Non‐synonynous <i>APOE</i> variants association in diverse ancestries

We identified two novel Native American-specific missense variants at APOE-W294C and R189C-that modulate AD risk and confirmed established protective and risk-increasing alleles. Of note, the mature APOE3 amino-acid chain (excluding the 18-residue signal peptide) contains only one cysteine at position 112, underscoring the protein's sensitivity to cysteine substitutions. The disproportionate impact of these thiol-forming changes-akin to those defining ε2 (R158C) and ε4 (C112R)-highlights a critical role for cysteine chemistry in APOE function and AD pathogenesis. Functional characterization of W294C and R189C may reveal novel therapeutic pathways.