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

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; Dan Rujescu; Norbert Scherbaum; Jürgen Deckert; Steffi Riedel-Heller; Lucrezia Hausner; Laura Molina-Porcel; Emrah Düzel; Timo Grimmer; Jens Wiltfang; Stefanie Heilmann-Heimbach; Susanne Moebus; Thomas Tegos; Nikolaos Scarmeas; Oriol Dols-Icardo; Fermin Moreno; Jordi Pérez-Tur; María J Bullido; Pau Pastor; Raquel Sánchez-Valle; Victoria Álvarez; Han Cao; Nancy Y Ip; Amy K Y Fu; Fanny C F Ip; Natividad Olivar; Carolina Muchnik; EADB; Willemijn Jansen; Inez Ramakers; Frans Verhey; Jean-Charles Lambert

doi:10.1038/s41588-025-02227-w

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

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 FongangQiong Yang, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina-Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Han Cao, Nancy Y Ip, Amy K Y Fu, Fanny C F Ip, Natividad Olivar, Carolina Muchnik, EADB, Willemijn Jansen, Inez Ramakers, Frans Verhey, Jean-Charles Lambert^*

^*Corresponding author for this work

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

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	13
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

Access to Document

10.1038/s41588-025-02227-wLicence: CC BY-NC-ND

Cite this

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., Satizabal, C. L., ... Lambert, J.-C. (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

@article{32b34c9d52ff45c2ab894451746fc023,

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.",

author = "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 Dan Rujescu and Norbert Scherbaum and J{\"u}rgen Deckert and Steffi Riedel-Heller and Lucrezia Hausner and Laura Molina-Porcel and Emrah D{\"u}zel and Timo Grimmer and Jens Wiltfang and Stefanie Heilmann-Heimbach and Susanne Moebus and Thomas Tegos and Nikolaos Scarmeas and Oriol Dols-Icardo and Fermin Moreno and Jordi P{\'e}rez-Tur and Bullido, \{Mar{\'i}a J\} and Pau Pastor and Raquel S{\'a}nchez-Valle and Victoria {\'A}lvarez and Han Cao and Ip, \{Nancy Y\} and Fu, \{Amy K Y\} and Ip, \{Fanny C F\} and Natividad Olivar and Carolina Muchnik and EADB and Willemijn Jansen and Inez Ramakers and Frans Verhey and Jean-Charles Lambert",

year = "2025",

month = jul,

day = "1",

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

language = "English",

volume = "57",

pages = "1598--1610",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "7",

}

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, EADB, Jansen, W , Ramakers, I , Verhey, F & Lambert, J-C 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

TY - JOUR

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

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 - Rujescu, Dan

AU - Scherbaum, Norbert

AU - Deckert, Jürgen

AU - Riedel-Heller, Steffi

AU - Hausner, Lucrezia

AU - Molina-Porcel, Laura

AU - Düzel, Emrah

AU - Grimmer, Timo

AU - Wiltfang, Jens

AU - Heilmann-Heimbach, Stefanie

AU - Moebus, Susanne

AU - Tegos, Thomas

AU - Scarmeas, Nikolaos

AU - Dols-Icardo, Oriol

AU - Moreno, Fermin

AU - Pérez-Tur, Jordi

AU - Bullido, María J

AU - Pastor, Pau

AU - Sánchez-Valle, Raquel

AU - Álvarez, Victoria

AU - Cao, Han

AU - Ip, Nancy Y

AU - Fu, Amy K Y

AU - Ip, Fanny C F

AU - Olivar, Natividad

AU - Muchnik, Carolina

AU - EADB

AU - Jansen, Willemijn

AU - Ramakers, Inez

AU - Verhey, Frans

AU - Lambert, Jean-Charles

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.

U2 - 10.1038/s41588-025-02227-w

DO - 10.1038/s41588-025-02227-w

M3 - Article

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

Access to Document

Fingerprint

Cite this