Alzheimer's Disease Therapeutics Targeting Apolipoprotein E

The apolipoprotein E (APOE) gene strongly affects risk for Alzheimer's disease (AD). The ε4 allele increases whereas the ε2 allele decreases risk relative to the ε3 allele. The apoE protein is produced predominantly by astrocytes in the brain, and a large body of literature indicates that apoE plays a role in AD pathogenesis mainly by affecting amyloid-β (Aβ) aggregation and clearance, which influences the onset, amount, and location of Aβ deposition into either amyloid plaques or cerebral amyloid angiopathy. ApoE may also modify AD pathogenesis by additional Aβ-independent mechanisms. ApoE genotype, levels, and lipidation status influence apoE function and its likely role in AD pathogenesis. Since the exact mechanism by which apoE affects AD pathogenesis is not entirely clear, apoE targeting therapeutics are still at an early stage. Current proposed strategies include blocking the apoE/Aβ interaction, apoE passive immunotherapy, and modifying apoE levels, structure, lipidation, or fragmentation.