APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study

The apolipoprotein E (APOE) gene may act differently in young and old persons, known as antagonistic pleiotropy. We therefore examined the prospective associations between the APOE ε4 allele and cognitive functioning, and the modifying effect of age, in 375 nondemented adults (mean age 57 ± 10 years; follow-up period 3.8 ± 0.2 years) with available data on APOE genotype and cognitive functioning, within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) cohort study. Neuropsychological tests assessing memory performance and executive functioning were performed at baseline and follow-up, and composite z-scores were calculated. Age significantly modified the association of APOE ε4 with change in memory performance (p interaction = 0.02). In persons ≤ 57 years (median split), an APOE ε4 allele was associated with an increase in immediate recall (B = 0.42; 95% confidence interval [CI], 0.17 to 0.66) and delayed recall (B = 0.37; 95% CI, 0.09 to 0.64), while in persons > 57 years, an APOE ε4 allele was associated with decline in immediate recall (B = -0.25; 95% CI, -0.52 to 0.01). Our findings suggest that the APOE ε4 allele has a differential effect on change in verbal memory performance depending on age, consistent with the hypothesis of antagonistic pleiotropy.