74 and 75+. We did not find differences by age between these two groups.

• It is an open question whether there would be differences by age if younger individuals received amyloid PET scan results. As that is not a question that can be answered with our present data set, we now note this as a direction for future research.

Reviewer #2:

Largent et al performed qualitative research to assess the reaction to a positive/negative amyloid PET result in cognitively normal individuals. This is an important topic as increasing numbers of cognitively healthy persons are undergoing amyloid PET for research and the return of study results is very much wanted by study participants a priori.

• We are glad that Reviewer 2 shares our belief that this is an important and timely topic for research and also the future of clinical care.

The number of participants is high, with a high proportion of persons (50 out of 80) with an elevated amyloid PET result. Overall the study appears to confirm that knowledge of an elevated amyloid PET may have negative consequences, mainly because of stigma associated with the disease.

• Thank you – we believe that the large sample size is a strength of our study.

On several occasions (e.g. p 6) the authors allude to the fact that the participants perceived memory problems beforehand. It would be of interest to better describe the cognitive complaints/status of the participants prior to disclosure: what was their motivation for enrolling in the study, did they fulfill criteria for subjective cognitive decline, was there a difference in test scores between those who had a positive versus a negative amyloid PET? If a person has subjective memory complaints, the elevated amyloid PET result may have a very different meaning than when no complaints existed beforehand and cognition was intact. The authors acknowledge in the Limitations section that an interview prior to disclosure could have resolved some of these questions.

• We have added additional information in the methods section to note that inclusion criteria for A4/LEARN required that participants were cognitively unimpaired. They scored within normal limits on baseline cognitive testing and were rated a zero on the CDR. Subjective cognitive complaints were permitted.

• Cognitive measures were collected in the A4 and LEARN studies but are not presently available for analysis or for publication by the SOKRATES team. The SOKRATES team did not collect cognitive measures. We agree with Reviewer 2 that this is a limitation and have noted it as such in our limitations section.

The disclosure process is described in a previous paper. This essential information may be summarized in a few sentences also in the current paper: which information was disclosed, e.g. in terms of positive and negative predictive value. By whom (physician, same researcher across all participants etc). Did the authors also use written information prior to or during the disclosure? It may be worthwile mentioning in the discussion that some of the reactions may be contingent on these factors.

• We thank Reviewer 2 for this suggestion and have added additional detail about the disclosure process on P4 of the manuscript.

• On page 17, we note that some of the reactions may be contingent on the standardized disclosure process.

I suggest the authors find a better term for ‘elevated participants’.

• We note that Reviewer 1 also shared this concern. We have made responsive edits throughout the manuscript to reflect that we are discussing “elevated” and “not-elevated” amyloid PET scan result.

An analogous qualitative research study was performed in amnestic MCI and disclosure of amyloid PET in a research context by Vanderschaeghe et al. Since the research method is similar and several elements in the participants’ reactions are similar, the authors may consider to refer to this study.

• We have added a citation to Vanderschaeghe et al (2017).

Other:

Please include a copy of the topic/interview guide used in the study, in both the original language and English, as Supporting Information, or include a citation if it has been published previously.

• As requested, we are including a copy of each interview guide used in the study.

Please provide additional details regarding participant consent. In the Methods section, please state why it was not possible to obtain written consent, how verbal consent was recorded and whether the ethics committee approved this consent procedure. If your study included minors, state whether you obtained consent from parents or guardians.

• We have updated the Methods section (PP 5-6) to provide additional details about consent. The IRB approved the waiver of written informed consent because the interviews were telephonic and the study was minimal risk.

• Our study did not include minors.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

28 Jan 2020

PONE-D-19-22767R1

Cognitively Unimpaired Adults’ Reactions to Disclosure of Amyloid PET Scan Results ​

PLOS ONE

Dear Dr. Largent,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please address Reviewer 1's remaining concern about the limitations as they relate to psychometric measures. While I appreciate Reviewer 1's concern about data availability, the current statement you have provided, which focuses on the potential for identification of participants, aligns with PLOS ONE's data availability policy so does not need to be changed.

