How does APOE genotype moderate the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model

Abstract

BackgroundEvidence suggests that physical activity (PA) confers protection against Alzheimer’s disease (AD), while the Apolipoprotein E (APOE) ε4 allele represents the greatest genetic risk factor. Extensive research has thus far failed to establish whether frequent PA can mitigate the increased AD risk associated with APOE ε4. Studies looking at various AD‐related traits (e.g., amyloid beta burden or cortical atrophy) might show diverse results because the biological pathways involved are differentially influenced by PA, APOE ε4 carriage and their interaction. In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model of how PA and APOE ε4 carriage, independently and in combination, may alter well‐established molecular mechanisms underlying AD pathogenesis.MethodAvailable literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aβ) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response, and glucose metabolism.ResultWe have identified potential pathways through which the beneficial effects of PA might offset some of the detrimental outcomes of APOE ε4 carriage. Nonetheless, PA does not seem to be able to entirely prevent or revert the noxious effects of genetic risk. Our integrative model includes evidence‐based and theoretical synergistic interactions across mechanisms, and a proposal of testable hypotheses for future studies.ConclusionPA influences a wide array of molecular targets involved in AD neuropathology. A better understanding of where, when and most importantly, how, PA decreases AD risk in the presence of the APOE ε4 allele is essential to formulate combined therapeutic approaches.