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

Ann Intern Med. 2016 Feb 2;164(3):155-63. doi: 10.7326/M15-0187. Epub 2016 Jan 26.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / psychology
  • Anxiety / etiology
  • Apolipoprotein E4 / genetics
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / psychology
  • Depression / etiology
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • Health Behavior
  • Humans
  • Male
  • Middle Aged
  • Risk Assessment*
  • Stress, Psychological / etiology
  • Young Adult


  • Apolipoprotein E4

Associated data

  • ClinicalTrials.gov/NCT00462917