Association of rare APOE missense variants with Alzheimer's disease in the Japanese population

BackgroundAPOE is a major susceptibility gene for Alzheimers disease (AD). Recent studies in Europe and the US have identified rare missense variants (RMVs) in APOE which are significantly associated with AD. However, little is known regarding APOE RMVs in East Asians, including the Japanese, and their association with AD and lipid metabolism. ObjectiveTo identify APOE RMVs in the Japanese population and investigate their association with AD and lipid metabolism, including low-density lipoprotein cholesterol levels. SubjectsAPOE RMVs were explored in the NIG (2,589 subjects) and ToMMo (3,307 subjects) cohorts. A case-control study was performed involving 6,471 AD and 20,270 control subjects. MethodsSanger sequencing or whole-exome sequencing was performed on NIG subjects. We used genotype data from ToMMo. APOE RMV frequencies in the Japanese were compared with various ethnic populations. Associations among APOE RMV genotypes, AD, and lipoproteins were examined. ResultsFourteen RMVs were identified (minor allele frequency 0.02 - 0.73%), 10 of which were specifically found in East Asians. Five RMVs previously reported overseas were not detected in Japanese individuals. Two RMVs (rs140808909 and rs190853081) exhibiting complete linkage disequilibrium were associated with AD protective effects: PBonferroni = 3.63E-02, OR (95% CI) = 0.70 (0.54-0.92). No significant differences in cholesterol levels were observed between RMV carriers and non-carriers. ConclusionsAPOE RMVs were identified in the Japanese population, with two showing potential protective effects against AD. Further studies involving larger cohorts are required to confirm our findings and investigate the role of APOE RMVs in AD and lipid metabolism.