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

Masataka Kikuchi; Akinori Miyashita; Norikazu Hara; Kensaku Kasuga; Yuko Saito; Shigeo Murayama; Akiyoshi Kakita; Hiroyasu Akatsu; Kouichi Ozaki; Shumpei Niida; Ryozo Kuwano; Takeshi Iwatsubo; Akihiro Nakaya; Takeshi Ikeuchi; the Alzheimer’s Disease Neuroimaging Initiative; Michael Walter Weiner; Sara S. Mason; Colleen S. Albers; David S. Knopman; Kris Johnson; Paul S. S. Aisen; Ronald Carl Petersen; Clifford R. Jack; William J. Jagust; John Q. Trojanowki; Arthur W. Toga; Lon S. S. Schneider; Sonia Pawluczyk; Mauricio Beccera; Liberty Teodoro

doi:10.1186/s13195-024-01414-x

Genetic & Genomic MedicineAlzheimer s Research & TherapyFeb 27, 2024

Peer-reviewed journal article

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

Masataka Kikuchi iD, Akinori Miyashita iD, Norikazu Hara iD, Kensaku Kasuga iD, Yuko Saito iD, Shigeo Murayama iD, Akiyoshi Kakita iD, Hiroyasu Akatsu iD, Kouichi Ozaki iD, Shumpei Niida iD, Ryozo Kuwano iD, Takeshi Iwatsubo iD, Akihiro Nakaya iD, Takeshi Ikeuchi iD, the Alzheimer’s Disease Neuroimaging Initiative, Michael Walter Weiner iD, Sara S. Mason, Colleen S. Albers, David S. Knopman iD, Kris Johnson iD, Paul S. S. Aisen, Ronald Carl Petersen iD, Clifford R. Jack iD, William J. Jagust iD, John Q. Trojanowki, , Gary R. Conrad

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Abstract

BackgroundPolygenic 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 Alzheimers 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 GWAS statistics from Europeans. MethodsIn 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 Alzheimers 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. ResultsThe 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 ({beta} estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE {varepsilon}4 noncarriers with a hazard rate of 2.22. ConclusionsWe 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.