Getting physically active in midlife, late life lowers dementia risk

Higher levels of physical activity help fight dementia, especially for middle-aged and older adults, according to a study.

The highest quintiles of physical activity levels in midlife were associated with a 40-percent lower risk of all-cause dementia compared with the lowest quintile (Q4 vs Q1: hazard ratio [HR], 0.60, 95 percent confidence interval [CI], 0.41–0.89; Q5 vs Q1: HR, 0.59, 95 percent CI, 0.40–0.88). [JAMA Netw Open 2025;8:e2544439]

Similarly, higher quintiles of physical activity levels in late life were associated with a 36-percent to 45-percent decrease in the risk of all-cause dementia compared with the lowest quintile (Q4 vs Q1: HR, 0.64, 95 percent CI, 0.42–1.00; Q5 vs Q1: HR, 0.55, 95 percent CI, 0.35–0.87).

For the risk of Alzheimer’s disease, the highest vs the lowest quintile of physical activity levels in both midlife and late life were associated with a more than 40-percent risk reduction (midlife: HR, 0.55, 95 percent CI, 0.33–0.94; late life: HR, 0.53, 95 percent CI, 0.29–0.95).

No associations were observed between physical activity in early adult–life and dementia risk.

“Overall, these results support the importance of midlife and late-life physical activity for dementia risk reduction, highlighting key stages of the adult life course for intervention planning and public health promotion,” the investigators said.

“When evaluating specific physical activity intensities, we found that moderate or heavy physical activity in midlife was associated with lower dementia risk, but that risk did not differ across intensities of late-life physical activity. This builds on previous findings to support moderate or heavy midlife physical activity and any late-life physical activity as possible interventions for dementia risk reduction,” they added.

Notably, the benefits of midlife or late-life physical activity also differed by APOE ε4 status. Higher midlife physical activity was only associated with lower dementia risk among noncarriers (Q4 vs Q1: HR, 0.51, 95 percent CI, 0.31–0.83; Q5 vs Q1: HR, 0.41, 95 percent CI, 0.24–0.70). Meanwhile, higher late-life physical activity was protective against dementia risk among both carriers (HR, 0.34, 95 percent CI, 0.12–0.94) and noncarriers (HR, 0.54, 95 percent CI, 0.31–0.95).

“Physical activity and APOE ε4 exert opposite effects on many neuropathological changes including, but not limited to, Aβ deposition, brain neurotrophic factors, and cerebrovascular function,” the investigators noted.

“Physical activity may partly, but not fully, offset or delay these APOE ε4-related changes, which could be a potential reason why findings were observed in middle and late life for noncarriers but only in late life among carriers,” they explained.

The investigators called for additional studies to ascertain whether physical activity levels during certain periods of the adult life course confer differential dementia risk reduction by APOE ε4 status.

For the study, the investigators used data from the Framingham Heart Study Offspring cohort. A total of 1,526 early adult–life (mean age 36.7 years, 53.8 percent female), 1,943 midlife (mean age 54 years, 52 percent female), and 885 late-life participants (mean age 71 years, 53.4 percent female) were included in the analysis.

Late-life participants tended to have higher BMI, were less likely to be current smokers, and had a higher prevalence of hypertension, diabetes, and hypercholesteremia compared with younger participants.

All-cause dementia was documented in 567 participants, including 62 early adult–life (4 percent), 273 midlife (14 percent), and 232 late-life participants (26 percent), during the follow-up. Mean follow-up was 37.2, 25.9, and 14.5 years, respectively.