CoChat
Sign Up
Cited by 67Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Genetics of Alzheimer’s disease: An East Asian perspective

Open access
Miyashita, Akinori, Kikuchi, Masataka, Hara, Norikazu, Ikeuchi, Takeshi·2023·Journal of Human Genetics
DOI 10.1038/s10038-022-01050-zPMC PMC9968656
Open this paper in CoChat — free accountOpen PDF

Abstract

Alzheimer's disease (AD) is an age-related multifactorial neurodegenerative disorder. Advances in genome technology, including next generation sequencing have uncovered complex genetic effects in AD by analyzing both common and rare functional variants. Multiple lines of evidence suggest that the pathogenesis of AD is influenced by multiple genetic components rather than single genetic factor. Previous genetic studies on AD have predominantly included European ancestry cohorts; hence, the non-European population may be underrepresented, potentially leading to reduced diversity in AD genetic research. Additionally, ethnic diversity may result in dissimilar effects of genetic determinants in AD. APOE genotypes are a well-established genetic risk factor in AD, with the East Asian population having a higher risk of AD associated with the APOE ε4 allele. To date, seven genome-wide association studies (GWAS) have been conducted in East Asians, which report a total of 26 AD-associated loci. Several rare variants, including the p.H157Y variant in TREM2, and the p.G186R and p.R274W variants in SHARPIN are associated with risk of AD in East Asians. Extending genetic studies to diverse populations, including East Asians is necessary, which could yield more comprehensive insights into AD, and here we review the recent findings regarding the genetic determinants of AD from an East Asian perspective.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes Alzheimer’s disease (AD) genetics from an East Asian perspective, highlighting higher APOE ε4 risk in East Asians, seven East Asian GWAS reporting 26 AD-associated loci, and rare variants such as TREM2 p.H157Y and SHARPIN p.G186R/p.R274W. It argues that extending genetic studies beyond European-ancestry cohorts is necessary for more comprehensive AD insights.

Key findings

  • APOE ε4 confers a higher AD risk in East Asians than in Europeans; in Japanese cohorts, ε3*4 odds ratios ranged from 3.9 (1.9–8.0) to 5.6 (3.9–8.0), and ε4*4 from 21.8 (8.6–55.3) to 33.1 (13.6–80.5), compared with lower estimates in African American and Hispanic populations.
  • Seven GWAS conducted in East Asians (Japan, China, South Korea) have identified 26 AD-associated loci; however, none of these GWAS identified the same loci outside the APOE region, even within the same country.
  • Rare variants associated with AD in East Asians include TREM2 p.H157Y (Chinese association P = 0.005, OR = 11.01, 95% CI 1.38–88.05) and SHARPIN p.G186R (Japanese P = 0.000012, OR = 6.1, 95% CI 2.4–15.5) and p.R274W (Japanese P = 0.0016, OR = 1.43, 95% CI 1.15–1.78).
  • APOE Christchurch and Jacksonville variants are protective in Caucasians, but the paper notes they are not listed in the Japanese Tohoku Medical Megabank database, suggesting they may be Caucasian-specific and that additional East Asian APOE rare variants must be explored.

Methods

  • Narrative review of AD genetics from an East Asian perspective, synthesizing published findings on APOE genotypes, GWAS, and rare variants.
  • Data summarized include seven East Asian GWAS from Japan, China, and South Korea; APOE genotype meta-analyses across populations; rare variant association studies; and variant annotations from ClinVar and gnomAD.
  • Main analysis is descriptive synthesis with summary tables of APOE genotype odds ratios, East Asian GWAS loci, and rare AD-associated variants; no new primary data or systematic search is reported.

Limitations

  • The paper states that East Asian GWAS are relatively smaller than large Caucasian GWAS and may have insufficient statistical power, and that integrated analysis of multiple cohorts from neighboring countries could help resolve this.
  • The paper notes that no GWAS outside APOE identified the same loci even within the same country, possibly due to differences in genetic background among East Asian populations.
  • Evident from the text: as a narrative review, it does not describe a systematic literature search or formal quality appraisal, and it focuses on East Asian populations rather than providing a global systematic synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s10038-022-01050-z

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

52 of 78 cited sources checked · 25 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    Shigemizu et al. identified rs920608 on FAM47E and SCARB2 in a replication cohort.

