BackgroundLittle is known about the rare missense variants (RMVs) of in East Asians, including the Japanese, and their association with Alzheimer's disease (AD) and lipid metabolism.ObjectiveTo identify RMVs in the Japanese population and investigate their association with AD and lipid metabolism, including low-density lipoprotein cholesterol levels.Methods RMVs were explored in the Niigata (NIG; 2589 subjects) and Tohoku (ToMMo; 3307 subjects) cohorts. A case-control study included 6261 AD cases and 16,331 controls, all of whom were aged 65 or older. Sanger sequencing, whole-exome sequencing, or a combination of both was performed on the NIG subjects. We used the genotype data from the ToMMo cohort. RMV frequencies in the Japanese population were compared with various ethnic populations. Associations between RMV genotypes, AD, and lipoproteins were examined.ResultsFourteen RMVs were identified (minor allele frequency 0.02-0.73%), with 10 unique to East Asians. Five previously reported RMVs, such as the Christchurch RMV, were absent in Japanese individuals. Two RMVs (rs140808909 and rs190853081), which exhibit complete linkage disequilibrium, were found to have protective effects against AD:  = 4.28E-02, OR (95% CI) = 0.70 (0.54-0.92). No significant differences in cholesterol levels were observed between RMV carriers and non-carriers.ConclusionsThe two RMVs identified in Japanese individuals may have exhibited potential protective effects against AD. Further large-scale studies are needed to confirm these findings and to explore their roles in AD and lipid metabolism.