The Effects of Aerobic Exercise on Amyloid-β and Tau Pathology in APOE ε4 Carriers

Background/Objective: The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), accelerating both amyloid-β (Aβ) accumulation and tau hyperphosphorylation. Aerobic exercise is a promising strategy for reducing AD pathology. However, its effects on Aβ and tau biomarkers specifically in APOE ε4 carriers remain poorly characterized. By examining both Aβ and tau outcomes exclusively in APOE ε4 carriers, this study evaluates whether aerobic exercise is associated with AD pathology in those at the highest genetic risk.

Methods: A PubMed and Google Scholar search of articles published between January 2021 and December 2025 identified 50 studies. Using a modified PRISMA 2020 approach, studies were screened in two stages with predefined inclusion criteria and a structured rubric assessing APOE ε4 stratification, biomarker specificity, and methodological rigor. The 12 highest scoring studies were included.

Results: Physically active APOE ε4 carriers consistently demonstrated lower cortical amyloid burden compared to inactive peers in observational and cross-sectional studies. Short-term randomized trials relying on blood-based biomarkers produced null results for both amyloid and tau. Evidence for tau modification associated with exercise in humans is absent, as mechanistic support comes almost entirely from animal studies. Analyses suggest that ε4 carriers may exhibit stronger neuroprotective responses to aerobic exercise than non-carriers.

Conclusion: Observational studies consistently associate exercise with reduced amyloid burden in APOE ε4 carriers, but there lacks direct evidence for tau modification in humans. Longer randomized trials using sensitive central biomarkers, stratified by APOE genotype, are needed to determine whether exercise can meaningfully alter AD progression in ε4 carriers.