Sex and APOE ε2 Interactive Effects on the Longitudinal Change in Cognition in a Population-Based Cohort of Older Adults with Vascular Risk Factors

Abstract

Cognitive aging trajectories differ widely across individuals, and genetic factors such as APOE and BDNF polymorphisms may contribute to this variability. While APOE ε4 has been widely studied, the influence of APOE ε2, particularly in interaction with sex, remains underexplored. This study aims to examine the longitudinal trajectory of APOE ε2 individuals on cognitive performance, and their interactions with sex, age, and BDNF Val66Met polymorphism, in a population-based cohort of older adults with vascular risk. We analyzed data from 386 participants (mean age: 71.8) from the Barcelona-AsIA Neuropsychology Study, followed over a 7-year period. Verbal memory, verbal fluency, and visuospatial domains were assessed. Linear regression models tested associations between cognitive change and genotypes, controlling for age, sex, education, depression, and vascular risk. Interaction terms and permutation testing were applied. Regression to the mean (RTM) effects were assessed. BDNF showed no significant associations with cognitive performance. RTM effects were evident across subgroups, particularly among ε2 carriers, suggesting this phenomenon partly explains the divergent results over time. APOE ε2 does not confer a consistent protective effect on cognition over time. Our results highlight that APOE ε2 may be detrimental to verbal memory in aging males.