Apolipoprotein E Genotype and Mortality: Findings from the Cache County Study

Objectives: To evaluate the association between apolipoprotein E (apo E) ɛ4 and mortality, the population attributable risk for mortality with ɛ4, and relative contributions of cardiovascular disease (CVD) and Alzheimer's disease (AD). Design: Population‐based cohort study. Setting: Community‐based. Participants: Permanent residents of Cache County, Utah, aged 65 and older as of January 1, 1995. Measurements: Participants were genotyped at the apo E locus using buccal‐swab deoxyribonucleic acid. Cardiovascular health was ascertained using self‐ or proxy‐report interviews at participants' residences. AD was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, and National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer's Disease and Related Disorders criteria. Utah Department of Vital Statistics quarterly reports were reviewed to identify participants who died. Results: Crude evaluations showed nonsignificantly greater risk of death for ɛ2/2 (hazard ratio (HR)=1.66, 95% confidence interval (CI)=0.92–2.76) and ɛ3/4 (HR=1.11, 95% CI=0.97–1.26) genotypes and significantly greater risk for ɛ4/4 (HR=1.48, 95% CI=1.09–1.96). After adjustment for age, age2, sex, and education, risks increased to 1.98 (95% CI=1.08–3.35), 1.28 (95% CI=1.12–1.46), and 2.02 (95% CI=1.47–2.71), respectively, compared with ɛ3/3 genotypes. Adjustment for presence of any CVD did not change the risk of death for ɛ3/4 and ɛ4/4. Adjustment for AD reduced the risk of death for ɛ3/4 (HR=1.13, 95% CI=0.99–1.30) and ɛ4/4 (HR=1.59, 95% CI=1.15–2.14). The population attributable risk of death for ɛ3/4 and ɛ4/4 genotypes combined is estimated at 9.6%. Conclusion: These findings suggested that the ɛ2/2, ɛ3/4, and ɛ4/4 genotypes have greater early mortality risks. Further analyses showed that AD partially mediates the association between ɛ3/4, ɛ4/4, and death.