Apolipoprotein E epsilon 4 allele (APOE ε4) (APOE ε4)

The APOE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer's disease (AD), with carriers of one or two copies showing a significantly increased risk and earlier age of onset [3, 5, 15]. It encodes the apolipoprotein E4 (ApoE4) protein, which differs from the common ApoE3 isoform by a single amino acid substitution (Cys112Arg) [14, 15]. This structural change leads to both a loss of neuroprotective functions—such as efficient amyloid-beta clearance and lipid transport—and a gain of toxic functions, including increased tau phosphorylation, neuroinflammation, and blood-brain barrier breakdown [2, 5, 16]. Therapeutic approaches targeting this locus include gene silencing with antisense oligonucleotides (ASOs) to reduce toxic ApoE4 levels, gene therapy to introduce the protective APOE2 allele, and small-molecule correctors designed to shift the ApoE4 protein into an ApoE3-like conformation [1, 3, 14]. Despite its promise, targeting APOE ε4 presents challenges, notably the risk of amyloid-related imaging abnormalities (ARIA) and potential systemic effects on cholesterol metabolism [2, 9].

Other names

APOE4APOE-epsilon4rs429358APOE*E4Apolipoprotein E4 allele

Gene silencing (ASOs/siRNA) to reduce toxic APOE4 levels, gene therapy (AAV-APOE2) for isoform conversion, small-molecule structure correction to an APOE3-like state, and enhancement of amyloid-beta clearance [1, 3, 14, 16].