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

Alzheimers Res Ther. 2024 Feb 27;16(1):45. doi: 10.1186/s13195-024-01414-x.

Kikuchi M1,2, Miyashita A3, Hara N3, Kasuga K3, Saito Y4, Murayama S4,5, Kakita A6, Akatsu H7, Ozaki K8,9, Niida S10, Kuwano R11, Iwatsubo T12, Nakaya A1, Ikeuchi T3; Alzheimer's Disease Neuroimaging Initiative; Japanese Alzheimer's Disease Neuroimaging Initiative.

  1. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Science, The University of Tokyo.
  2. Department of Medical Informatics, Graduate School of Medicine, Osaka University.
  3. Department of Molecular Genetics, Brain Research Institute, Niigata University.
  4. Brain Bank for Aging Research (Department of Neuropathology), Tokyo Metropolitan Institute of Geriatrics and Gerontology.
  5. Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, United Graduate School of Child Development, Osaka University.
  6. Department of Pathology, Brain Research Institute, Niigata University.
  7. Department of General Medicine & General Internal Medicine, Nagoya City University Graduate School of Medicine.
  8. Medical Genome Center, National Center for Geriatrics and Gerontology, Research Institute.
  9. RIKEN Center for Integrative Medical Sciences.
  10. Core Facility Administration, National Center for Geriatrics and Gerontology, Research Institute.
  11. Social Welfare Corporation Asahigawaso, Asahigawaso Research Institute.
  12. Department of Neuropathology, Graduate School of Medicine, The University of Tokyo.


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.

*Reprinted under the terms of the Creative Commons Attribution License (CC BY).

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