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.

Modifiable dementia risk factors and AT(N) biomarkers: findings from the EPAD cohort

“…APOE increases tau hyperphosphorylation, yet APOE ε4 carriers and non-carriers show similar benefits to brain health as a result of engagement in physical activity ( Pearce et al, 2022 ). Given physical activity engagement entails a suite of biological processes, it is likely that many of these molecular targets align with AD neuropathology and therefore require further investigation ( de Frutos Lucas et al, 2023 ). We also found lower BMI was associated with higher levels of p-tau 181 in CSF, where the prevailing evidence seems to indicate an association ( Mathys et al, 2017 ; Bos et al, 2019 ; Zhang et al, 2022 ) rather than a lack of association ( Pegueroles et al, 2020 ; Sun et al, 2020 ).…”

Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline

“…Together, while the underpinnings of the beneficial effect of PE on apoE4-associated demyelination remains to be further clarified [147], the wide array of molecular targets that PE activates might contribute to moderating this pathology. One human study did report more declined WM integrity in physically active APOE4 carriers compared to less-active APOE4 carriers [148].…”

Association between Mineral Intake and Cognition Evaluated by Montreal Cognitive Assessment (MoCA): A Cross-Sectional Study

“…Physical activity data were recorded via ActiGraph wGT3X-BT accelerometers (Pensacola, FL, USA). The participants wore the accelerometer on the right hip for 7 days, and finally, data from those who recorded more than 10 h per day on at least 4 days of the week were taken, with a minimum of one of those days falling on the weekend [54][55][56][57]. ActiLife software (6.13.3) (LLC, Pensacola, FL, USA) was used to collect physical activity data of the participants.…”