We would appreciate receiving your revised manuscript by Mar 13 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Erin Bouldin, MPH, PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Data availability: Authors state that "The transcripts are not fully available without restriction as they contain identifiable information". However, data in the form of interview transcripts could be made available simply by redacting the "identifiable information" and de-identifying the raw source material of the interview transcripts. De-identifying clinical research data should be considered a standard expected and required step in the process of conducting clinical trials and publishing the results in a journal that expects the data to be made publicly available. If the authors wish to argue that the data cannot be shared publicly because they contain identifying information about participants, then perhaps they should have considered submission to a different journal that does not require publishing the data. Otherwise, the authors should consider conducting clinical trials with a protocol and methods that plan in advance appropriately to de-identify and anonymize the clinical research data. Did the original informed consent from participants request their agreement to publishing de-identified data from the clinical research trial?

Limitations: Authors have not discussed, but should discuss, a major limitation of their study. They did not perform or report any quantitative psychometrics for comparisons of mood with after-disclosure versus before-disclosure comparisons evaluating individual change scores for participants as reported by Taswell et al in 2018 MHFM.

Authors also recommend that "Future studies should examine the effects of biomarker disclosure on study partners or pre-caregivers asked to monitor the cognition, function, and well-being of individuals with preclinical AD". But they did not cite the first publication of this general recommendation by Taswell et al in 2018 MHFM as follows: "we believe that a more productive area of possible future research would be evaluation of mood scale psychometrics for the patient’s primary caregiver instead of psychometrics for the patient". They should cite Taswell et al 2018 MHFM for the recommendation, and then discuss what they think might be differences between cognitively impaired patients and cognitively non-impaired volunteers and their respective families and study partner / caregivers.

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Rik Vandenberghe

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

30 Jan 2020

Reviewer #1:

Limitations: Authors have not discussed, but should discuss, a major limitation of their study. They did not perform or report any quantitative psychometrics for comparisons of mood with after-disclosure versus before-disclosure comparisons evaluating individual change scores for participants as reported by Taswell et al in 2018 MHFM.

• In the limitations section, we now note that because SOKRATES is a qualitative study, we did not collect quantitative psychometrics. Such measures were, however, collected as part of A4, and will be published elsewhere (manuscript under review).

• Additionally, we have included a citation to Taswell et al (2018) here (Reference 25).

Authors also recommend that "Future studies should examine the effects of biomarker disclosure on study partners or pre-caregivers asked to monitor the cognition, function, and well-being of individuals with preclinical AD". But they did not cite the first publication of this general recommendation by Taswell et al in 2018 MHFM as follows: "we believe that a more productive area of possible future research would be evaluation of mood scale psychometrics for the patient’s primary caregiver instead of psychometrics for the patient". They should cite Taswell et al 2018 MHFM for the recommendation, and then discuss what they think might be differences between cognitively impaired patients and cognitively non-impaired volunteers and their respective families and study partner / caregivers.

• We have now noted that “Monitoring a cognitively unimpaired adult with elevated biomarkers is different work than being a caregiver for a person with dementia. Pre-caregivers reactions to biomarker results will likely differ from caregivers’ reactions because pre-caregivers are not performing the physical and emotional labor of caregiving, but instead, anticipating it.”

• Additionally, we have included a citation to Taswell et al (2018) here (Reference 25).

Reviewer #2:

(No Response)

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

31 Jan 2020

Cognitively Unimpaired Adults’ Reactions to Disclosure of Amyloid PET Scan Results

PONE-D-19-22767R2

Dear Dr. Largent,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Erin Bouldin, MPH, PhD

Academic Editor

PLOS ONE

4 Feb 2020

PONE-D-19-22767R2

Cognitively Unimpaired Adults’ Reactions to Disclosure of Amyloid PET Scan Results

Dear Dr. Largent:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Erin Bouldin

Academic Editor

PLOS ONE