Apolipoprotein E gene (APOE*ε4 allele) (APOE4)

The Apolipoprotein E (APOE) gene, specifically the ε4 allele, is the most significant genetic risk factor for late-onset Alzheimer's disease (AD) (National Institute on Aging, 2023). The APOE4 genomic DNA sequence is distinguished from the common ε3 allele by a single nucleotide polymorphism (SNP) at rs429358, which results in a cysteine-to-arginine substitution at position 112 of the protein (Corder et al., 1993; PubMed: 8332898). This genetic variation leads to impaired amyloid-beta clearance, increased tau phosphorylation, and heightened neuroinflammation in the brain (Yamazaki et al., 2019; PubMed: 31455803). As a therapeutic target, the genomic DNA is the focus of precision medicine approaches such as CRISPR/Cas9 gene editing, which aims to permanently convert the pathogenic ε4 allele into a neutral or protective variant (Komor et al., 2016; PubMed: 27096365). Additionally, gene therapy candidates like LX1001 utilize viral vectors to introduce the protective APOE2 allele into the central nervous system of APOE4 carriers to slow disease progression (Lexeo Therapeutics, 2024). While most current clinical efforts target the protein or mRNA, direct modification of the APOE4 genomic DNA represents a potential curative strategy for individuals at high genetic risk for neurodegeneration.

Other names

APOE-epsilon 4APOE-ε4AD2LPGApolipoprotein E4 geners429358

Gene editing (CRISPR/Cas9) to convert the ε4 allele to the ε3 or ε2 variant; Gene therapy (AAV-mediated) to deliver protective APOE2 alleles to the CNS; Antisense oligonucleotides (ASOs) to silence the expression of the APOE4 transcript.