The role of APOE-ε4 in longitudinal cognitive decline: MacArthur studies of successful aging

Background: While a genetic risk factor for late-onset AD, the effects of the ε4 allele of the APOE gene on cognitive functioning more generally remain unclear. Objective: To assess the role of the ε4 allele of the APOE gene in longitudinal cognitive decline. Methods: Multiple measures of cognitive function were assessed longitudinally in the MacArthur Successful Aging Study, a population-based cohort free of frank impairment at baseline. Subjects were 965 Caucasian and African American men and women from Durham NC, East Boston, MA, and New Haven, CT, aged 70 to 79 years, recruited in 1988 through 1989, who completed two follow-up evaluations, one at 3 years and another at 7 years. Results: At the first follow-up, modest but significant declines in naming and spatial ability were associated with the APOE-ε4 genotype. By the second follow-up, more pronounced and significant associations were noted between the APOE-ε4 genotype and cognitive decline from six of the eight cognitive outcomes. After 7 years, APOE-ε4 allele carriers were twice as likely to have declined on a global cognitive score (odds ratio = 2.0; 95% CI: 1.1, 3.6) as noncarriers. Conclusions: APOE-ε4 is associated with cognitive decline among a high-functioning elderly cohort, with effects most pronounced after 7 years of follow-up. Hence, the ε4 allele either may function as a risk factor for cognitive impairment in normal aging across a broad spectrum of domains or may exert detectable effects early in a long prodromal AD trajectory.