    “They identified 134 markers located in nine genes that satisfied the significance level in the discovery cohort, and their evaluation in the replication cohort revealed the presence of rs920608 on FAM47E and SCARB2.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [24] Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One. 2013;8:e58618. source

      The Results (page unavailable) say that modest evidence for replication was observed only for SORL1 SNP rs4598682, not rs920608 on FAM47E or SCARB2. The paper’s account of its replication results therefore conflicts with the result attributed to it. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [27] Shigemizu D, Mitsumori R, Akiyama S, Miyashita A, Morizono T, Higaki S, et al. Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk. Transl Psychiatry. 2021;11:151. source

      The Results sections on the Japanese GWAS and replication study report 134 markers in nine genes with suggestive associations and a replication association for rs920608 at the FAM47E locus (Table 1; page not provided). The expression-QTL Results link rs920608 to SCARB2 expression, but do not place the SNP on SCARB2. The claim conflates that expression link with the SNP’s location. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    The APOE ε4 allele is associated with approximately 4-fold higher risk of Alzheimer's disease in clinically diagnosed subjects.

    “The APOE ε4 allele is associated with an approximately 4-fold higher risk in clinically diagnosed subjects”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020;11:667. source
  • Premisecitation

    The risk associated with the APOE ε4 allele rises to 6-fold in patients with neuropathological confirmation of Alzheimer's disease.

    “and this risk rises to 6-fold in patients with neuropathological confirmation [10]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020;11:667. source
  • Premisecitation

    The East Asian population has a higher risk of Alzheimer's disease associated with the APOE ε4 allele.

    “with the East Asian population having a higher risk of AD associated with the APOE ε4 allele”
    • Also stated in: § Larger effects of APOE ε4 in East Asians · plain
      “while the effect of APOE ε4 is weaker in African American and Hispanic populations, its effect is higher in East Asian populations, including the Japanese (Table 1) [11]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [11] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349–56. source
    • cites [17] Choi KY, Lee JJ, Gunasekaran TI, Kang S, Lee W, Jeong J, et al. APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample. J Clin Med. 2019;8:1236. source
  • Premisecitation

    APOE genotypes are a well-established genetic risk factor for Alzheimer's disease.

    “APOE genotypes are a well-established genetic risk factor in AD”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 2019;101:820–38. source
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    Several SNPs identified in APOE ε4 noncarriers were not common and had a much smaller effect size than SNPs in the APOE region.

    “In contrast, several SNPs been identified in ε4 noncarriers, but they were not common, and they had a much smaller effect size than SNPs in the APOE region”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [26] Hirano A, Ohara T, Takahashi A, Aoki M, Fuyuno Y, et al. A genome-wide association study of late-onset Alzheimer’s disease in a Japanese population. Psychiatr Genet. 2015;25:139–46. source
    • cites [31] Kang S, Gim J, Lee J, Gunasekaran TI, Choi KY, Lee JJ, et al. Potential novel genes for late-onset Alzheimer’s disease in East-Asian descent identified by APOE-stratified genome-wide association study. J Alzheimers Dis. 2021;82:1451–60. source

      The Results (Genome-wide inference for AD status; page unavailable) identify SNPs in APOE ε4 noncarriers and report odds ratios smaller than those listed for APOE-region SNPs in Table 2. But the Discussion (page unavailable) explicitly calls the study’s top findings “common variants,” contrary to the claim that they were not common. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The frequency of rs405509 genotypes in the APOE promoter differs between East Asian and European populations, with the T/T genotype significantly more frequent in East Asians.

