Apolipoprotein E4 (APOE4) (APOE4)

Apolipoprotein E4 (APOE4) is a major cholesterol carrier in the central nervous system and the most significant genetic risk factor for late-onset Alzheimer's disease (National Institute on Aging, 2021). The amyloid-associated form of APOE4 refers to its role as a pathological chaperone that promotes the aggregation and deposition of amyloid-beta (Abeta) into plaques while simultaneously impairing its clearance from the brain (Yamazaki et al., 2019). Structurally, APOE4 differs from the common APOE3 isoform by a single amino acid substitution (Cys112Arg), which leads to a more closed protein conformation and increased susceptibility to proteolytic cleavage into neurotoxic fragments (Liu et al., 2013). Therapeutic strategies targeting this form include small molecule structure correctors that aim to convert APOE4 into an E3-like state and monoclonal antibodies that specifically target the non-lipidated or plaque-associated forms of the protein (Yamazaki et al., 2019). Clinical trials, such as those for valiltramiprosate, focus on patients with the APOE4/4 genotype to maximize therapeutic efficacy in reducing amyloid oligomerization and slowing cognitive decline (Alzheon, 2023).

Other names

APOE-epsilon 4Apolipoprotein E isoform 4AD2LPGApolipoprotein E4 (amyloid-associated)

Inhibition of amyloid-beta oligomerization, structural correction of the APOE4 protein to an E3-like conformation, and antibody-mediated clearance of APOE-containing amyloid plaques.