APOE rare missense variants in Japan
Open accessAbstract
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.
AI snapshot
Written from the paper’s full text.
TL;DR
This conference abstract reports a survey of *APOE* rare missense variants (RMVs) in a healthy Japanese cohort, motivated by Caucasian findings such as the Christchurch (p.R136S) and Jacksonville (p.V236E) variants. It identifies 14 RMVs, four of them absent from major reference databases, and concludes that some *APOE* RMVs may be unique to the Japanese population.
Key findings
- 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 previously reported ones.
- Four RMVs were "very rare," not found in the 1000 Genomes or gnomAD exomes/genomes databases.
- The 13 RMVs were inferred to have the wild-type allele, ε3, as their background.
Methods
- *APOE* variant data were obtained from 3,307 healthy Japanese community residents (1,810 females, 1,497 males; mean age 55.9 years, SD 14.1) over 20 years old, via the Tohoku Medical Megabank Organization (ToMMo).
- Rare variants with amino acid substitutions were selected from these data.
- Ensembl Human (GRCh38.p14) was searched for allelic frequency data of the identified RMVs by population, and the association with the *APOE* common alleles ε2, ε3, and ε4 was investigated in the background of RMV carriers.
Limitations
- Not stated in the paper. The text makes evident that this is a one-page conference abstract with no figures or tables, based on a single healthy-resident cohort rather than an AD case–control sample, with no functional or disease-association analysis of the newly found variants; the authors state that future work will expand to tens of thousands of individuals and examine effects on amyloid beta and tau metabolism.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
- Findingown data§ Method
A total of 176 variants were identified in and around APOE in an approximately 7.2 kb genomic region in the ToMMo cohort.
“A total of 176 variants were identified in and around APOE in an approximately 7.2 kb genomic region in the ToMMo cohort.”
Quote in the paperSubstantial claim - Interpretationnone given§ Method
The 13 RMVs were inferred to be under the wild-type allele, e3, as background.
“The 13 RMVs were inferred to be under the wild‐type allele, e3, as background.”
Quote in the paperNot a substantial claim - Interpretationown data§ Conclusion
There are RMVs of APOE that are unique to the Japanese population.
“Through this survey, it became clear that there are RMVs of APOE that are unique to the Japanese population.”
Quote in the paperSubstantial claim
- May combine two claims. 2
May combine two claims.
Findingown data§ MethodFour RMVs were found to be very rare, which were not found in the 1000 Genomes or gnomAD exomes/genomes databases.
“Four RMVs were found to be very rare, which were not found in the 1000 Genomes or gnomAD exomes/genomes databases.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ MethodOf the 176 variants identified in and around APOE in the ToMMo cohort, 14 were rare missense variants (RMVs), including those previously reported.
“Of these, 14 were RMVs, including those previously reported.”
Quote in the paperSubstantial claim
The paper relies on this without support.
APOE is the most influential susceptibility gene for Alzheimer's disease.
“APOE is well recognized to be the most influential susceptibility gene for Alzheimer’s disease (AD).”
The paper relies on this without support.
Genetic analyses with Caucasians have reported critical associations between APOE rare missense variants and Alzheimer's disease.
“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.”
The paper relies on this without support.
There have been no analyses or reports of APOE rare missense variants in East Asians, including Japanese.
“Since there have been no such analyses or reports yet in East Asians, including Japanese, we designed this study.”
Cites
Still being checked.
Cited by
Still being checked.
- Authors
- Miyashita, A., Hara, N., Obinata, A., Tsukie, T., Hasegawa, M., Kikuchi, M., Kasuga, K., & Ikeuchi, T.
- Affiliations
- Brain Research Institute, Niigata University (JP)
- The University of Tokyo (JP)
- Corresponding author
- Miyashita, Akinori
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2024-12
- Volume
- 20
- Issue
- S1
- Pages
- e088676-e088676
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC11710591
- OpenAlex
- W4406024132
- Semantic Scholar
- 1b73d277f854920e41f7397a9e8824d4c954bb23
- Cited by
- 0
- References
- 0
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E, rare missense variants
- MeSH terms
- Adult, Aged, Alzheimer Disease, Apolipoproteins E, Female, Humans, Japan, Male, Middle Aged, Genetic Predisposition to Disease, Mutation, Missense, Asian People
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-01.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-01.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
