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

The apolipoprotein E (<i>APOE</i>) 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 <i>APOE</i> ε7, composed of p.E262 K and p.E263 K within the C-terminal lipid-binding domain. These results reinforce the functional heterogeneity of <i>APOE</i> and suggest that rare variants may also modulate AD susceptibility. This commentary discusses the implications of such findings for <i>APOE</i>-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 <i>APOE</i> ε7 could provide natural models for drug discovery and help reconcile ongoing paradoxes in <i>APOE</i> biology, including the nuanced role of ε4 in different molecular contexts.