This study utilized whole-genome sequencing (WGS) data from 140 individuals with probable Alzheimer's disease (AD) and 798 cognitively normal elder controls, along with single-nucleotide polymorphism genotyping data from a large independent Japanese AD cohort, to identify rare variants associated with AD. Two rare variants were identified as candidates: a missense variant in OR5G1 and a stop-gain variant in MLKL. In vitro functional analysis showed that the MLKL stop-gain variant increased the ratio of Aβ40 to Aβ42 and contributed to the accumulation of abnormal cells. Gene-based association tests identified further AD candidate genes, and a network-based meta-analysis revealed four functionally important hub genes (NCOR2, PLEC, DMD, and NEDD4). These findings offer novel insights into AD pathogenesis.
