Revisiting APOE : Insights from rare variants and the expanding landscape of Alzheimer's disease genetics

Abstract

The apolipoprotein E (APOE) gene is the most robust genetic risk factor for Alzheimer's disease (AD), with the ε4 allele conferring elevated risk and ε2 providing protection. While research has largely focused on common variants, recent findings by Miyashita et al. highlight the role of rare missense variants (RMVs) such as APOE ε7, composed of p.E262 K and p.E263 K within the C-terminal lipid-binding domain. These results reinforce the functional heterogeneity of APOE and suggest that rare variants may also modulate AD susceptibility. This commentary discusses the implications of such findings for APOE-targeted therapeutic development, the necessity of functional validation, and the importance of expanding cross-ethnic research efforts to uncover variant-specific effects. Understanding rare protective variants like APOE ε7 could provide natural models for drug discovery and help reconcile ongoing paradoxes in APOE biology, including the nuanced role of ε4 in different molecular contexts.