Human apolipoprotein (APO) E has three common isoforms that differentially affect lipid and neuronal homeostasis. 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 for 65-80% of all AD cases, highlighting the importance of APOE4 in AD pathogenesis. Emerging data suggest that APOE4 contributes to AD through various pathways, some of which are dependent on amyloid-beta (Abeta). Although these Abeta-dependent roles of APOE4 have been widely studied, APOE4 has detrimental effects on neurons independent of Abeta: aberrant proteolysis of APOE4 generates neurotoxic fragments, stimulates Tau phosphorylation, which disrupts the cytoskeleton, and impairs mitochondrial function.
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