Staying active during your 40s and 50s could help your brain resist early Alzheimer’s changes, especially if you follow WHO activity recommendations, this study finds.
Study: Physical activity changes during midlife link to brain integrity and amyloid burden. Image Credit: goodluz / Shutterstock
In a recent article published in the journal Alzheimer’s & Dementia, researchers investigated how changes in physical activity during midlife may impact brain changes associated with Alzheimer’s disease (AD) in individuals at higher risk of developing the disease.
Their findings indicate that becoming physically active at the levels recommended by the World Health Organization (WHO) was associated with reduced amyloid burden in the brain, and both becoming and remaining active, even at less than recommended levels, were linked to greater cortical thickness in areas vulnerable to AD, compared to remaining sedentary. Conversely, remaining sedentary was implicated in reduced cortical thickness in areas vulnerable to AD.
Background
Alzheimer’s disease (AD) begins with a long preclinical phase marked by early brain changes, such as neurodegeneration and amyloid-β (Aβ) buildup, which may be detected through biomarkers years before symptoms begin to emerge.
Researchers believe that up to one-third of cases are linked to modifiable lifestyle factors, and there is increasing interest in AD prevention through behavioral changes, particularly physical activity.
Sedentary behavior is a known risk factor for dementia, while midlife physical activity has been shown to reduce the risk of AD and cognitive decline. This could be through pathways such as improved mental and cardiovascular health.
Midlife is a crucial period because age-related brain changes and AD pathologies often begin then, especially in people at genetic or familial risk. While prior studies have shown cross-sectional links between physical activity and reduced AD biomarkers, few have examined how changes in activity levels – especially adherence to WHO recommendations – affect the progression of AD-related changes in at-risk individuals.
About the study
In this study, researchers assessed a critical research gap by investigating whether increases in physical activity, including adherence to WHO guidelines, are associated with lower Aβ burden and better brain structure in cognitively unimpaired middle-aged adults at risk for AD.
They analyzed data from 337 cognitively unimpaired participants in Catalonia from a larger study on preclinical Alzheimer’s disease (AD). Participants, aged between 45 and 65 and mostly with a family history of AD, had physical activity data collected at baseline (2013–2014) and follow-up (approximately 4 years later). Only those with MRI and/or amyloid-PET data at follow-up were included.
Physical activity was assessed using a questionnaire that recorded the weekly minutes of moderate or vigorous activity. Participants were grouped based on observance of WHO physical activity guidelines at both time points: maintained sedentary, maintained non-adherence, became adherent, became non-adherent, and maintained adherence. A continuous measure of activity change was also calculated.
Brain amyloid burden was assessed through positron emission tomography (PET) imaging, and cortical thickness in AD-sensitive regions was measured using structural magnetic resonance imaging (MRI). The AD-signature region was defined using a composite of medial temporal lobe areas vulnerable to early AD atrophy.
Statistical models examined how physical activity group and changes in activity predicted amyloid burden and cortical thickness at follow-up, adjusting for age, sex, education, apolipoprotein E (APOE)-ε4 status, and the time between assessments.
Sensitivity analyses also controlled for cardiovascular and mental health factors such as symptoms of depression and anxiety.
It is worth noting that brain imaging outcomes were measured only at follow-up, so causality cannot be firmly established. Additionally, 99.4% of participants were Caucasian, which limits the generalizability of the results to other populations.
Findings
Participants were categorized into five groups based on adherence to the WHO physical activity guidelines. Nearly 30% remained sedentary, while 15.7% became adherent to their treatment. Those who became adherent showed the greatest increase in physical activity minutes. No significant group differences emerged for age, education, sex, or APOE-ε4 status.
Participants who maintained sedentary behavior had significantly lower cortical thickness in Alzheimer’s disease (AD)-sensitive brain regions than those who maintained or became adherent, or even those who were non-adherent but not sedentary. Additionally, those who became adherent had a significantly lower amyloid-β (Aβ) burden than those who became non-adherent, a finding that remained statistically significant even after correction for multiple comparisons. The difference in amyloid burden between those who became adherent and those who remained sedentary was also present but less robust.
A dose-response association was found, with increased physical activity correlating with a lower Aβ burden; however, this dose-dependent effect was not observed for cortical thickness. These results remained largely robust after adjusting for cardiovascular risk and mental health scores, although some associations with cortical thickness were attenuated after these adjustments.
Conclusions
The study reveals that increased or sustained physical activity during midlife is associated with a lower Aβ burden and greater cortical thickness in AD-vulnerable brain regions, underscoring its potential neuroprotective effects.
Even partial adherence to activity guidelines (i.e., non-adherent but not sedentary) appeared beneficial. A dose-dependent relationship between increased activity and reduced Aβ supports this link.
Strengths of this analysis include longitudinal design, biomarker data, and adjustment for confounders. However, the study is limited by the observational nature of the survey design, limited ethnic diversity, the use of self-reported physical activity, and the inability to rule out reverse causation due to brain outcomes being measured only at follow-up. Potential unmeasured mediators, such as sleep or neurogenesis, were also not assessed.
Overall, the findings suggest that adopting the WHO-recommended physical activity during midlife may enhance resilience against early AD pathology, even in individuals at risk.
Journal reference:
- Physical activity changes during midlife are linked to brain integrity and amyloid burden. Akinci, M., Aguilar-Domínguez, P., Palpatzis, E., Shekari, M., García-Prat, M., Deulofeu, C., Fauria, K., García-Aymerich, J., Gispert, J.D., Suárez-Calvet, M., Grau-Rivera, O., Sánchez-Benavides, G., Arenaza-Urquijo, E.M. Alzheimer’s & Dementia (2025). DOI: 10.1002/alz.70007, https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.70007