Several mechanisms have been proposed to understand the differential effects of apoE isoforms on AD pathogenesis. Evidence suggests that the major effect of apoE isoforms on the risk of developing AD is via its effect on Aβ aggregation and clearance, influencing the onset of Aβ deposition. Other mechanisms, including the effects of apoE isoforms on synaptic function, neurotoxicity, tau hyper-phosphorylation, and neuroinflammation, may also contribute to the disease process. Independent of APOE genotype, differences in the apoE levels and lipidation state may also mediate processes involved in AD pathogenesis.