Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.
Andersen OM., de Waal MWJ., Monti G., Tesi N., Jensen AMG., de Geus C., van Spaendonk R., Vogel M., Ahmad S., Amin N., Amouyel P., Beecham GW., Bellenguez C., Berr C., Bis JC., Boland A., Bossù P., Bouwman F., Bras J., Charbonnier C., Clarimon J., Cruchaga C., Daniele A., Dartigues J-F., Debette S., Deleuze J-F., Denning N., DeStefano AL., Dols-Icardo O., van Duijn CM., Farrer LA., Fernández MV., van der Flier WM., Fox NC., Galimberti D., Genin E., Gille JJP., Grenier-Boley B., Grozeva D., Guen YL., Guerreiro R., Haines JL., Holmes C., Hummerich H., Arfan Ikram M., Kamran Ikram M., Kawalia A., Kraaij R., Lambert J-C., Lathrop M., Lemstra AW., Lleó A., Myers RM., Mannens MMAM., Marshall R., Martin ER., Masullo C., Mayeux R., Mead S., Mecocci P., Meggy A., Mol MO., Nacmias B., Naj AC., Napolioni V., Nicholas Cochran J., Nicolas G., Pasquier F., Pastor P., Pericak-Vance MA., Pijnenburg YAL., Piras F., Quenez O., Ramirez A., Raybould R., Redon R., Reinders MJT., Richard A-C., Riedel-Heller SG., Rivadeneira F., van Rooij JGJ., Rousseau S., Ryan NS., Sanchez-Juan P., Schellenberg GD., Scheltens P., Schott JM., Seshadri S., Sie D., Sims R., Sistermans EA., Sorbi S., van Swieten JC., Tijms B., Uitterlinden AG., Visser PJ., Wagner M., Wallon D., Wang L-S., Williams J., Yokoyama JS., Zarea A., van der Lee SJ., Olsen JG., Hulsman M., Holstege H.
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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00907-z.