Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 27;16(1):45.
doi: 10.1186/s13195-024-01414-x.

Polygenic effects on the risk of Alzheimer's disease in the Japanese population

Masataka Kikuchi  1   2 , Akinori Miyashita  3 , Norikazu Hara  3 , Kensaku Kasuga  3 , Yuko Saito  4 , Shigeo Murayama  4   5 , Akiyoshi Kakita  6 , Hiroyasu Akatsu  7 , Kouichi Ozaki  8   9 , Shumpei Niida  10 , Ryozo Kuwano  11 , Takeshi Iwatsubo  12 , Akihiro Nakaya  13 , Takeshi Ikeuchi  14 ; Alzheimer’s Disease Neuroimaging Initiative; Japanese Alzheimer’s Disease Neuroimaging Initiative
Collaborators, Affiliations

Polygenic effects on the risk of Alzheimer's disease in the Japanese population

Masataka Kikuchi et al. Alzheimers Res Ther. .

Erratum in

  • Correction: Polygenic effects on the risk of Alzheimer's disease in the Japanese population.
    Kikuchi M, Miyashita A, Hara N, Kasuga K, Saito Y, Murayama S, Kakita A, Akatsu H, Ozaki K, Niida S, Kuwano R, Iwatsubo T, Nakaya A, Ikeuchi T; Alzheimer’s Disease Neuroimaging Initiative; Japanese Alzheimer’s Disease Neuroimaging Initiative. Kikuchi M, et al. Alzheimers Res Ther. 2024 Jul 10;16(1):158. doi: 10.1186/s13195-024-01514-8. Alzheimers Res Ther. 2024. PMID: 38987831 Free PMC article. No abstract available.

Abstract

Background: Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer's disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans.

Methods: In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.

Results: The PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results.

