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

Abstract

BackgroundLittle is known about the rare missense variants (RMVs) of APOE in East Asians, including the Japanese, and their association with Alzheimer's disease (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.MethodsAPOE 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. APOE RMV frequencies in the Japanese population were compared with various ethnic populations. Associations between APOE 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: p_Bonferroni = 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 APOE 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.

Keywords: APOE; Alzheimer's disease; Japanese; cholesterol; lipid; rare missense variants.

Figure 1.

Case-control study on APOE RMVs identified. Of the 14 APOE RMVs identified in this study, four imputed variants were included in the analysis. Two RMVs, rs140808909 and rs190853081, which were in complete LD (Supplemental Figure 2) and define the ε7 allele, remained statistically significant after multiple comparison corrections in Models 1, 2, and 4. The OR was less than 1.0, suggesting a protective effect against AD. However, after adjusting for the ε4 allele in Models 3 and 5, the significant association of the ε7 allele disappeared. This suggests that the ε7 allele is not independent of the ε4 allele but rather is a dependent allele. The detailed numerical data are presented in Table 4. Bold text denotes that the 95% CI of the OR does not contain 1.00.

Figure 2.

Case-control study on common APOE genotypes and alleles in carriers with APOE RMVs identified. For the four APOE RMVs analyzed in the case-control study (Table 4, Figure 1), we conducted a case-control analysis focusing on subjects carrying alternative alleles, examining common APOE genotypes (A) and alleles (B). Forest plots showing OR and 95% CI are provided. For genotypes (A), the OR (95% CI) of ε3*4 relative to ε3*3 was calculated. For alleles (B), the OR (95% CI) of the ε4 allele relative to the ε3 allele was calculated. Bold text denotes that the 95% CI of the OR does not contain 1.00. “All” indicates the OR and its 95% CI for all subjects (6261 AD cases and 16,331 controls) as presented in Table 3. Importantly, both the ε5 (rs121918392) and ε7 alleles (rs140808909-rs190853081) tended to attenuate the AD risk conferred by the ε4 allele slightly. Ref: reference.

Figure 3.

APOE RMVs identified in this study. The 14 APOE RMVs identified in this study were added to the Alzforum MUTATIONS APOE diagram (https://www.alzforum.org/mutations/apoe). RMVs identified in both ToMMo and NIG cohorts are marked in red, whereas those identified only in ToMMo are marked in magenta. The five RMVs previously reported are labeled with the letters “a” to “e”. The ε7 allele, which is the primary focus of this paper, is defined by two RMVs that replace two glutamic acid (Glu, E) residues with lysine (Lys, K) at the entrance of the lipid-binding domain (colors are visible in the online version).