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

Nicolas, Aude, Sherva, Richard, Grenier-Boley, Benjamin, Kim, Yoontae, Kikuchi, Masataka, Timsina, Jigyasha, de Rojas, Itziar, Dalmasso, María Carolina, Zhou, Xiaopu, Le Guen, Yann, Arboleda-Bustos, Carlos E., Camargos Bicalho, Maria Aparecida, Guerchet, Maëlenn, van der Lee, Sven, Goss, Monica, Castillo, Atahualpa, Bellenguez, Céline, Küçükali, Fahri, Satizabal, Claudia L., Fongang, Bernard, Yang, Qiong, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Deckert, Jürgen, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina-Porcel, Laura, Düzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Dols-Icardo, Oriol, Moreno, Fermin, Pérez-Tur, Jordi, Bullido, María J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Cao, Han, Ip, Nancy Y., Fu, Amy K. Y., Ip, Fanny C. F., Olivar, Natividad, Muchnik, Carolina, Cuesta, Carolina, Campanelli, Lorenzo, Solis, Patricia, Politis, Daniel Gustavo, Kochen, Silvia, Brusco, Luis Ignacio, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Piñol-Ripoll, Gerard, García-Alberca, Jose María, Royo, Jose Luís, Rodriguez-Rodriguez, Eloy, Soininen, Hilkka, Heikkinen, Sami, de Mendonça, Alexandre, Mehrabian, Shima, Traykov, Latchezar, Hort, Jakub, Vyhnalek, Martin, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Pijnenburg, Yolande A. L., Holstege, Henne, van Swieten, John C., Seelaar, Harro, Claassen, Jurgen A. H. R., Jansen, Willemijn J., Ramakers, Inez, Verhey, Frans, van der Lugt, Aad, Scheltens, Philip, Ortega-Rojas, Jenny, Concha Mera, Ana Gabriela, Mahecha, Maria F., Pardo, Rodrigo, Arboleda, Gonzalo, Bahrami, Shahram, Fominykh, Vera, Selbæk, Geir, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Deleuze, Jean-François, de Marco, Luiz Armando, de Moraes, Edgar Nunes, de Mattos Viana, Bernardo, Túlio Gualberto Cintra, Marco, Juarez-Cedillo, Teresa, Griswold, Anthony J., Forund, Tatiana, Haines, Jonathan, Farrer, Lindsay, DeStefano, Anita, Wijsman, Ellen, Mayeux, Richard, Pericak-Vance, Margaret, Kunkle, Brian, Goate, Alison, Schellenberg, Gerard D., Vardarajan, Badri, Wang, Li-San, Leung, Yuk Yee, Dalgard, Clifton L., Nicolas, Gael, Wallon, David, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stéphanie, Grünblatt, Edna, Popp, Julius, Angel, Bárbara, Gloger, Sergio, Chacon, Maria Victoria, Aranguiz, Rafael, Orellana, Paulina, Slachevsky, Andrea, Gonzalez-Billault, Christian, Albala, Cecilia, Fuentes, Patricio, Sachdev, Perminder, Mather, Karen A., Hauger, Richard L., Merritt, Victoria, Panizzon, Matthew, Zhang, Rui, Gaziano, J. Michael, Ghidoni, Roberta, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Piras, Fabrizio, Moreno-Grau, Sonia, Amin, Najaf, Holmans, Peter A. ORCID: https://orcid.org/0000-0003-0870-9412, Kleineidam, Luca, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcón-Martín, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Armstrong, Nicola J., Anthoula, Tsolaki, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Pastor, Ana Belén, Bellini, Sonia, Berr, Claudine, Besse, Céline, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boschi, Silvia, Bossù, Paola, Bråthen, Geir, Bresner, Catherine ORCID: https://orcid.org/0000-0003-2673-9762, Brodaty, Henry, Brookes, Keeley J., Buiza-Rueda, Dolores, Bûrger, Katharina, Burholt, Vanessa, Calero, Miguel, Chene, Geneviève, Carracedo, Ángel, Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chillotti, Caterina, Ciccone, Simona, Clarimon, Jordi, Clark, Christopher, Conti, Elisa, Corma-Gómez, Anaïs, Giuffrè, Guido Maria, Custodero, Carlo, Daian, Delphine, Dardiotis, Efthimios, de Deyn, Peter Paul, del