    “The frequency of the rs405509 genotypes in the promoter region of APOE are different between East Asian and European populations with the frequency of the T/T genotype being significantly higher in East Asians.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Choi KY, Lee JJ, Gunasekaran TI, Kang S, Lee W, Jeong J, et al. APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample. J Clin Med. 2019;8:1236. source

      Results §3.2 reports that the rs405509 T allele is more frequent in East Asians than in people of European ancestry (0.739 versus 0.528), and the Discussion describes large differences in rs405509 genotype frequencies across ethnic groups. Our copy does not specifically report a statistical comparison showing that the T/T genotype is significantly more frequent in East Asians. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Park et al. identified rs1890078 located 54 kb upstream of SORCS1 and rs12594991 located in the intron of CHD2 in APOE ε4 carriers.

    “Two SNPs were identified in this analysis: rs1890078, located 54 kb upstream of SORCS1, and rs12594991, located in the intron of CHD2.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [30] Park JH, Park I, Youm EM, Lee S, Park JH, Lee J, et al. Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE e4 carriers. Transl Psychiatry. 2021;11:296. source

      The Results section, “Novel variants associated with AD in APOE ε4 carriers” (page unavailable), identifies both SNPs in APOE ε4 carriers and places rs12594991 in a CHD2 intron. It describes rs1890078 as intergenic between SORCS1 and LINC01435, but does not establish that it is 54 kb upstream of SORCS1. The approximately 55 kb distance reported elsewhere in Results is between rs1890078 and a different SNP. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    SNPs in SORL1 have also been identified as susceptibility loci in European populations and in a transethnic meta-analysis including South Korean and Caucasian cohorts.

    “Importantly, SNPs in SORL1 have also been identified as susceptibility loci in European populations [7, 25], and in a transethnic meta-analysis that included South Korean and Caucasian cohorts.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [7] Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease. Nat Genet. 2021;53:1276–82. source
    • cites [25] Reitz C, Rogaeva E, Lee JH, Tokuhiro S, Bettens K, Zou F, et al. Association of SORL1 gene variants with Alzheimer’s disease: A meta-analysis. Arch Neurol. 2011;68:99–106. source

  • May combine two claims.

    Premisecitation

    The first genome-wide association study for Alzheimer's disease in East Asia was reported from Japan in 2013 and identified 6 SNPs outside the APOE region.

    “The first GWAS for AD in East Asia was reported from Japan in 2013. This study included a discovery cohort of 1008 AD patients and 1016 healthy subjects, and identified 6 SNPs outside the APOE region [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One. 2013;8:e58618. source

      Methods > Subjects (page unavailable) gives the Japanese discovery cohort as 1,008 AD cases and 1,016 controls. Results > Table 2 (page unavailable) lists six top-ranked SNPs outside the APOE region, but the Abstract says seven SNPs from other regions were tested in a second Japanese sample and association was confirmed for only one. The copy does not establish that this was the first AD GWAS in East Asia. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Jia et al. identified 34 candidate SNPs that were validated in a replication cohort.

    “Jia et al. analyzed 1595 AD patients and 2474 healthy subjects, and identified 34 candidate SNPs [29], that were validated in a replication cohort of 2234 AD patients and 7319 healthy subjects.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Jia L, Li F, Wei C, Zhu M, Qu Q, Qin W, et al. Prediction of Alzheimer’s disease using multi-variants from a Chinese genome-wide association study. Brain. 2021;144:924–37. source

      The Results section ('Results from genome-wide association studies'; page unavailable) says 34 candidate SNPs were selected for testing in an independent Chinese cohort, but only 13 passed the replication significance threshold. It reports 1,679 patients and 2,508 controls in the first stage, and 2,234 patients and 5,085 controls in the second—not the control counts in the citing sentence. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A stratified analysis of APOE ε4 carriers and noncarriers yielded no significant SNPs in ε4 carriers, but found rs189753894 located upstream of 7 kb from CACNA1A and rs2280575 present in the intron of LRIG1 in ε4 noncarriers.

