Physical Activity in Mid- and Late Life Linked to Markedly Lower Risk of Dementia

Higher levels of physical activity in midlife and late life were associated with a 36% to 45% lower risk of all-cause dementia in a long-term analysis of the Framingham Heart Study Offspring cohort published today in JAMA Network Open. Activity in midlife (ages 45-64) was associated with a 40% reduction in dementia risk over 26 years for individuals in the top 2 activity quintiles (HR 0.60, 95% CI 0.41-0.89; HR 0.59, 95% CI 0.40-0.88). 1

Activity in late-life (ages 65-88) showed similar associations over 15 years (HR 0.64, 95% CI 0.42-1.00; HR 0.55, 95% CI 0.35-0.87). In contrast, physical activity in early adulthood did not correlate with incident dementia. Findings were consistent for Alzheimer disease and suggest that midlife and late-life may represent critical intervention windows for dementia prevention, according to lead author Phillip Hwang, PhD, MPH, assitant professor in the department of epidemiology at the Boston University School of Public Health and colleagues.1

Exercise Has Proven Benefits

As the population ages and rates of Alzheimer and related dementias continue to rise, there are no cures on the horizon, and pharmacologic interventions for Alzheimer disease offer limited benefit and can carry adverse effects, Hwant et al wrote.1 As a result, researchers has increasingly focused on examining modifiable risk factors across the life course. The 2024 Lancet Commission reported that up to 45% of dementia cases could be preventable by addressing 14 recognized risk factors, including physical inactivity in midlife.2 Prior research supports associations between physical activity and brain volume, connectivity, and preserved cognitive function, but many studies have relied on individuals' recall in later life of activity patters in earlier life, leaving uncertainty about when during adulthood activity confers the greatest protection.1

"More research is needed to determine whether physical activity exerts a stronger influence on dementia risk during different periods of the adult life course," Hwang et al wrote. "This has important implications for intervention planning and public health promotion."1

Findings were consistent for Alzheimer disease and suggest that midlife and late-life may represent critical intervention windows for dementia prevention.

Framingham Heart Study Offspring Cohort

For their research, Hwang and colleagues used prospective data from 4,354 adults in the Framingham Heart Study Offspring cohort. Participants were dementia-free at baseline and had self-reported physical activity measured in early adulthood (ages 26–44; n=1,526), midlife (45–64; n=1,943), or late life (65–88; n=885). Activity scores were derived using the physical activity index (PAI), which weights hours spent in sleep, sedentary behavior, and slight, moderate, or heavy activity over a 24-hour periodm according to the study.1

Researchers followed participants for a mean of 37.2 years (early adulthood group), 25.9 years (midlife), and 14.5 years (late life). Over the study period, 567 individuals developed all-cause dementia: 62 in the early adult group (4%), 273 in midlife (14%), and 232 in late life (26%).1

Hwang et al adjusted models for age, sex, education, BMI, smoking status, hypertension, diabetes, hyperlipidemia, and APOE ε4 status. In a secondary analysis, the investigators stratified each age group by APOE ε4 carrier status.1

Findings

The researchers reported that physical activity in early adulthood showed no association with dementia risk. In midlife and late life, however, activity levels in the fourth and fifth quintiles consistently predicted lower risk of all-cause dementia and Alzheimer dementia.1

For midlife activity, the found that only the highest 2 quintiles were linked to lower dementia risk. Compared with quintile 1:

• Quintile 4 activity was linked with a 40% lower risk (HR 0.60, 95% CI 0.41-0.89)
• Quintile 5 activity was linked with with a 41% lower risk (HR 0.59, 95% CI 0.40-0.88)

Late-life activity showed a similar pattern: individuals in quintile 4 had a 36% lower risk (HR 0.64, 95% CI 0.42-1.00), and those in quintile 5 had a 45% lower risk (HR 0.55, 95% CI 0.35-0.87).

Activity intensity mattered in midlife. Moderate activity in quintile 4 or 5 was associated with 35% to 38% lower dementia risk (HR 0.65, 95% CI 0.44-0.97; HR 0.62, 95% CI 0.42-0.92). Heavy activity in quintile 5 also showed benefit (HR 0.66, 95% CI 0.44-1.00). In late life, however, the effect did not differ by activity intensity.

Associations varied by APOE ε4 status. Midlife physical activity reduced dementia risk only among ε4 noncarriers, whereas late-life activity showed benefit in both carriers and noncarriers.

Approximately half of each age group were women and, according to the study, participants in late life teneded to have lower education, higher BMI, lower levels of smoking, and greater levels of commond chronic conditions (eg, hypertension, diabetes).1

Biological Mechanisms

The authors cited several proposed mechanisms linking physical activity to cognitive health, including increased cerebral blood flow, reduced systemic inflammation, enhanced neuroplasticity, and improved glucose metabolism. Exercise also increases the expression of brain-derived neurotrophic factor in animal models, supporting hippocampal neurogenesis and synaptic resilience.3,4

Amng the study's limitations the Hwang and colleagues acknowledge that physical activity was self-reported at a single time point in each life period, which may have led to misclassification. Among the age groups, the early-life group had fewer dementia events, which limits inference about early-life exposure. The full cohort was of predomiantly European ancestry, reducing the ability to generalize the findings and, finally, higher mortality in lower-activity groups may have attenuated associations.1

"This study is among the first to evaluate the potential critical periods for physical activity in association with dementia risk," the authors wrote. "These findings may inform future efforts to delay or prevent dementia through timing interventions and public health promotion efforts during the most relevant stages of the adult life course."

References

1. Marino F, Lye C, Li Y, Liu T, Au R, Hwang PH. References Physical activity over the life course and risk of dementia in the Framingham Heart Study. JAMA Netw Open. 2025;8(11):e2544439. doi:10.1001/jamanetworkopen.2025.44439
2. Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404(10452):572-628. doi:10.1016/S0140-6736(24)01296-0
3. de Frutos Lucas J, Sewell KR, García-Colomo A, Markovic S, Erickson KI, Brown BM. How does apolipoprotein E genotype influence the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model. Alzheimers Res Ther. 2023;15(1):22. doi:10.1186/s13195-023-01170-4
4. Arida RM, Teixeira-Machado L. The contribution of physical exercise to brain resilience. Front Behav Neurosci. 2021;14:626769. doi:10.3389/fnbeh.2020.626769