Apolipoprotein E and Amyloid-β-Independent Mechanisms in Alzheimer's Disease

Apolipoprotein E (apoE) is a key protein linked to the pathogenesis of Alzheimer's disease (AD) beyond its central roles in lipid metabolism. Among the three human APOE gene alleles, APOE4 is the strongest genetic risk factor for AD, while APOE2 is protective. Although apoE isoforms regulate amyloid-β (Aβ) metabolism with apoE4 exacerbating Aβ deposition, emerging evidence indicates that apoE isoforms influence cognition through various pathways in Aβ-independent manners. ApoE isoforms also regulate neuronal cholesterol metabolism, brain glucose metabolism, mitochondrial functions, cerebrovascular system, and immune responses, which substantially contribute to AD pathogenesis. Therefore, apoE isoforms likely regulate critical pathways influencing brain homeostasis and cognition independent of Aβ-related effects. Better understanding of the link between apoE isoforms and Aβ-independent mechanisms in AD pathogenesis should allow us to define novel targets for AD therapy.