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.
Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations / A. Nicolas, R. Sherva, B. Grenier-Boley, Y. Kim, M. Kikuchi, J. Timsina, I. De Rojas, M.C. Dalmasso, X. Zhou, Y. Le Guen, C.E. Arboleda-Bustos, M.A. Camargos Bicalho, M. Guerchet, S. Van Der Lee, M. Goss, A. Castillo, C. Bellenguez, F. Küçükali, C.L. Satizabal, B. Fongang, Q. Yang, O. Peters, A. Schneider, M. Dichgans, D. Rujescu, N. Scherbaum, J. Deckert, S. Riedel-Heller, L. Hausner, L. Molina-Porcel, E. Düzel, T. Grimmer, J. Wiltfang, S. Heilmann-Heimbach, S. Moebus, T. Tegos, N. Scarmeas, O. Dols-Icardo, F. Moreno, J. Pérez-Tur, M.J. Bullido, P. Pastor, R. Sánchez-Valle, V. Álvarez, H. Cao, N.Y. Ip, A.K.Y. Fu, F.C.F. Ip, N. Olivar, C. Muchnik, C. Cuesta, L. Campanelli, P. Solis, D.G. Politis, S. Kochen, L.I. Brusco, M. Boada, P. García-González, R. Puerta, P. Mir, L.M. Real, G. Piñol-Ripoll, J.M. García-Alberca, J.L. Royo, E. Rodriguez-Rodriguez, H. Soininen, S. Heikkinen, A. De Mendonça, S. Mehrabian, L. Traykov, J. Hort, M. Vyhnalek, K.L. Rasmussen, J.Q. Thomassen, Y.A.L. Pijnenburg, H. Holstege, J.C. Van Swieten, H. Seelaar, J.A.H.R. Claassen, W.J. Jansen, I. Ramakers, F. Verhey, A. Van Der Lugt, P. Scheltens, J. Ortega-Rojas, A.G. Concha Mera, M.F. Mahecha, R. Pardo, G. Arboleda, S. Bahrami, V. Fominykh, G. Selbæk, C. Graff, G. Papenberg, V. Giedraitis, A. Boland, J. Deleuze, L.A. De Marco, E.N. De Moraes, B. De Mattos Viana, M. Túlio Gualberto Cintra, T. Juarez-Cedillo, A.J. Griswold, T. Forund, J. Haines, L. Farrer, A. Destefano, E. Wijsman, R. Mayeux, M. Pericak-Vance, B. Kunkle, A. Goate, G.D. Schellenberg, B. Vardarajan, L. Wang, Y.Y. Leung, C.L. Dalgard, G. Nicolas, D. Wallon, C. Dufouil, F. Pasquier, O. Hanon, S. Debette, E. Grünblatt, J. Popp, B. Angel, S. Gloger, M.V. Chacon, R. Aranguiz, P. Orellana, A. Slachevsky, C. Gonzalez-Billault, C. Albala, P. Fuentes, P. Sachdev, K.A. Mather, R.L. Hauger, V. Merritt, M. Panizzon, R. Zhang, J.M. Gaziano, R. Ghidoni, D. Galimberti, B. Arosio, P. Mecocci, V. Solfrizzi, L. Parnetti, A. Squassina, L. Tremolizzo, B. Borroni, B. Nacmias, P. Caffarra, D. Seripa, I. Rainero, A. Daniele, F. Piras, H.L. Leonard, J.S. Yokoyama, M.A. Nalls, A. Miyashita, N. Hara, K. Ozaki, S. Niida, J. Williams, C. Masullo, P. Amouyel, P. Preux, P. Mbelesso, B. Bandzouzi, A. Saykin, F. Jessen, P.G. Kehoe, C. Van Duijn, N. Ben Salem, R. Frikke-Schmidt, L. Cherni, M.D. Greicius, M. Tsolaki, P. Sánchez-Juan, M.A. Romano Silva, T. Porter, S.M. Laws, K. Sleegers, M. Ingelsson, J. Dartigues, S. Seshadri, G. Rossi, L. Morelli, M. Hiltunen, R. Sims, W. Van Der Flier, O.A. Andreassen, H. Arboleda, C. Cruchaga, V. Escott-Price, A. Ruiz, K.H. Lee, T. Ikeuchi, A. Ramirez, J. Gim, M. Logue, J. Lambert. - In: NATURE GENETICS. - ISSN 1061-4036. - (2025), pp. 1-24. [Epub ahead of print] [10.1038/s41588-025-02227-w]
Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations
D. Galimberti;B. Arosio;L. Morelli;
2025
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.
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