%0 Journal Article
%A Andersen, Olav M
%A de Waal, Matthijs W J
%A Monti, Giulia
%A Tesi, Niccolo
%A Jensen, Anne Mette G
%A de Geus, Christa
%A van Spaendonk, Rosalina
%A Vogel, Maartje
%A Ahmad, Shahzad
%A Amin, Najaf
%A Amouyel, Philippe
%A Beecham, Gary W
%A Bellenguez, Céline
%A Berr, Claudine
%A Bis, Joshua C
%A Boland, Anne
%A Bossù, Paola
%A Bouwman, Femke
%A Bras, Jose
%A Charbonnier, Camille
%A Clarimon, Jordi
%A Cruchaga, Carlos
%A Daniele, Antonio
%A Dartigues, Jean-François
%A Debette, Stéphanie
%A Deleuze, Jean-François
%A Denning, Nicola
%A DeStefano, Anita L
%A Dols-Icardo, Oriol
%A van Duijn, Cornelia M
%A Farrer, Lindsay A
%A Fernández, Maria Victoria
%A van der Flier, Wiesje M
%A Fox, Nick C
%A Galimberti, Daniela
%A Genin, Emmanuelle
%A Gille, Johan J P
%A Grenier-Boley, Benjamin
%A Grozeva, Detelina
%A Guen, Yann Le
%A Guerreiro, Rita
%A Haines, Jonathan L
%A Holmes, Clive
%A Hummerich, Holger
%A Arfan Ikram, M.
%A Kamran Ikram, M.
%A Kawalia, Amit
%A Kraaij, Robert
%A Lambert, Jean-Charles
%A Lathrop, Marc
%A Lemstra, Afina W
%A Lleó, Alberto
%A Myers, Richard M
%A Mannens, Marcel M A M
%A Marshall, Rachel
%A Martin, Eden R
%A Masullo, Carlo
%A Mayeux, Richard
%A Mead, Simon
%A Mecocci, Patrizia
%A Meggy, Alun
%A Mol, Merel O
%A Nacmias, Benedetta
%A Naj, Adam C
%A Napolioni, Valerio
%A Nicholas Cochran, J.
%A Nicolas, Gaël
%A Pasquier, Florence
%A Pastor, Pau
%A Pericak-Vance, Margaret A
%A Pijnenburg, Yolande A L
%A Piras, Fabrizio
%A Quenez, Olivier
%A Ramirez, Alfredo
%A Raybould, Rachel
%A Redon, Richard
%A Reinders, Marcel J T
%A Richard, Anne-Claire
%A Riedel-Heller, Steffi G
%A Rivadeneira, Fernando
%A van Rooij, Jeroen G J
%A Rousseau, Stéphane
%A Ryan, Natalie S
%A Sanchez-Juan, Pascual
%A Schellenberg, Gerard D
%A Scheltens, Philip
%A Schott, Jonathan M
%A Seshadri, Sudha
%A Sie, Daoud
%A Sims, Rebecca
%A Sistermans, Erik A
%A Sorbi, Sandro
%A van Swieten, John C
%A Tijms, Betty
%A Uitterlinden, André G
%A Visser, Pieter Jelle
%A Wagner, Michael
%A Wallon, David
%A Wang, Li-San
%A Williams, Julie
%A Yokoyama, Jennifer S
%A Zarea, Aline
%A van der Lee, Sven J
%A Olsen, Johan G
%A Hulsman, Marc
%A Holstege, Henne
%T Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.
%J Molecular neurodegeneration
%V 20
%N 1
%@ 1750-1326
%C London
%I Biomed Central
%M DZNE-2025-01340
%P 122
%D 2025
%X 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.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.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.Our results justify a debate on whether HPV carriers should be considered for clinical counseling.The online version contains supplementary material available at 10.1186/s13024-025-00907-z.
%K Age at onset (Other)
%K Alzforum mutation database (Other)
%K Alzheimer’s disease (Other)
%K Disease risk (Other)
%K Domain-mapping disease-mutations (Other)
%K Genetics (Other)
%K Penetrance (Other)
%K Rare variants (Other)
%K SORL1 (Other)
%K SORLA (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41327266
%2 pmc:PMC12667055
%R 10.1186/s13024-025-00907-z
%U https://pub.dzne.de/record/282580