Apolipoprotein E, Receptors, and Modulation of Alzheimer's Disease

Biol Psychiatry. 2018 Feb 15;83(4):347-357. doi: 10.1016/j.biopsych.2017.03.003. Epub 2017 Mar 14.


Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not limited to the metabolism, aggregation, and toxicity of amyloid-β peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation. Emerging knowledge on apoE-related pathways in the pathophysiology of AD presents new opportunities for AD therapy. We describe the biochemical and biological features of apoE and apoE receptors in the central nervous system. We also discuss the evidence and mechanisms addressing differential effects of apoE isoforms and the role of apoE receptors in AD pathogenesis, with a particular emphasis on the clinical and preclinical studies related to amyloid-β pathology. Finally, we summarize the current strategies of AD therapy targeting apoE, and postulate that effective strategies require an apoE isoform-specific approach.

Keywords: Alzheimer’s disease; Amyloid-β; Apolipoprotein E; Low-density lipoprotein receptor family; Synaptic plasticity; Tauopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Apolipoproteins E / drug effects*
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*


  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Low Density Lipoprotein Receptor-Related Protein-1