Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations

EADB; Aude Nicolas; Richard Sherva; Benjamin Grenier-Boley; Yoontae Kim; Masataka Kikuchi; Jigyasha Timsina; Itziar de Rojas; María Carolina Dalmasso; Xiaopu Zhou; Yann Le Guen; Carlos E Arboleda-Bustos; Maria Aparecida Camargos Bicalho; Maëlenn Guerchet; Sven van der Lee; Monica Goss; Atahualpa Castillo; Céline Bellenguez; Fahri Küçükali; Claudia L Satizabal; Bernard Fongang; Qiong Yang; Oliver Peters; Anja Schneider; Martin Dichgans; Patrick G Kehoe; Seth Love; Olivia A Skrobot; Jean-Charles Lambert; et al

doi:10.1038/s41588-025-02227-w

Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations

EADB, Aude Nicolas^*, Richard Sherva, Benjamin Grenier-Boley, Yoontae Kim, Masataka Kikuchi, Jigyasha Timsina, Itziar de Rojas, María Carolina Dalmasso, Xiaopu Zhou, Yann Le Guen, Carlos E Arboleda-Bustos, Maria Aparecida Camargos Bicalho, Maëlenn Guerchet, Sven van der Lee, Monica Goss, Atahualpa Castillo, Céline Bellenguez, Fahri Küçükali, Claudia L SatizabalBernard Fongang, Qiong Yang, Oliver Peters, Anja Schneider, Martin Dichgans, Patrick G Kehoe, Seth Love, Olivia A Skrobot, Jean-Charles Lambert^*, et al

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

Original language	English
Pages (from-to)	1598-1610
Number of pages	24
Journal	Nature Genetics
Volume	57
Issue number	7
Early online date	18 Jun 2025
DOIs	https://doi.org/10.1038/s41588-025-02227-w
Publication status	Published - 1 Jul 2025

Bibliographical note

Publisher Copyright:
© 2025. The Author(s).

Keywords

Alzheimer Disease/genetics
Humans
Multifactorial Inheritance/genetics
Genetic Predisposition to Disease
White People/genetics
Genome-Wide Association Study
Europe/epidemiology
Apolipoproteins E/genetics
Female
Risk Factors
Male
Polymorphism, Single Nucleotide
Aged
Biomarkers/cerebrospinal fluid
Genetic Risk Score

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EADB, Nicolas, A., Sherva, R., Grenier-Boley, B., Kim, Y., Kikuchi, M., Timsina, J., de Rojas, I., Dalmasso, M. C., Zhou, X., Le Guen, Y., Arboleda-Bustos, C. E., Camargos Bicalho, M. A., Guerchet, M., van der Lee, S., Goss, M., Castillo, A., Bellenguez, C., Küçükali, F., ... al, E. (2025). Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations. Nature Genetics, 57(7), 1598-1610. https://doi.org/10.1038/s41588-025-02227-w

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title = "Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations",

abstract = "A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.",

keywords = "Alzheimer Disease/genetics, Humans, Multifactorial Inheritance/genetics, Genetic Predisposition to Disease, White People/genetics, Genome-Wide Association Study, Europe/epidemiology, Apolipoproteins E/genetics, Female, Risk Factors, Male, Polymorphism, Single Nucleotide, Aged, Biomarkers/cerebrospinal fluid, Genetic Risk Score",

author = "EADB and Aude Nicolas and Richard Sherva and Benjamin Grenier-Boley and Yoontae Kim and Masataka Kikuchi and Jigyasha Timsina and \{de Rojas\}, Itziar and Dalmasso, \{Mar{\'i}a Carolina\} and Xiaopu Zhou and \{Le Guen\}, Yann and Arboleda-Bustos, \{Carlos E\} and \{Camargos Bicalho\}, \{Maria Aparecida\} and Ma{\"e}lenn Guerchet and \{van der Lee\}, Sven and Monica Goss and Atahualpa Castillo and C{\'e}line Bellenguez and Fahri K{\"u}{\c c}{\"u}kali and Satizabal, \{Claudia L\} and Bernard Fongang and Qiong Yang and Oliver Peters and Anja Schneider and Martin Dichgans and Kehoe, \{Patrick G\} and Seth Love and Skrobot, \{Olivia A\} and Jean-Charles Lambert and et al",

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year = "2025",

month = jul,

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doi = "10.1038/s41588-025-02227-w",

language = "English",

volume = "57",

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EADB, 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, Kehoe, PG , Love, S , Skrobot, OA, Lambert, J-C & al, E 2025, 'Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations', Nature Genetics, vol. 57, no. 7, pp. 1598-1610. https://doi.org/10.1038/s41588-025-02227-w

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T1 - Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations

AU - EADB

AU - Nicolas, Aude

AU - Sherva, Richard

AU - Grenier-Boley, Benjamin

AU - Kim, Yoontae

AU - Kikuchi, Masataka

AU - Timsina, Jigyasha

AU - de Rojas, Itziar

AU - Dalmasso, María Carolina

AU - Zhou, Xiaopu

AU - Le Guen, Yann

AU - Arboleda-Bustos, Carlos E

AU - Camargos Bicalho, Maria Aparecida

AU - Guerchet, Maëlenn

AU - van der Lee, Sven

AU - Goss, Monica

AU - Castillo, Atahualpa

AU - Bellenguez, Céline

AU - Küçükali, Fahri

AU - Satizabal, Claudia L

AU - Fongang, Bernard

AU - Yang, Qiong

AU - Peters, Oliver

AU - Schneider, Anja

AU - Dichgans, Martin

AU - Kehoe, Patrick G

AU - Love, Seth

AU - Skrobot, Olivia A

AU - Lambert, Jean-Charles

AU - al, et

PY - 2025/7/1

Y1 - 2025/7/1

N2 - A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

AB - A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

KW - Alzheimer Disease/genetics

KW - Humans

KW - Multifactorial Inheritance/genetics

KW - Genetic Predisposition to Disease

KW - White People/genetics

KW - Genome-Wide Association Study

KW - Europe/epidemiology

KW - Apolipoproteins E/genetics

KW - Female

KW - Risk Factors

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Aged

KW - Biomarkers/cerebrospinal fluid

KW - Genetic Risk Score

U2 - 10.1038/s41588-025-02227-w

DO - 10.1038/s41588-025-02227-w

M3 - Article (Academic Journal)

C2 - 40533518

SN - 1061-4036

VL - 57

SP - 1598

EP - 1610

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations

Abstract

Bibliographical note

Keywords

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