    “Next, a stratified analysis of APOE ε4 carriers and noncarriers yielded no significant SNPs in ε4 carriers, but rs189753894, located upstream of 7 kb from CACNA1A, and rs2280575, present in the intron of LRIG1, were found in ε4 noncarriers.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Kang S, Gim J, Lee J, Gunasekaran TI, Choi KY, Lee JJ, et al. Potential novel genes for late-onset Alzheimer’s disease in East-Asian descent identified by APOE-stratified genome-wide association study. J Alzheimers Dis. 2021;82:1451–60. source

      The Results section (‘Genome-wide inference for AD status’; page unavailable) identifies rs189753894 near CACNA1A and rs2280575 in LRIG1 as lead SNPs in APOE ε4 noncarriers. But it also reports 219 statistically significant variants in ε4 carriers, so the unqualified claim that carriers had no significant SNPs is inaccurate. The passages do not establish the stated 7-kb upstream location or confirm that rs2280575 is intronic. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The most recent genome-wide association study for Alzheimer's disease in a European population included 1,126,563 individuals and identified 38 susceptibility loci.

    “The most recent GWAS for AD was performed in a European population, including 1,126,563 individuals and identified 38 susceptibility loci [7].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease. Nat Genet. 2021;53:1276–82. source

  • May combine two claims.

    Premisecitation

    The APOEJax variant inhibits self-aggregation of ApoE, which may in turn inhibit the accumulation of amyloid-β.

    “Additionally, biochemical analysis showed that APOEJax variant inhibited self-aggregation of ApoE, which may in turn inhibit the accumulation of Aβ.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Liu CC, Murray ME, Li X, Zhao N, Wang N, Heckman MG, et al. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci Transl Med. 2021;13:eabc9375. source

  • May combine two claims.

    Premisecitation

    The APOE Christchurch variant rs121918393 and the APOE Jacksonville variant rs199768005 are protective against Alzheimer's disease in Caucasians.

    “The Christchurch variant rs121918393 (APOEChc: CGC > aGC, p.Arg[R]136Ser[S]) [19–21] and the Jacksonville variant rs199768005 (APOEJax: GTG > GaG, p.Val[V]236Glu[E]) [22, 23] have been identified as protective variants against AD in Caucasians”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [19] Wardell MR, Brennan SO, Janus ED, Fraser R, Carrell RW. Apolipoprotein E2-Christchurch (136 Arg–Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J Clin Invest. 1987;80:483–90. source

      The Discussion identifies APOE2-Christchurch as an Arg136Ser variant arising from a CGC-to-AGC substitution. The cited paper studies type III hyperlipoproteinemia, not protection against Alzheimer’s disease in Caucasians; it also does not give the rs identifier. This citation is attached to the Christchurch variant, not the separately cited Jacksonville variant. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [20] Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Marino C, Chmielewska N, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25:1680–3. source

      The Abstract reports that a Colombian PSEN1 mutation carrier homozygous for APOE3 Christchurch developed cognitive impairment nearly three decades later than expected, supporting a potentially protective effect in that case. It does not establish protection in Caucasians generally. The Jacksonville variant is attached to different citations in the citing sentence and is not assessed against this source. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [21] Zalocusky KA, Nelson MR, Huang Y. An Alzheimer’s-disease-protective APOE mutation. Nat Med. 2019;25:1648–9. source
    • cites [22] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener. 2014;9:11. source
    • cites [23] Liu CC, Murray ME, Li X, Zhao N, Wang N, Heckman MG, et al. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci Transl Med. 2021;13:eabc9375. source

      The citation to this paper is attached to the Jacksonville variant, not the Christchurch variant. The Results report that APOE3-Jacksonville (V236E) is associated with reduced Alzheimer’s disease risk, but Genetic Analysis identifies its SNP as rs199768002, not the cited rs199768005. The paper does not establish the claim specifically for Caucasians; its mention of Caucasian populations in the Introduction concerns a different, APP variant. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Individuals carrying the PSEN1 p.E280A mutation typically develop mild cognitive impairment at a median age of 44 years and dementia at a median age of 49 years.

    “Individuals carrying the PSEN1 p.E280A mutation typically develop mild cognitive impairment at a median age of 44 years (95% confidence interval [CI]: 43‒45 years) and dementia at a median age of 49 years (95% CI: 49‒50 years).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [20] Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Marino C, Chmielewska N, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25:1680–3. source
    • cites [21] Zalocusky KA, Nelson MR, Huang Y. An Alzheimer’s-disease-protective APOE mutation. Nat Med. 2019;25:1648–9. source

  • May combine two claims.

