APOE ε4, physical activity, and the brain: a review of systematic reviews

Nada Ali, Noelle Chakbazof, Sara Ghasem Pour, Lorena Contreras, Jimena Estrada, Gene E. Alexander, David A. Raichlen, Hussein N. Yassine

Background Physical activity (PA) is often proposed as a modifiable strategy to reduce cognitive decline and dementia risk, particularly among individuals at elevated genetic risk for Alzheimer’s disease (AD). However, it remains unclear whether the existing literature tests PA at the disease stage and in the populations most likely to show benefit. Objective This umbrella review evaluated whether associations between PA and cognitive, fluid biomarker, neuroimaging, and vascular/metabolic outcomes differ by apolipoprotein E ε4 ( APOE ε4) genotype across stages of cognitive aging, with particular attention to how study design and baseline cognitive status shape interpretation of the evidence. Methods Systematic reviews and meta-analyses were screened for primary studies examining PA in adults classified by baseline cognitive status as cognitively unimpaired, mild cognitive impairment (MCI), or dementia. Primary studies reporting APOE ε4-stratified outcomes were extracted and qualitatively synthesized by outcome domain, cognitive stage, and study design. Results Of 2,100 records identified, seven systematic reviews met inclusion criteria, yielding 68 unique primary studies. Favorable associations between PA and cognitive, biomarker, neuroimaging, and vascular/metabolic outcomes were most often reported in observational studies of younger or cognitively unimpaired adults. Several studies suggested stronger associations among APOE ε4 carriers, including midlife cognitive associations, neuroimaging markers, and vascular/metabolic outcomes such as lipid profiles. In contrast, randomized controlled trials were few, generally enrolled older adults with MCI or dementia, included small APOE ε4 subgroups, and reported largely null or mixed genotype-specific effects. Conclusion The current evidence does not establish a definitive APOE ε4-specific preventive effect of PA. Future studies may be most informative if they target earlier-stage, low-active, or metabolically at-risk APOE ε4 carriers using objective PA measures and proximal vascular, metabolic, imaging, or blood-based biomarker outcomes.