Abstract Background The apolipoprotein E ( APOE ) ε4 allele is a risk factor for late-onset Alzheimer’s disease; however, risk varies by sex and lifestyle. Regular physical activity is known to mitigate cognitive decline; whether the degree of benefit differs by APOE genotype, sex, and race remains unknown. Methods Analyses utilized data from 2,985 participants in the Health, Aging, and Body Composition (HABC) cohort, comprising community-dwelling black and white older adults followed for 10 years. Cognitive performance was assessed multiple times across the 10 years using the Digit Symbol Substitution Test (DSST) for executive functions and processing speed and the Modified Mini-Mental State Examination (3MS) for global cognition. APOE genotypes were categorized into ε2, ε3, and ε4 groups. Annual self-reported walking time was used to quantify physical activity. Linear mixed models and latent growth curve modeling examined the interactions between APOE genotype, sex, and walking on cognitive trajectories with adjustments for race, study location, health score, age, education attained, and body mass index. Results APOE ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared to ε3 carriers, irrespective of sex (all β 0.27, all p < 0.044). Discussion These findings underscore the importance of public messaging about the benefits of regular physical activity for retaining cognitive function especially for persons genetically at heightened risk.
Burma et al. (2026) studied this question.