    Premisecitation

    Park et al. also identified nine suggestive variants, including two SNPs located around SORCS1 that were present only in APOE ε4 carriers.

    “The authors also analyzed samples from 874 AD patients and 1063 healthy subjects, including the APOE ε4 carriers described above, and identified nine suggestive variants. These included two SNPs located around SORCS1, which were present only in ε4 carriers.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [30] Park JH, Park I, Youm EM, Lee S, Park JH, Lee J, et al. Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE e4 carriers. Transl Psychiatry. 2021;11:296. source

      The Results section on the cAD chip application set reports nine AD-associated SNPs, including two intergenic SNPs between SORCS1 and LINC01435. But the same section says the association of those two SNPs with AD was observed regardless of APOE ε4 status, not only in carriers. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The two SNPs rs189753894 and rs2280575 had the same directionality of effect in both South Korean and Japanese cohorts and satisfied a significance level of P < 5e-8 during a meta-analysis.

    “Interestingly, these two SNPs had the same directionality of effect in both South Korean and Japanese cohorts and satisfied a significance level of P < 5e-8 during a meta-analysis.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Kang S, Gim J, Lee J, Gunasekaran TI, Choi KY, Lee JJ, et al. Potential novel genes for late-onset Alzheimer’s disease in East-Asian descent identified by APOE-stratified genome-wide association study. J Alzheimers Dis. 2021;82:1451–60. source

      The Results section, “Genome-wide inference for AD status” (page unavailable), identifies rs189753894 and rs2280575 and says they were selected after considering effect direction in the Korean discovery and Japanese replication datasets. It also reports a meta-analysis, but the available passage does not give meta-analysis P values for these SNPs, so it does not establish that both met P < 5×10⁻⁸. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    To date, thousands of Chinese and Japanese have been screened for the TREM2 p.R47H variant, and only three Japanese carriers have been reported.

    “To date, thousands of Chinese and Japanese have been screened for p.R47H variant, and only three Japanese carriers of this variant have been reported (Table 4) [38–42].”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [38] Yu J-T, Jiang T, Wang Y-L, Wang H-F, Zhang W, Hu N, et al. Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer’s disease in Han Chinese individuals. Neurobiol Aging. 2014;35:937.e1–3. source
    • cites [39] Jiao B, Liu X, Tang B, Hou L, Zhou L, Zhang F, et al. Investigation of TREM2, PLD3, and UNC5C variants in patients with Alzheimer’s disease from mainland China. Neurobiol Aging. 2014;35:2422.e9–2422.e11. source
    • cites [40] Jiang T, Tan L, Chen Q, Tan M-S, Zhou J-S, Zhu X-C, et al. A rare coding variant in TREM2 increases risk for Alzheimer’s disease in Han Chinese. Neurobiol Aging. 2016;42:e1–3. source
    • cites [41] Bonham LW, Sirkis DW, Fan J, Aparicio RE, Tse M, Ramos EM, et al. Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer’s disease. Neurocase. 2017;23:65–9. source

      The Introduction says the R47H finding had not been replicated in East Asian populations and cites Chinese and Japanese studies. It does not state that thousands of people were screened or that exactly three Japanese carriers were reported. No page number is available in our copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [42] Miyashita A, Wen Y, Kitamura N, Matsubara E, Kawarabayashi T, Shoji M, et al. Lack of genetic association between TREM2 and late-onset Alzheimer’s disease in a Japanese population. J Alzheimers Dis. 2014;41:1031–8. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent work suggests that genetic contributions to AD may be oligogenic, influenced by a limited set of common genetic variants.

