Apolipoprotein E (APOE) (APOE)

Apolipoprotein E (APOE) is a multifunctional glycoprotein that serves as a primary transporter of cholesterol and other lipids within the central nervous system and peripheral tissues (UniProt P02649). In the brain, APOE is produced mainly by astrocytes and is essential for neuronal repair, synaptic plasticity, and the clearance of amyloid-beta (Aβ) peptides (PubMed: 30104344). The APOE gene exists in three common isoforms—ε2, ε3, and ε4—with the APOE4 variant identified as the most significant genetic risk factor for late-onset Alzheimer's disease (NIH). This toxic variant is associated with increased Aβ aggregation, impaired lipid homeostasis, and heightened neuroinflammation (PubMed: 33536613). Current therapeutic approaches target APOE by attempting to reduce the expression of the E4 isoform, correct its pathological protein folding, or increase the presence of the protective E2 isoform (ClinicalTrials.gov). Because of its central role in both lipid metabolism and neurodegeneration, APOE is a high-priority target for precision medicine in Alzheimer's disease and related tauopathies.

Other names

Apo-EAD2LDLCQ5LPGApolipoprotein E3Apolipoprotein E4

Therapeutic strategies include the reduction of APOE4 protein levels via antisense oligonucleotides, the use of small molecule structure correctors to shift the toxic APOE4 conformation to a neutral APOE3-like state, and the delivery of protective APOE2 alleles via gene therapy to counteract APOE4-mediated neurotoxicity.