Physical activity and Alzheimer's disease risk across genetic susceptibility: a prospective UK Biobank study using accelerometer data.
Level 3 - non-randomized controlled study
Prospective observational cohort study
PubMed 41329349 · doi:10.1007/s00415-025-13524-z
What was done
Analyzed 93,578 UK Biobank participants aged 40–70 years who had wrist-worn accelerometer data and genome-wide genotyping. Physical activity was quantified continuously in milligravity (mg) and dichotomized using an optimal threshold from maximally selected rank statistics. Genetic susceptibility was evaluated via polygenic risk scores (PRS) and APOE ε4 carrier status. Cox proportional hazards models estimated hazard ratios for incident Alzheimer's disease (AD) across genetic risk groups and evaluated interactions over a median 15.5-year follow-up.
What was found
Among 401 incident AD cases, high physical activity reduced AD risk by 48% (HR 0.517, 95% CI 0.300–0.891), while high PRS increased risk (HR 2.423, 95% CI 1.757–3.343). The protective association of physical activity was consistent across all PRS and APOE ε4 strata, with no significant additive (RERI = -0.566, 95% CI -4.574 to 3.441) or multiplicative interaction. Dose-response analysis identified an optimal benefit threshold at 21.7 mg, corresponding to light-intensity physical activity.
Why it matters
This study demonstrates that the protective association between objectively tracked physical activity and Alzheimer's disease extends across all genetic risk tiers, including APOE ε4 carriers. It suggests that even light-intensity physical activity may serve as an effective lifestyle intervention for dementia risk reduction.
Limits
The observational design cannot establish causality or completely eliminate the possibility of reverse causation (preclinical cognitive decline reducing physical activity). Physical activity was measured during a single accelerometer assessment rather than over a lifetime. The UK Biobank is subject to healthy volunteer selection bias and consists largely of individuals of European ancestry.
Cited by
- partial People with the APOE4 allele are significantly less likely to develop Alzheimer's disease if they exercise, with more intense exercise providing greater protection.