Differential mortality by APOE epsilon4 genotype: Due to cardiovascular disease, Alzheimer's disease, or both? The Cache County study (Utah)

Fewer persons with apolipoprotein E (APOE) ϵ4 genotype survive to old age than those with one or two copies of the ϵ3 or ϵ2 allele(s). Individuals with two ϵ4 alleles have an even higher risk of early mortality. The APOE ϵ4 allele has been associated with cardiovascular disease (CVD) and more recently with Alzheimer's disease (AD), both of which are leading causes of death in the elderly. Growing evidence suggests an etiologic connection between CVD and AD; however, the primary reason for early mortality among persons with APOE ϵ4 genotype has not been determined.; Potential associations between APOE ϵ4 genotype, CVD, and AD were examined in a large population-based cohort study of persons from Cache County, Utah, aged 65+ as of January 1, 1995. Self or proxy-reported measures of CVD were used in conjunction with death records obtained from the Utah Department of Vital Statistics. AD was ascertained via a two-stage screening procedure in which all persons suspected of AD participated in additional neuropsychological tests, provided labs, and MRIs when possible. A team of geriatric psychiatrists, neuropsychologists, and nurses assigned diagnoses according to standard criteria at adjudication conferences. Logistic regression methods and Cox proportional hazards survival analysis examined the potential relationships between APOE, CVD, AD, and eventual mortality.; APOE ϵ3/4 genotype was associated with a significantly increased risk of mortality (HR 1.27, 95% CI 1.12–1.45). A stronger association was found among those with two copies of the ϵ4 allele (HR 2.02, 95% CI 1. 51–2.69). The APOE gene was associated with AD, and AD with increased mortality. In contrast, the APOE gene did not appear to be associated with CVD, nor was CVD associated with AD. These findings suggested that AD might play a larger role than CVD in mediating the relationship between the APOE gene and excess mortality. Analyses to specifically test whether AD or CVD mediate the association of APOE and death supported this conclusion. The estimated population attributable risk of death due the ϵ3/4 or ϵ4/4 genotypes was 9.4%. The portion of excess risk that can be attributed to mediation through AD was estimated at 3.5%.