Ser, Teodoro, Denning, Nicola, Diehl-Schmid, Janine, Diez-Fairen, Mónica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Engelborghs, Sebastiaan, Espinosa, Ana, Ewers, Michael, Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Farotti, Lucia, Fenoglio, Chiara, Fernández-Fuertes, Marta, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fließbach, Klaus, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macías, Emlio, Frank-García, Ana, Froelich, Lutz, García-Alberca, Jose Maria, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Giegling, Ina, Giorgio, Giaccone, Goldhardt, Oliver, González-Pérez, Antonio, Grande, Giulia, Green, Emma, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Hampel, Harald, Hardy, John, Hartmann, Annette M., Harwood, Janet, Helisalmi, Seppo, Heneka, Michael T., Hernández, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Huerto Vilas, Raquel, Hulsman, Marc, Biessels, Geert Jan, Johansson, Charlotte, Kilander, Lena, Ståhlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Lage, Carmen, Laukka, Erika J., Lauria, Alessandra, Lehtisalo, Jenni, Lerch, Ondrej, Lleó, Alberto, López-de Munain, Adolfo, Love, Seth, Löwemark, Malin, Luckcuck, Lauren, Macías, Juan, MacLeod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquié, Marta, Marshall, Rachel, Montes, Angel Martín, Martínez Rodríguez, Carmen, Mead, Simon, Medina, Miguel, Meggy, Alun, Mendoza, Silvia, Menéndez-González, Manuel, Mol, Merel, Montrreal, Laura, Morgan, Kevin, Möthen, Markus M., Ngandu, Tiia, Nordestgaard, Børge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Pérez-Cordón, Alba, Pericard, Pierre, Pineda, Juan A., Pisanu, Claudia, Polak, Thomas, Posthuma, Danielle, Priller, Josef, Quenez, Olivier, Quintela, Inés, Rábano, Alberto, Reinders, Marcel J. T., Riederer, Peter, Roberto, Natalia, Rongve, Arvid, Allende, Irene Rosas, Rosende-Roca, Maitée, Royo, Jose Luis, Rubino, Elisa, Sáez, María Eugenia, Sakka, Paraskevi, Saltvedt, Ingvild, Sanabria, Ángela, Bernal Sánchez-Arjona, María, Sanchez-Garcia, Florentino, Sánchez-Juan, Pascual, Sando, Sigrid B., Scamosci, Michela, Scarpini, Elio, Scherer, Martin, Schmid, Matthias, Schott, Jonathan M., Shadrin, Alexey A., Skrobot, Olivia, Solomon, Alina, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spottke, Annika, Stordal, Eystein, Tartan, Juan Pablo, Tárraga, Lluís, Tesí, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tybjærg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Van Broeckhoven, Christine, Van Dongen, Jasper, Vandenberghe, Rik, Vidal, Jean-Sébastien, Vogelgsang, Jonathan, Wagner, Michael, Weinhold, Leonie, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zulaica, Miren, Leonard, Hampton L., Yokoyama, Jenifer S., Nalls, Mike A., Miyashita, Akinori, Hara, Norikazu, Ozaki, Kouichi, Niida, Shumpei, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Masullo, Carlo, Amouyel, Philippe, Preux, Pierre-Marie, Mbelesso, Pascal, Bandzouzi, Bébène, Saykin, Andy, Jessen, Frank, Kehoe, Patrick G., Van Duijn, Cornelia, Ben Salem, Nesrine, Frikke-Schmidt, Ruth, Cherni, Lotfi, Greicius, Michael D., Tsolaki, Magda, Sánchez-Juan, Pascual, Romano Silva, Marco Aurélio, Porter, Tenielle, Laws, Simon M., Sleegers, Kristel, Ingelsson, Martin, Dartigues, Jean-François, Seshadri, Sudha, Rossi, Giacomina, Morelli, Laura, Hiltunen, Mikko, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, van der Flier, Wiesje, Andreassen, Ole A., Arboleda, Humberto, Cruchaga, Carlos, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Ruiz, Agustín, Lee, Kun Ho, Ikeuchi, Takeshi, Ramirez, Alfredo, Gim, Jungsoo, Logue, Mark and Lambert, Jean-Charles 2025. Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations. Nature Genetics 10.1038/s41588-025-02227-w

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	1 July 2025
Date of Acceptance:	29 April 2025
Last Modified:	01 Jul 2025 10:03
URI:	https://orca.cardiff.ac.uk/id/eprint/179409

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