Fig. 3

Proposed mechanism for physical activity-induced beneficial effects on brain health in APOE ε4 carriers and non-carriers. Physical activity (PA) is associated with decreased functional connectivity (FC) both in APOE ε4 carriers and non-carriers. We propose that this relationship could be mediated by a PA-induced increase in neurogenesis and synaptogenesis. Such processes could in turn prevent the loss of inhibitory synapses that has been identified to cause hyperexcitability in temporal regions in prodromal Alzheimer’s disease (AD). Interestingly, this decrease in FC manifests differently according to AD genetic risk. In ε4 carriers, this profile is linked to reduced anxiety and preserved brain structure. Conversely, in ε4 non-carriers, it is associated with enhanced cognition. One possibility behind this pattern of results could be that ε4 carriers were at higher risk of neuronal damage, which in normal aging would appear later. Therefore, at the specific time when we are taking these measurements, PA has more room to exert its beneficial effect on brain structure in ε4 carriers, while in non-carriers, at lower risk for neuropathological burden, it is associated with improved cognitive functioning. Hence, it remains plausible that at older ages, PA could also relate to greater structural integrity. However, we cannot rule out the possibility that PA affected ε4 carriers and non-carriers through different mechanisms