Disclosing genetic risk for Alzheimer's dementia to individuals with mild cognitive impairment

Abstract Introduction The safety of predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia using apolipoprotein E (APOE) genotyping is unknown. Methods We randomized 114 individuals with MCI to receive estimates of 3‐year risk of conversion to AD dementia informed by APOE genotyping (disclosure arm) or not (non‐disclosure arm) in a non‐inferiority clinical trial. Primary outcomes were anxiety and depression scores. Secondary outcomes included other psychological measures. Results Upper confidence limits for randomization arm differences were 2.3 on the State Trait Anxiety Index and 0.5 on the Geriatric Depression Scale, below non‐inferiority margins of 3.3 and 1.0. Moreover, mean scores were lower in the disclosure arm than non‐disclosure arm for test‐related positive impact (difference: ‐1.9, indicating more positive feelings) and AD concern (difference: ‐0.3). Discussion Providing genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits.

Discussion: Providing genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits.

K E Y W O R D S
Alzheimer's disease, anxiety, apolipoprotein E4, cognitive dysfunction, dementia, depression, emotions, genetic testing, health behavior, humans, random allocation, risk assessment, risk INTRODUCTION Genomic testing is increasingly used to diagnose and treat disease, 1,2 but its use to estimate risks for developing dementia remains controversial, [3][4][5][6] particularly for conditions such as Alzheimer's disease (AD) for which proven strategies to prevent or delay disease onset are lacking. Consensus statements discourage genetic susceptibility testing for AD when individuals are asymptomatic for reasons that include its potential to cause psychological harm. 7,8 People with symptoms that may suggest subclinical levels of disease may be especially vulnerable to anxiety, depression, or even suicidality. 9 Prior research has shown that disclosing apolipoprotein E (APOE) genotypes and communicating AD risk to asymptomatic individuals in clinical settings does not cause psychological harm for most individuals 1012 although questions remain about direct-to-consumer contexts. 13 But these studies enrolled participants who, if they were to develop AD, were often decades away from developing symptoms.
Questions remain about whether genetic risk disclosure is safe for individuals who have memory problems and may progress to AD dementia in the near future.
To address this gap in knowledge, we conducted a randomized trial of individuals with amnestic mild cognitive impairment (MCI), a clinical syndrome characterized by memory problems without significant impairment in social or occupational functioning. 14 Approximately 10% to 15% of MCI patients progress to AD dementia annually, 15 depending on factors that include APOE genotype. 16 We compared participant outcomes when risk assessments for progressing to AD dementia within 3 years included or omitted disclosure of APOE genotypes. We hypothesized that participants who learned their APOE genotype would experience no greater anxiety or depression than participants who did not receive genotype disclosure. We hypothesized secondarily that participants who learned they were APOE 4-positive would experience no greater anxiety or depression than participants who learned they were APOE 4-negative.

Design overview
As described in prior reports, 10 After verbal consent and a phone interview to assess eligibility ( Figure 1), participants met with a study clinician (typically a genetic counselor) for screening and to provide written consent. Participants also learned more about MCI and AD, and reviewed the benefits, risks, and limitations of genetic risk assessment for AD. Risks and limitations included potential difficulties coping with test results and the lack of "proven ways to prevent Alzheimer's disease." If participants met inclusion criteria and wished to proceed, blood was drawn for APOE genotyping. Participants were randomized 2:1 in blocks of six to groups that received APOE genotype disclosure (disclosure arm) or did not receive genotype disclosure (non-disclosure arm). Randomization strata were defined by site and age.
Approximately 1 month after the blood draw, participants returned to the clinic to receive results in person. Participants in both randomization arms received education about MCI and AD and personalized estimates from a study clinician about the likelihood they would progress to AD dementia within 3 years. These estimates, provided as part of a semi-scripted protocol, ranged from 8% to 57% (see Appendix S2 in supporting information) and were created using data from the Memory Impairment Study. 18 Personalized estimates for progressing to AD dementia were based on participants' age stratum and their MCI diagnoses. 17 For participants in the disclosure arm, personalized estimates of conversion to AD were additionally based on the presence ("APOE 4-positive") or absence ("APOE 4negative") of a copy of the APOE 4 allele (APOE 4 heterozygotes and homozygotes were provided the same AD risk estimates). All personalized risk estimates included written information, a pictogram, and a line graph (see Appendix S3 in supporting information). Participants were followed for 6 months after disclosure sessions, with assessments conducted in person at 6 weeks and via telephone and mail at 6 months.
A 1-year follow-up visit was originally planned, but was shortened to 6 months to reduce demands on participants and because prior studies 10 and anecdotal descriptions had suggested that there were no additional changes in psychosocial outcomes after 6 months. Participants in the genotype non-disclosure arm had the option to learn their APOE genotypes after completing their final follow-up survey.

