APOE ε4 allele (mechanism)

The APOE ε4 allele encodes apolipoprotein E isoform E4, which differs from the ε3 isoform at residue 112 (cysteine→arginine), altering lipoprotein binding preferences and reducing efficient clearance of triglyceride-rich remnants and LDL from circulation. In the brain, E4 impairs amyloid-β clearance via the blood-brain barrier and through astrocytic and microglial processing, promotes tau pathology, and potentiates neuroinflammation via microglial activation — effects partly independent of amyloid. The allele confers dose-dependent Alzheimer's disease risk: one ε4 copy increases risk approximately 3–4-fold, two copies approximately 8–12-fold in European populations, with risk magnitudes varying across ancestries. Despite its disease associations, the ε4 allele has been maintained at roughly 14% average global allele frequency (with substantial regional variation, ~5% in East Asia to >30% in some African populations), likely reflecting ancient trade-offs involving immune function, fertility, and early cognitive performance.