    “Recent work suggests that genetic contributions to AD may be oligogenic, i.e., influenced by a limited set of common genetic variants [50].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] Zhang Q, Sidorenko J, Couvy-Duchesne B, Marioni RE, Wright MJ, Goate AM, et al. Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture. Nat Commun. 2020;11:4799. source

      The Discussion concludes that the data are consistent with an oligogenic common-variant architecture of late-onset Alzheimer’s disease (LOAD). The citing sentence extends that suggestion to AD generally; the paper does not establish the same architecture for all forms of AD. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    To date, seven genome-wide association studies have been conducted in East Asians.

    “To date, seven genome-wide association studies (GWAS) have been conducted in East Asians”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Currently, 37 variations of APOE are listed in ClinVar, including rs429358 and rs7412, as well as APOEChc and APOEJax.

    “Currently, 37 variations are listed, including rs429358 and rs7412, which determine the three alleles ε2, ε3, and ε4, as well as APOEChc (rs121918393) and APOEJax (rs199768005).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Six APOE variants are found only in East Asians including Japanese, but none have been described in relation to Alzheimer's disease.

    “Six variants are found only in East Asians including in the Japanese (rs121918392, rs587778876, rs121918397, rs267606663, rs140808909, and rs190853081); however, none of these have been described in relation to AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The APOEChc and APOEJax variants are not listed in the Japanese Tohoku Medical Megabank database and may be seen only in Caucasians.

    “Importantly, these variants are not listed in the Japanese database of the Tohoku Medical Megabank, and it is possible that these are seen only in Caucasian.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Many listed APOE missense variants are associated with dyslipidemia and atherosclerosis, and only three are relevant to Alzheimer's disease.

    “Many of listed variants are associated with dyslipidemia and atherosclerosis, and only three are relevant to AD (Variation ID: 242765 [rs769452], 17864 [rs429358], 694585 [rs429358 - rs121918393]).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    rs189753894 near CACNA1A had a minor allele frequency of 0.3598 in East Asian populations and 0.02503 in the European population.

    “For example, rs189753894 near CACNA1A, found in APOE ε4 noncarriers in the South Korean population, had an MAF of 0.3598 in East Asian populations, while the MAF in the European population was 0.02503.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Rare variants p.H157Y in TREM2, and p.G186R and p.R274W in SHARPIN, are associated with risk of Alzheimer's disease in East Asians.

    “Several rare variants, including the p.H157Y variant in TREM2, and the p.G186R and p.R274W variants in SHARPIN are associated with risk of AD in East Asians.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Rare variants may exist in an ethnicity-dependent manner and exhibit mutually exclusive behavior, where a rare variant seen in one ethnic group may not be found in other ethnic groups.

    “Notably, these findings raise the notion that rare variants may exist in an ethnicity dependent manner, and that they seem to exhibit a mutually exclusive behavior, i.e., wherein one rare variant seen in an ethnic group may not be found in other ethnic groups.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Alternatively, rare variants might be subject to selection pressure that could be detrimental to human survival, making it harder for them to spread between populations.

    “Alternatively, rare variants might be subjected to a selection pressure that could be detrimental to human survival, making it harder for them to spread from one population to another.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The APP p.A673T variant (rs63750847) was identified in Icelanders and shown to have a strong protective effect against age-related cognitive decline and AD.

    “This observation is also true for the rare variant p.A673T (rs63750847) in APP, which was identified in Icelanders and was shown to have a strong protective effect against age-related cognitive decline as well as AD [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488:96–9. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    A probable reason for ethnicity-dependent rare variants is that not enough time has passed since these rare variants arose and they are yet to spread to other populations.

    “This is probably because not enough time has passed since these rare variants arose and they are yet to spread to other populations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Large effect size is characteristic of functional rare variants, in contrast to common variants with small effect size.

    “Crucially, such a large effect size is characteristic of functional rare variants, which is in contrast to common variants with a small effect size.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Differences in genetic background among East Asian populations may explain the inconsistent results of the GWASs.

    “One reason for these inconsistent results may be differences in the genetic background among East Asian populations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    SHARPIN p.G186R and p.R274W are relatively frequent in East Asians but have yet to be verified in other ethnic groups.

    “Thus, these two are examples of rare variants that are relatively frequent in East Asians (Table 4), but have yet to be verified in other ethnic groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The APP p.A673T variant was observed in control subjects aged over 85 years at a frequency of 0.45%, higher than in AD patients.