Conclusions: We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

Keywords: Alzheimer’s disease; Mild cognitive impairment; Polygenic risk score.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The PRS.noAPOE in the ADD group was significantly higher than those in the CU and MCI groups. The PRS.noAPOEs (A) or PRS.adjLD (B) in each group were represented by violin plots (CU, n = 145; MCI, n = 220; ADD, n = 139). Each violin plot includes the kernel probability density of the data at different values and the box plots with the median value and the interquartile range. Tukey’s HSD test was used to perform multiple comparisons of PRSs among each group. We normalized the PRS distribution to have a mean of 0 and an SD of 1. CN = cognitively normal; MCI = mild cognitive impairment; ADD = Alzheimer’s disease dementia
Fig. 2
Fig. 2
The PRS.noAPOE and PRS.adjLD correlated with CSF Tau/Aβ42 ratios in the MCI. CSF tTau/Aβ42 (A, C) and pTau/Aβ42 (B, D) ratios by decile of PRS are shown in each diagnostic group. The participants were divided into ten groups based on the PRS.noAPOE, ranging from the lowest group (1st decile) to the highest group (10th decile). CN = cognitively normal; MCI = mild cognitive impairment; ADD = Alzheimer’s disease dementia
Fig. 3
Fig. 3
The high-PRS group was more likely to convert to AD than the low-PRS group in the APOE ε4 non-carrier individuals with MCI. Kaplan–Meier survival curves for conversion rates of MCI to AD in the low-PRS group (1st tertile) and the high-PRS group (3rd tertile). The shaded area represents the 95% confidence interval
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • Dynamics of Cognitive Impairment in MCI Patients over a Three-Year Period: The Informative Role of Blood Biomarkers, Neuroimaging, and Genetic Factors.
    Morozova I, Zorkina Y, Berdalin A, Ikonnikova A, Emelyanova M, Fedoseeva E, Antonova O, Gryadunov D, Andryushchenko A, Ushakova V, Abramova O, Zeltser A, Kurmishev M, Savilov V, Osipova N, Preobrazhenskaya I, Kostyuk G, Morozova A. Morozova I, et al. Diagnostics (Basel). 2024 Aug 28;14(17):1883. doi: 10.3390/diagnostics14171883. Diagnostics (Basel). 2024. PMID: 39272668 Free PMC article.
  • Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.
    Nicolas A, Sherva R, Grenier-Boley B, Kim Y, Kikuchi M, Timsina J, de Rojas I, Dalmasso MC, Zhou X, Le Guen Y, Arboleda-Bustos CE, Camargos Bicalho MA, Guerchet M, van der Lee S, Goss M, Castillo A, Bellenguez C, Küçükali F, Satizabal CL, Fongang B, Yang Q, Peters O, Schneider A, Dichgans M, Rujescu D, Scherbaum N, Deckert J, Riedel-Heller S, Hausner L, Molina-Porcel L, Düzel E, Grimmer T, Wiltfang J, Heilmann-Heimbach S, Moebus S, Tegos T, Scarmeas N, Dols-Icardo O, Moreno F, Pérez-Tur J, Bullido MJ, Pastor P, Sánchez-Valle R, Álvarez V, Cao H, Ip NY, Fu AKY, Ip FCF, Olivar N, Muchnik C, Cuesta C, Campanelli L, Solis P, Politis DG, Kochen S, Brusco LI, Boada M, García-González P, Puerta R, Mir P, Real LM, Piñol-Ripoll G, García-Alberca JM, Royo JL, Rodriguez-Rodriguez E, Soininen H, Heikkinen S, de Mendonça A, Mehrabian S, Traykov L, Hort J, Vyhnalek M, Rasmussen KL, Thomassen JQ, Pijnenburg YAL, Holstege H, van Swieten JC, Seelaar H, Claassen JAHR, Jansen WJ, Ramakers I, Verhey F, van der Lugt A, Scheltens P, Ortega-Rojas J, Concha Mera AG, Mahecha MF, Pardo R, Arboleda G, Bahrami S, Fominykh V, Selbæk G, Graff C, Papenberg G, Giedraitis V, Boland A, Deleuze JF, de Marco LA, de … See abstract for full author list ➔ Nicolas A, et al. Nat Genet. 2025 Jul;57(7):1598-1610. doi: 10.1038/s41588-025-02227-w. Epub 2025 Jun 18. Nat Genet. 2025. PMID: 40533518 Free PMC article.
  • Development of a Japanese polygenic risk score model for amyloid-β PET imaging in Alzheimer's disease.
    Kaishima M, Ito J, Takahashi K, Tai K, Kuromitsu J, Bun S, Ito D. Kaishima M, et al. Alzheimers Res Ther. 2025 May 22;17(1):112. doi: 10.1186/s13195-025-01754-2. Alzheimers Res Ther. 2025. PMID: 40405310 Free PMC article.
  • Insights into ancestral diversity in Parkinson's disease risk: a comparative assessment of polygenic risk scores.
    Saffie-Awad P, Grant SM, Makarious MB, Elsayed I, Sanyaolu AO, Crea PW, Schumacher Schuh AF, Levine KS, Vitale D, Koretsky MJ, Kim J, Peixoto Leal T, Periñán MT, Dey S, Noyce AJ, Reyes-Palomares A, Rodriguez-Losada N, Foo JN, Mohamed W, Heilbron K, Norcliffe-Kaufmann L; 23andMe Research Team; Rizig M, Okubadejo N, Nalls MA, Blauwendraat C, Singleton A, Leonard H; Global Parkinson’s Genetics Program (GP2); Mata IF, Bandres-Ciga S. Saffie-Awad P, et al. NPJ Parkinsons Dis. 2025 Jul 3;11(1):201. doi: 10.1038/s41531-025-00967-4. NPJ Parkinsons Dis. 2025. PMID: 40610451 Free PMC article.
  • AD-GCN: A novel graph convolutional network integrating multi-omics data for enhanced Alzheimer's disease diagnosis.
    Li Z, Li Q, Li X, Luo W, Guo H, Zhao C, Yang C, Xie A, Hu K, Guo Y. Li Z, et al. PLoS One. 2025 Jun 2;20(6):e0325050. doi: 10.1371/journal.pone.0325050. eCollection 2025. PLoS One. 2025. PMID: 40455746 Free PMC article.
See all "Cited by" articles

References

    1. Lourida I, Hannon E, Littlejohns TJ, Langa KM, Hypponen E, Kuzma E, et al. Association of lifestyle and genetic risk with incidence of dementia. JAMA. 2019;322(5):430–437. doi: 10.1001/jama.2019.9879. - DOI - PMC - PubMed
    1. Licher S, Ahmad S, Karamujic-Comic H, Voortman T, Leening MJG, Ikram MA, et al. Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population. Nat Med. 2019;25(9):1364–1369. doi: 10.1038/s41591-019-0547-7. - DOI - PMC - PubMed
    1. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–446. doi: 10.1016/S0140-6736(20)30367-6. - DOI - PMC - PubMed
    1. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63(2):168–174. doi: 10.1001/archpsyc.63.2.168. - DOI - PubMed
    1. Karlsson IK, Escott-Price V, Gatz M, Hardy J, Pedersen NL, Shoai M, et al. Measuring heritable contributions to Alzheimer's disease: polygenic risk score analysis with twins. Brain Commun. 2022;4(1):fcab308. doi: 10.1093/braincomms/fcab308. - DOI - PMC - PubMed

Publication types

MeSH terms