Disclosing Pleiotropic Effects During Genetic Risk Assessment for Alzheimer Disease: A Randomized Trial

Abstract

Background: Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information.

Objective: To determine the safety and behavioral effect of disclosing modest associations between apolipoprotein E (APOE) genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer disease (AD).

Design: Randomized, multicenter equivalence clinical trial. (ClinicalTrials.gov: NCT00462917).

Setting: 4 teaching hospitals.

Participants: 257 asymptomatic adults were enrolled, 69% of whom had 1 AD-affected first-degree relative.

Intervention: Disclosure of genetic risk information about AD and CAD (AD+CAD) or AD only (AD-only).

Measurements: Primary outcomes were Beck Anxiety Inventory (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes were all measures at 6 weeks and 6 months and test-related distress and health behavior changes at 12 months.

Results: At 12 months, mean BAI scores were 3.5 in both the AD-only and AD+CAD groups (difference, 0.0 [95% CI, -1.0 to 1.0]), and mean CES-D scores were 6.4 and 7.1 in the AD-only and AD+CAD groups, respectively (difference, 0.7 [CI, -1.0 to 2.4]). Both confidence bounds fell within the equivalence margin of ±5 points. Among carriers of the APOE ε4 allele, distress was lower in the AD+CAD groups (difference, -4.8 [CI, -8.6 to -1.0]) (P = 0.031 for the interaction between group and APOE genotype). Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype.

Limitations: Outcomes were self-reported by volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomly assigned participants.

Conclusion: Disclosure of pleiotropic information did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions. Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk.

Primary funding source: National Human Genome Research Institute.

Figure 1

Enrollment and outcomes * A second randomization occurred here to determine whether subjects would receive in-person disclosure or telephone disclosure

Figure 2

AD+CAD vs. AD-Only differences in the percent reporting health behavior changes 12 months after genetic risk disclosure.* * Plots display between arm (AD+CAD – AD-Only) differences in the percentage of participants reporting a health behavior change. Estimates are from an analysis using logistic regression, accounting for APOE status, its interaction with pleiotropy randomization arm and the genetic counselor providing disclosure (except for stress reduction, where genetic counselor was omitted because some combinations of randomization status, APOE status, and genetic counselor had no events). Adjusted percentages are conditional probabilities estimated from the logistic model with all covariates set to their mean values (SAS lsmeans). P-values for interaction correspond to the p-values from the randomization arm x APOE status interaction terms. Unadjusted number of participants reporting changes to each health behavior: diet, 86; exercise, 91; mental activities, 76; dietary supplements, 71; stress reduction, 57; medications, 37.