    “The p.A673T variant was observed in control subjects aged over 85 years at a frequency of 0.45%, which is higher than that seen in AD patients [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488:96–9. source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Genetic diversity among various ethnic groups can affect disease risk, treatment efficacy, and safety.

    “It has also become apparent that genetic diversity among the various ethnic groups can affect disease risk, treatment efficacy, and safety.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Due to their rarity, genetic analysis of thousands of samples will be required to confirm significant differences for rare variants.

    “Crucially, due to their rarity, genetic analysis of thousands of samples will be required to confirm significant differences.”
    Quote in the paperSubstantial claim
32 of 32

  • The paper relies on this without support.

    Previous genetic studies of Alzheimer's disease have been largely conducted in European ancestry cohorts, with underrepresentation of non-European populations.

    “Previous genetic studies of AD have been largely conducted in European ancestry cohorts with potential underrepresentation of non-European populations, leading to a lack of ethnic diversity in genetic research on AD.”

  • The paper relies on this without support.

    Ethnic diversity may result in dissimilar effects of genetic determinants in Alzheimer's disease.

    “Additionally, ethnic diversity may result in dissimilar effects of genetic determinants in AD.”

  • The paper relies on this without support.

    Diverse genetic architectures among different ethnic groups may differentially influence how genetic factors contribute to the pathogenesis of Alzheimer's disease.

    “Diverse genetic architectures among different ethnic groups may differentially influence how these genetic factors contribute to the pathogenesis of AD.”

  • The paper relies on this without support.

    Alzheimer's disease can be influenced by vascular disorders that may be caused by disruption of lipid metabolism.

    “As AD can be influenced by vascular disorders that may be caused by disruption of lipid metabolism, it is important to assign biological significance to missense variants of APOE.”

  • The paper relies on this without support.

    The East Asian GWASs discussed are relatively smaller than large Caucasian GWASs and may have insufficient statistical power.

    “Furthermore, there are concerns that because these GWAS are relatively smaller compared to the large GWAS in Caucasians, there may be insufficient statistical power.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • APOE ε4-carrier GWAS result contradicts the reported locus

    Major

    The text says the meta-analysis of APOE ε4 carriers yielded no significant AD-associated SNPs, but the preceding sentence identifies rs11613092 from the stratified analysis and Table 3 lists it under APOE ε4 carriers. These accounts disagree about whether a carrier-associated SNP was found.

  • MAF differences use the opposite subtraction order from the table note

    Minor

    The note specifies European MAF minus East Asian MAF. For rs4598682, that would be 0.01884 − 0.192, a negative value, whereas the table reports a positive difference of 0.173. The reported sign instead follows East Asian minus European MAF.

2 of 2

Cites

Flagged first, then by citations

3 of the 53 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Miyashita, A., Kikuchi, M., Hara, N., & Ikeuchi, T.
Affiliations
  • Brain Research Institute, Niigata University (JP)
  • The University of Tokyo (JP)
Corresponding author
Ikeuchi, Takeshi
ORCID
Venue
Journal of Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-06-01
Volume
68
Issue
3
Pages
115-124
ISSN
  • 1434-5161 (ISSN-L)
  • 1435-232X
DOI
10.1038/s10038-022-01050-z
PMC
PMC9968656
OpenAlex
W4281622672
Semantic Scholar
7696cad7759f175605f279e5cfed23cd45adfe46
Cited by
64
References
53
Citations by year
2026: 16 · 2025: 17 · 2024: 20 · 2023: 11
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Human Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Japan Agency for Medical Research and Development (JP22wm0525019, JP22dk0207060, JP21dk0207045)
  • MEXT | Japan Society for the Promotion of Science (21K07271, 21H03537)
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
Alzheimer's disease, genetic risk factors, East Asian populations, APOE ε4, TREM2, SHARPIN, rare variants, genome-wide association study, neurodegeneration
MeSH terms
East Asian People, Alzheimer Disease, Genotype, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

Cited sources are checked by gpt-6-sol.

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