Study population
We recruited individuals with amnestic MCI who were ages 55 to 90 years from memory clinics, neurology and medicine departments, and AD centers. MCI was defined as having (1)   concern. 29,30 GDS scores ranged from 0 to 15, with higher scores indicating greater depression and scores of 5 or above indicating clinical concern. 23,24 Secondary psychological measures included test-related distress, as measured by the Impact of Event Scale (IES) 25  lower scores indicate greater positive feelings). We also assessed hopelessness with the four-item Beck Hopelessness Scale (BHS; range: 0-4, higher scores indicate greater hopelessness), 27 and a 4-item AD concern scale (range: 1-5, higher scores indicate greater concern about AD). 28 Participants who scored above 8 on the 15-item GDS, above 56 on the 6-item STAI, or endorsed at least two out of four statements on the BHS received additional follow-up and monitoring. Test-related distress and positive impact scales were administered only after AD risk assessments. All other measures were assessed at baseline and again at 6 weeks and 6 months after AD risk assessments. As in prior REVEAL Study trials, [28][29][30] we also assessed participants' risk perceptions at all time points by asking them to estimate their chances of AD conversion within the next 3 years on a scale of 0% to 100%.

Statistical analysis
We planned to enroll 180 participants and provide 151 risk assessments. We used a non-inferiority framework to test the primary hypothesis that participants in the genotype disclosure arm would report no greater anxiety or depression than participants in the non-disclosure arm. 31 We also used a non-inferiority framework to test the secondary hypothesis that, within the genotype disclosure arm, participants who received APOE 4-positive results would report no greater symptoms of anxiety or depression than participants who received APOE 4-negative results. In this paper therefore, the phrase "non-inferiority of genotype disclosure" means the comparison of scores of one group to another showed that genetic risk disclosure did not increase scores of psychological harm more than a margin of error from that of the comparison group.
We used t tests and chi-squared tests to compare demographics of the randomization arms and to analyze who dropped out after randomization. We used chi-squared tests to compare dropout of study arms after randomization, but before results were communicated to participants. For all other analyses, we used generalized linear models fit with generalized estimating equations to compare time-averaged and time-specific outcomes by randomization arm or by APOE status.
Analyses of STAI, GDS, IES, test-related distress with the IGT-AD, and BHS used a log link and gamma distribution because the distributions of these outcomes were highly skewed. A value of one was added to each of these scales, except the STAI, to shift their distributions away from zero. Analyses of positive impact, AD concern, and perceived risk for AD conversion used an identity link and normal distribution. Models included interaction terms between time and randomization status because prior work has shown that, when observed, the psychological impact of genetic information typically fades over time. 32 All models included terms for randomization status, time as a categorical variable, and interaction between time and randomization arm. We included baseline scores, where applicable, age, sex, race, education, and, given imbalances by randomization status, marital status as covariates in F I G U R E 1 Study flow diagram analyses of continuous outcomes. The analytic approach followed our initial statistical analysis plans (these covariates were omitted from analyses of dichotomous outcomes because statistical models that included them were unstable). We also included the clinician who disclosed results as a covariate in the analyses of continuous outcomes to account for potential confounding. 33 We included baseline scores where available (STAI, GDS, BHS, and AD concern) given their strong associations with scores at follow-up and best practices. 10,34 Analyses that compared participants by APOE status included a dichotomous variable to distinguish participants with no copies of the 4 allele and participants with at least one copy, as well as terms for interaction between APOE status and randomization status; APOE status and time; and APOE status, randomization status, and time.
For non-inferiority testing, we calculated 97.5% confidence limits (CL), using upper bounds of two-sided confidence intervals (Cis) of (1 -2 ) × 100%, with equal to 2.5% (0.05/2) to account for multiple testing across 2 primary outcomes. 35 We asserted non-inferiority (ie, no greater anxiety or depression) if 97.5% CL for the differences between randomization arms or APOE genotypes were below non-inferiority margins (because all scales indicated worse scores with higher val-ues, we were able to focus on upper bounds). The same approach was used to examine all outcomes at specific time points and all secondary psychological outcomes. More details about the margins that defined non-inferiority and the statistical models are provided in Appendix S4.
Analyses included all randomized participants. Analyses were conducted using R version 3.5.1 or SAS, version 9.4 (SAS Institute). We assumed that data were missing at random (up to 19 participants were missing data on primary and secondary outcomes), and imputed missing data with fully conditional specification, running 100 iterations to create each of 20 imputed data sets.

