Basic Science and Pathogenesis.

Background: APOE is well recognized to be the most influential susceptibility gene for Alzheimer's disease (AD). For the wild-type allele, e3, it is known that the e4 allele is a risk for AD, while the e2 allele is protective. Recently, genetic analyses with Caucasians have reported the critical associations between APOE rare missense variants (RMVs) and AD, and their importance has been pointed out in terms of disease pathogenesis of AD. For example, the Christchurch (rs121918393, p.R136S [CGC > AGC]) and the Jacksonville (rs199768005, p.V236E [GTG > GAG]) variants can be mentioned. Since there have been no such analyses or reports yet in East Asians, including Japanese, we designed this study.

Objective: To identify APOE RMVs in a Japanese population.

Method: Through the Tohoku Medical Megabank Organization (ToMMo) with a cohort of healthy Japanese community residents, APOE variant data were obtained from 3,307 subjects (1,810 females, and 1,497 males; mean age 55.9 years [standard deviation 14.1]) over 20 years old. Rare variants with amino acid substitutions were selected from them. The human genome database, Ensemble Human (GRCh38.p14), was searched to obtain the allelic frequency data of identified RMVs by populations. We also investigated the association with APOE common alleles, e2, e3, and e4, in the background of RMV carriers.

Result: A total of 176 variants were identified in and around APOE in an approximately 7.2 kb genomic region in the ToMMo cohort. Of these, 14 were RMVs, including those previously reported. Four RMVs were found to be very rare, which were not found in the 1000 Genomes or gnomAD exomes/genomes databases. The 13 RMVs were inferred to be under the wild-type allele, e3, as background.

Conclusion: Through this survey, it became clear that there are RMVs of APOE that are unique to the Japanese population. In the future, we will expand the analysis to a discovery project on a scale of tens of thousands of individuals, including our subjects (n = approx. 2,500) collected so far. For the newly discovered RMVs, we plan to investigate their effects on the metabolism of amyloid beta and tau proteins in relation to AD.