APOE

HIGH

Apolipoprotein E

Chromosome: 19q13.32

Gene Overview

APOE encodes apolipoprotein E, a lipid-binding protein that mediates cholesterol and triglyceride transport in the brain and periphery. The epsilon4 allele (APOE4) is the strongest genetic risk factor for late-onset Alzheimer disease, conferring ~3-fold increased risk per copy. APOE influences amyloid-beta aggregation, clearance, and neuroinflammation. In the periphery, APOE modulates LDL metabolism and atherosclerosis. Expression is highest in liver, brain (astrocytes, microglia), and macrophages. APOE has three common isoforms (E2, E3, E4) differing in amino acids 112 and 158. E4 carriers show earlier amyloid deposition and faster cognitive decline.

Molecular Function

lipid binding
receptor binding
amyloid clearance
cholesterol transport

Protein class: apolipoprotein

Regulatory Annotation

Promoter activity: Liver-enriched transcription factors; NF-κB in inflammation.

Enhancer associations: AD-associated variants regulate APOE expression in brain cell types.

Methylation sensitivity: APOE promoter methylation varies with genotype and AD status.

eQTL tissues: brain, liver

Tissue Expression Context

brainTPM range: 15-50GTEx vv8

liverTPM range: 100-300GTEx vv8

Pathways

ldl-cholesterol-metabolism

Linked Diseases & Exposures

Diseases

alzheimers-disease— GWAS, strength 0.96
coronary-artery-disease— pathway, strength 0.72

Exposures

diet-quality— literature, strength 0.65

Mechanistic Hypotheses

APOE4 impairs amyloid-beta clearance and promotes aggregation; reduced lipid delivery to neurons and enhanced neuroinflammation contribute to Alzheimer pathogenesis.

Humanized APOE mouse models replicate AD pathology; APOE4 astrocytes show impaired Abeta phagocytosis.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

1.Corder EH, et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. doi:10.1126/science.8346443
2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
3.Montagne A, et al. (2020). APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. doi:10.1038/s41586-020-2247-3