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

Aude Nicolas; Richard Sherva; Benjamin Grenier-Boley; European Alzheimer & Dementia BioBank (EADB); 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; Henne Holstege; John C. van Swieten; Harro Seelaar; Aad van der Lugt; Cornelia Van Duijn; Kristel Sleegers

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
, European Alzheimer & Dementia BioBank (EADB)
, 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, Henne Holstege, John C. van Swieten, Harro Seelaar, Aad van der Lugt, Cornelia Van Duijn, Kristel Sleegers

^*Corresponding author for this work

Université de Lille
Sorbonne Université
Department of Veterans Affairs
Boston University
Chosun University
The University of Tokyo
Washington University School of Medicine in St. Louis
UIC Barcelona
Instituto de Salud Carlos III
University Hospital Cologne
Studies in Neuroscience and Complex Systems Unit (ENyS) CONICET-HEC-UNAJ
Hong Kong University of Science and Technology
Hong Kong Center for Neurodegenerative Diseases
HKUST Shenzhen Research Institute - Hong Kong Institute of Brain Science
Stanford University School of Medicine
Institut du Cerveau et de la Moelle Épinière
Universidad Nacional de Colombia
Universidade Federal de Minas Gerais
University of Abomey-Calavi
University of Texas Health Science Center at San Antonio
Cardiff University School of Medicine
Flanders Institute for Biotechnology
University of Antwerp
The Framingham Heart Study
Boston University School of Medicine
German Center for Neurodegenerative Diseases
Berlin Institute of Health
University Hospital Bonn
Klinikum der Universität München
Munich Cluster for Systems Neurology (SyNergy)
Medical University of Vienna
University of Duisburg-Essen
University of Würzburg
Leipzig University
Heidelberg University
Hospital Clinic de Barcelona
Otto von Guericke University Magdeburg
Technical University of Munich
University of Göttingen
University of Aveiro
University Hospital Essen
Aristotle University of Thessaloniki School of Medicine
National and Kapodistrian University of Athens Medical School
Columbia University
Research Institute of the Santa Creu i Sant Pau Hospital
Hospital Universitario Donostia
CSIC - Institute of Biomedicine of Valencia
CSIC-UAM: Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid
Hospital Universitario La Paz
Universidad Autónoma de Madrid
Generalitat de Catalunya
Institut Investigació Germans Trias i Pujol (IGTP)
University of Barcelona
Hospital Universitario Central de Asturias
Instituto de INvestigación Biosanitaria Del Principado de Asturias (ISPA)

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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	13
Journal	Nature Genetics
Volume	57
Issue number	7
DOIs	https://doi.org/10.1038/s41588-025-02227-w
Publication status	Published - 1 Jul 2025

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

s41588-025-02227-wFinal published version, 3.97 MBLicence: CC BY-NC-ND

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Nicolas, A., Sherva, R., Grenier-Boley, B., European Alzheimer & Dementia BioBank (EADB), 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., ... Sleegers, K. (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.",

author = "Aude Nicolas and Richard Sherva and Benjamin Grenier-Boley and \{European Alzheimer \& Dementia BioBank (EADB)\} 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 Henne Holstege and \{van Swieten\}, \{John C.\} and Harro Seelaar and \{van der Lugt\}, Aad and \{Van Duijn\}, Cornelia and Kristel Sleegers",

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year = "2025",

month = jul,

day = "1",

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

language = "English",

volume = "57",

pages = "1598--1610",

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Nicolas, A, Sherva, R, Grenier-Boley, B, European Alzheimer & Dementia BioBank (EADB), 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, Holstege, H, van Swieten, JC , Seelaar, H , van der Lugt, A, Van Duijn, C & Sleegers, K 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 - European Alzheimer & Dementia BioBank (EADB)

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 - Holstege, Henne

AU - van Swieten, John C.

AU - Seelaar, Harro

AU - van der Lugt, Aad

AU - Van Duijn, Cornelia

AU - Sleegers, Kristel

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.

UR - https://www.scopus.com/pages/publications/105012312720

U2 - 10.1038/s41588-025-02227-w

DO - 10.1038/s41588-025-02227-w

M3 - Article

C2 - 40533518

AN - SCOPUS:105012312720

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

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