Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease

Human apolipoprotein (APO) E has three common isoforms that differentially affect lipid and neuronal homeotasis. APOE4, the major known genetic risk factor for Alzheimer's disease (AD), increases the occurrence and lowers the age of onset of AD. APOE4 carriers account or 65-80% of all AD cases, highlighting the importance f APOE4 in AD pathogenesis. Emerging data suggest hat APOE4 contributes to AD through various path-ways, some of which are dependent on amyloid-beta A beta). Although these A beta-dependent roles of APOE4 have seen widely studied, APOE4 has detrimental effects on eurons independent of A beta: aberrant proteolysis of APOE4 generates neurotoxic fragments, stimulates au phosphorylation, which disrupts the cytoskeleton, nd impairs mitochondrial function.