Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

Andersen, Olav M., de Waal, Matthijs W. J., Monti, Giulia, Tesi, Niccolo, Jensen, Anne Mette G., de Geus, Christa, van Spaendonk, Rosalina, Vogel, Maartje, Ahmad, Shahzad, Amin, Najaf, Amouyel, Philippe, Beecham, Gary W., Bellenguez, Céline, Berr, Claudine, Bis, Joshua C., Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Charbonnier, Camille, Clarimon, Jordi, Cruchaga, Carlos, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L., Dols-Icardo, Oriol, van Duijn, Cornelia M., Farrer, Lindsay A., Fernández, Maria Victoria, van der Flier, Wiesje M., Fox, Nick C., Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan J. P., Grenier-Boley, Benjamin, Grozeva, Detelina ORCID: https://orcid.org/0000-0003-3239-8415, Guen, Yann Le, Guerreiro, Rita, Haines, Jonathan L., Holmes, Clive, Hummerich, Holger, Arfan Ikram, M., Kamran Ikram, M., Kawalia, Amit, Kraaij, Robert, Lambert, Jean-Charles, Lathrop, Marc, Lemstra, Afina W., Lleó, Alberto, Myers, Richard M., Mannens, Marcel M. A. M., Marshall, Rachel, Martin, Eden R., Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Nacmias, Benedetta, Naj, Adam C., Napolioni, Valerio, Nicholas Cochran, J., Nicolas, Gaël, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A., Pijnenburg, Yolande A. L., Piras, Fabrizio, Quenez, Olivier, Ramirez, Alfredo, Raybould, Rachel, Redon, Richard, Reinders, Marcel J. T., Richard, Anne-Claire, Riedel-Heller, Steffi G., Rivadeneira, Fernando, van Rooij, Jeroen G. J., Rousseau, Stéphane, Ryan, Natalie S., Sanchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seshadri, Sudha, Sie, Daoud, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Sistermans, Erik A., Sorbi, Sandro, van Swieten, John C., Tijms, Betty, Uitterlinden, André G., Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Yokoyama, Jennifer S., Zarea, Aline, van der Lee, Sven J., Olsen, Johan G., Hulsman, Marc and Holstege, Henne 2025. Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease. Molecular Neurodegeneration 20 , 122. 10.1186/s13024-025-00907-z

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Abstract

Background Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. Methods To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. Results In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. Conclusion Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	BioMed Central
Date of First Compliant Deposit:	16 December 2025
Date of Acceptance:	5 October 2025
Last Modified:	16 Dec 2025 10:31
URI:	https://orca.cardiff.ac.uk/id/eprint/183272

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