Apolipoprotein E is a secreted lipoprotein involved in cholesterol metabolism. Its three isoforms are ApoE2, ApoE3, and ApoE4. APOE genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease, with the ApoE4 risk allele ranking at the top of AlzGene since its discovery in 1993. Carrying one or two copies of ApoE4 increases AD risk by three- to 12-fold relative to ApoE3, while the rare ApoE2 allele is protective. Found in numerous populations, the ApoE4 effect is marked by earlier disease onset with more severe pathology, but otherwise typical clinical progression. Atypical forms of Alzheimer’s disease are not genetically linked to ApoE. ApoE4 predicts worse recovery and increased dementia following neurologic insults such as head trauma or stroke.
ApoE is expressed in the liver and macrophages. In the brain, it is secreted primarily by astrocytes and signals through lipoprotein receptors on neurons. ApoE’s underlying mechanisms of action in AD are partially understood. A large body of evidence points to differential clearance of Aβ from the brain and cerebral vasculature. ApoE may further influence AD pathogenesis via regulation of lipid homeostasis, synaptic transmission, and inflammatory damage to the blood-brain barrier.
Clinically, the APOE genotype is linked to various neuroimaging measures as well as to AD biomarker levels in the CSF and plasma, particularly in the disease’s prodromal phase. APOE genotype is sometimes used for stratification in clinical trials. ApoE itself has thus far proven to be an intractable AD drug target. Therapeutic approaches based on modulating its levels are largely at the preclinical stage or in Phase 1.
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- Holtzman DM, Herz J, Bu G. Apolipoprotein e and apolipoprotein e receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2012 Mar;2(3):a006312. PubMed.
- Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 2011 Mar;10(3):241-52. PubMed.
- Huang Y. Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends Mol Med. 2010 Jun;16(6):287-94. PubMed.
- Mahley RW, Rall SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507-37. PubMed.
- Herz J. Apolipoprotein E receptors in the nervous system. Curr Opin Lipidol. 2009 Jun;20(3):190-6. PubMed.