Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study.

BACKGROUND It remains unknown whether depression and apolipoprotein E genotype are risk factors for incident mild cognitive impairment (MCI). OBJECTIVE To determine whether elderly individuals with depression (measured by the short Geriatric Depression Scale) are at increased risk of developing incident MCI. DESIGN Prospective cohort study. SETTING Primary care clinic. PARTICIPANTS A cohort of 840 cognitively normal elderly subjects without depression at recruitment who were followed up prospectively for a median of 3.5 years (range, 0.4-12.8 years). Subjects who developed depression (score of >/=6 on the short Geriatric Depression Scale; depression cohort) were compared with all remaining subjects (referent cohort). MAIN OUTCOME MEASURES Incidence of MCI (primary outcome) and incidence of MCI or dementia (composite secondary outcome). RESULTS Individuals in the depression cohort were at significantly increased risk of subsequent incident MCI (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1) after adjusting for age (time scale), sex, and education, and considering dementia as a competing outcome. The association was stronger in men but did not vary by severity of depression. We observed a synergistic interaction between apolipoprotein E genotype (epsilon3/epsilon4 or epsilon4/epsilon4) and depression (joint effect HR, 5.1; 95% CI, 1.9-13.6; test for additive interaction, P = .03). We found a similar association between depression and the subsequent composite outcome of incident MCI or dementia (HR, 2.6; 95% CI, 1.6-4.3). CONCLUSIONS Cognitively normal elderly individuals who develop depression are at increased risk of subsequent MCI. We found a synergistic interaction between depression and apolipoprotein E genotype.