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

Trends Mol Med. 2010 Jun;16(6):287-94. doi: 10.1016/j.molmed.2010.04.004. Epub 2010 May 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Apolipoprotein E4 / genetics
  • Apolipoprotein E4 / metabolism*
  • Humans
  • Models, Biological
  • Neurons / metabolism
  • Neurons / pathology


  • Amyloid beta-Peptides
  • Apolipoprotein E4