Level of Physical Activity and ApoE Status - Effects on Alzheimer's Disease and on Mortality

Background: Alzheimer's disease and related dementias (ADRD) affect over 7.2 million Americans aged 65 and older, with the APOE-4 allele representing the strongest known genetic risk factor. Physical activity (PA) has been associated with reduced dementia risk, but its interaction with APOE genotype remains poorly characterized in large, genomically informed cohorts. Methods: We conducted a retrospective cohort analysis using linked genomic, survey, and longitudinal electronic health record data from the VA Million Veteran Program (MVP). Veterans aged <65 at enrollment with available APOE genotype data, at least 10 years of prior VA medical history, and a completed Lifestyle Survey were included. Individuals with a pre-existing ADRD diagnosis were excluded, yielding a final cohort of 137,593 veterans. Self-reported vigorous physical activity (PA) was ascertained from the MVP Lifestyle Survey and coded as both a four-level ordinal variable and a binary active/inactive classification. The primary composite outcome was incident ADRD or all-cause mortality. Cox proportional hazards models were fitted adjusting for age, sex, race/ethnicity, and baseline comorbidities. A multiplicative interaction term between APOE {varepsilon}4 allele count and PA level was included to formally test for effect modification. Results: Over a median follow-up of 84 months, 65,628 participants (47.7%) experienced the composite outcome. Each additional APOE-4 allele was associated with a 19% increase in risk (aHR = 1.19, 95% CI 1.17-1.21), while active individuals had a 33% lower risk compared to inactive individuals (aHR = 0.67, 95% CI 0.66-0.68). A statistically significant interaction between APOE-4 burden and PA was identified (p < 0.005). Stratified analyses demonstrated that the protective association of PA was present across all genotype groups, with homozygotes demonstrating a 22% risk reduction among active individuals. Conclusions: In this large veteran cohort, vigorous PA was independently and significantly associated with reduced risk of incident ADRD or death across all APOE genotype groups, with the greatest absolute benefit observed among individuals at highest genetic risk. These findings support the prioritization of PA as a targeted preventive strategy, particularly for APOE-4 carriers.