RESULTS
We enrolled 146 of the 386 participants that we recruited (37.8%), and ultimately provided results to 114 participants ( Figure 1). Characteristics of participants who were provided risk assessments are summarized in Table 1

Randomization arm comparisons
Mean anxiety and depression scores in both randomization arms were below cutoffs for concern at all time points (Table 2), and noninferiority of genotype disclosure was demonstrated in time-averaged analyses ( Figure 2). Mean adjusted time-averaged anxiety scores were 1.4 points lower in the disclosure arm than the non-disclosure arm, and the 97.5% CL (2.3) was below the non-inferiority margin (3.3). Mean adjusted time-averaged depression scores were the same in the disclosure and non-disclosure arms, and the 97.5% CL (0.5) was below non-inferiority margin (1.0). Non-inferiority of genotype disclosure was also supported on time-averaged analyses of all secondary psychological outcomes. Similar patterns were observed at 6 weeks. Non-inferiority of genotype disclosure at 6 months was observed only for positive impact and AD concern. Notably, participants were more likely to score above our pre-established cutoffs for increased monitoring on scales of anxiety, depression, and hopelessness if they were randomized to genotype non-disclosure compared to genotype disclosure (28.9% vs 13.5%, respectively, P value = .050).

Comparisons by APOE status
Mean anxiety and depression scores were still below cutoffs for concern regardless of APOE 4 status ( Table 3)

Comparisons of randomization arms by APOE status
We conducted exploratory analyses that compared genotype disclosure to genotype non-disclosure for participants with specific APOE Among individuals who were APOE 4-positive, genotype disclosure was non-inferior to genotype non-disclosure on time-averaged mea- AD concern 3.3 (0.1) 3.2 (0.1) 3.4 (0.1) 3.6 (0.1) 3.6 (0.1) 3.6 (0.2) a Scores were estimated using generalized estimating equations, with adjustment for demographic characteristics, disclosing clinician, and baseline values.
Models for all outcomes used a log link and gamma distribution. Abbreviations: IES, Impact of Event Scale; IGT-AD, Impact of Genetic Testing for Alzheimer's Disease scale F I G U R E 2 Noninferiority analyses comparing genotype disclosure to nondisclosure to non-disclosure at 6 weeks only for depression, positive impact, hopelessness, and AD concern, and for no psychological outcomes at 6 months except positive impact.

Perceptions of risk for converting to AD
Exploratory analyses also showed differences between randomization arms in perceived risk of progressing to AD within 3 years, contingent upon APOE status (Appendix S6 in supporting information). Among participants who were APOE 4-negative, individuals in the genotype disclosure arm provided time-averaged estimates of their risk of progressing to AD that were an average of 11.3% lower in the disclosure arm than the non-disclosure arm (24.6% vs 36.0%, respectively, P value = .010), although differences were not significant at 6 weeks.

DISCUSSION
This study showed that among individuals with MCI, disclosing genetic risk about progressing to AD dementia does not increase risks for clinically significant depression or anxiety, and overall reduced concern about AD. It also resulted in more positive feelings about the risk assessment experience. These findings are consistent with results from prior trials that demonstrated the safety of disclosing genetic risk information about AD when provided to volunteer populations by clinicians in a well-designed education and disclosure protocol [10][11][12]36 and that showed psychological benefits for participants who learned that they were APOE 4-negative. In this trial, it is likely that psychological benefits accrued, in part, because participants were expecting bad news given their mild memory prob- AD through studies of precision medicine, physicians, or direct-toconsumer options. 13,41,42 Most notably, 23andMe has FDA approval to include APOE results in their direct-to-consumer personal genome service. 43 Given the strong public interest in genetic susceptibility testing about AD 44,45 it is likely that the number of individuals with mild memory problems-and healthy individuals-who pursue APOE-based risk information about AD will only continue to increase.
In this trial, participants' distress responses to risk disclosure appeared to be greater than in prior studies of asymptomatic, atrisk adults. Mean scores on both test-related distress scales were higher at all time points than previously observed. [10][11][12]36 Differences in responses between trials may be the result of differences by trial in eligibility criteria (eg, MCI in this trial, no MCI in prior trials), the magnitude of numeric risk estimates, or the proximity of AD conversion (ie, risk was conveyed for the next 3 years in this trial, as opposed to by age 85 in prior trials). 46 These findings highlight the heightened risk for distress in disclosing AD risk information to individuals with MCI, regardless of whether APOE genotypes are disclosed, 47 and the need for carefully designed education, communication, and follow-up proto-