Figure 2.

Despite the high lifetime risk linked to the presence of the APOE ε3/ε4 and APOE ε4/ε4 genotypes (the greatest risk factor for developing Alzheimer’s disease, AD), stochastic factors (such as environment, diet, physical exercise, and aging), may play a significant role as epigenetic modifiers, influencing the imbalance among the different ApoE isoforms. The role of APOE ε4 allele in AD pathogenesis involves not only amyloid-β aggregation and clearance, but also tau-mediated neurodegeneration, microglia dysfunction, astrocyte reactivity, and blood–brain barrier disruption. These changes may only occur in brain regions profoundly affected by AD pathophysiology (highest levels in the cerebellum, with moderate levels in the hippocampus and the lowest levels in the frontal lobe).