How does apolipoprotein E genotype influence the relationship between physical activity and Alzheimer's disease risk? A novel integrative model

Abstract

Background: Wide evidence suggests that physical activity (PA) confers protection against Alzheimer's disease (AD). On the other hand, the apolipoprotein E gene (APOE) ε4 allele represents the greatest genetic risk factor for developing AD. Extensive research has been conducted to determine whether frequent PA can mitigate the increased AD risk associated with APOE ε4. However, thus far, these attempts have produced inconclusive results. In this context, one possible explanation could be that the influence of the combined effect of PA and APOE ε4 carriage might be dependent on the specific outcome measure utilised.

Main body: In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model on the interactive effects of PA and APOE ε4 carriage on well-established mechanisms underlying AD. Available 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. Finally, combining all this information, we have built an integrative model, which includes evidence-based and theoretical synergistic interactions across mechanisms. Moreover, we have identified key knowledge gaps in the literature, providing a list of testable hypotheses that future studies need to address.

Conclusions: We conclude that PA influences a wide array of molecular targets involved in AD neuropathology. A deeper understanding of where, when and, most importantly, how PA decreases AD risk even in the presence of the APOE ε4 allele will enable the creation of new protocols using exercise along pharmaceuticals in combined therapeutic approaches.

Keywords: APOE ε4; Alzheimer’s disease; Amyloid pathology; Cerebrovascular health; Glucose metabolism; Mitochondrial dysfunction; Neuroinflammation; Neurotrophic factors; Physical activity; Tau pathology.

Fig. 1

Hypothesised associations between apolipoprotein E gene allele, exercise, inflammatory factors and amyloid-beta. Solid lines indicate empirically supported pathways, and dashed lines indicate hypothesised pathways with preliminary evidence. Green lines indicate a positive effect, and red lines indicate a negative effect. Abbreviations: Aβ amyloid-beta, APOE apolipoprotein E, BBB blood–brain barrier, IL interleukin, TLR toll-like receptor, TNF tumour necrosis factor. Created by KS with BioRender.com

Fig. 2

Hypothesised associations between apolipoprotein E gene allele, physical activity and neurotrophic factors. Solid lines indicate empirically supported pathways, and dashed lines indicate hypothesised pathways with preliminary evidence. Green lines indicate a positive effect, and red lines indicate a negative effect. E4 > E2 indicates a greater effect for E4 carriers compared to E2 carriers, and E4 > E3 indicates a greater effect for E4 carriers compared to E3 carriers. Abbreviations: Aβ amyloid-beta, APOE apolipoprotein E, BDNF brain-derived neurotrophic factor, IGF insulin-like growth factor, p-tau phosphorylated tau, VEGF vascular endothelial growth factor. Created by KS with BioRender.com

Fig. 3

Hypothesised associations between apolipoprotein E, physical activity and cerebrovascular factors. Solid lines indicate empirically supported pathways, and dashed lines indicate hypothesised pathways with preliminary evidence. Green lines indicate a positive effect, and red lines indicate a negative effect. Abbreviations: Aβ amyloid-beta, APOE apolipoprotein E, p-tau phosphorylated tau, TLR toll-like receptor. Created by KS with BioRender.com

Fig. 4

An integrative model of hypothesised associations between apolipoprotein E ε4 carriage, physical activity and Alzheimer’s disease mechanisms. Green lines indicate a positive effect, and red lines indicate a negative effect. Abbreviations: Aβ amyloid-beta, APOE apolipoprotein E, p-tau phosphorylated tau. Created by KS with BioRender.com