The presence of apoE4, not the absence of apoE3, contributes to AD pathology

ApoE is a component of several classes of lipoproteins regulating lipid metabolism and redistribution [42] and is detected primarily in astrocytes in rodents and in astrocytes and neurons in humans [7,26, 51]. Neuronal apoE levels increase after CNS injuries in humans and rodents [33,38]. The three human isoforms, E2, E3, and E4, (alleles e2, e3, e4) differ by cysteines at two positions (112 and 158) [92]. All other mammalian apoE is E4-like at these cysteine residues, but numerous other differences exist, particularly in the C-terminus, such that rodent apoE cannot be equated with any particular human apoE isoform in its sequence [94]. This is an important consideration when attempting to compare effects of mouse and human apoE in transgenic models. ApoE isoform-specific activities could impact neuronal function through several direct and indirect mechanisms [84], raising the possibility that apoE isoforms differ in the mechanism by which they impact AD pathology [73]. Since the position defended here is that the presence of E4 confers greater risk of AD, an appropriate question is how selection for such a risk factor might occur. The E3 allele has risen to prominence in the last