ApoE and Aβ in Alzheimer's Disease: Accidental Encounters or Partners?

Among the three human apolipoprotein E (apoE) isoforms, apoE4 increases the risk of Alzheimer's disease (AD). While transporting cholesterol is a primary function, apoE also regulates amyloid-beta (A beta) metabolism, aggregation, and deposition. Although earlier work suggests that different affinities of apoE isoforms to A beta might account for their effects on A beta clearance, recent studies indicate that apoE also competes with A beta for cellular uptake through apoE receptors. Thus, several factors probably determine the variable effects apoE has on A beta. In this Review, we examine biochemical, structural, and functional studies and propose testable models that address the complex mechanisms underlying apoE-A beta interaction and how apoE4 may increase AD risk and also serve as a target pathway for therapy.