Journal Article

DZNE-2025-01340

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

Andersen, O. M. ; de Waal, M. W. J. ; Monti, G. ; Tesi, N. ; Jensen, A. M. G. ; de Geus, C. ; van Spaendonk, R. ; Vogel, M. ; Ahmad, S. ; Amin, N. ; Amouyel, P. ; Beecham, G. W. ; Bellenguez, C. ; Berr, C. ; Bis, J. C. ; 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, A. L. ; Dols-Icardo, O. ; van Duijn, C. M. ; Farrer, L. A. ; Fernández, M. V. ; van der Flier, W. M. ; Fox, N. C. ; Galimberti, D. ; Genin, E. ; Gille, J. J. P. ; Grenier-Boley, B. ; Grozeva, D. ; Guen, Y. L. ; Guerreiro, R. ; Haines, J. L. ; Holmes, C. ; Hummerich, H. ; Arfan Ikram, M. ; Kamran Ikram, M. ; Kawalia, A. ; Kraaij, R. ; Lambert, J.-C. ; Lathrop, M. ; Lemstra, A. W. ; Lleó, A. ; Myers, R. M. ; Mannens, M. M. A. M. ; Marshall, R. ; Martin, E. R. ; Masullo, C. ; Mayeux, R. ; Mead, S. ; Mecocci, P. ; Meggy, A. ; Mol, M. O. ; Nacmias, B. ; Naj, A. C. ; Napolioni, V. ; Nicholas Cochran, J. ; Nicolas, G. ; Pasquier, F. ; Pastor, P. ; Pericak-Vance, M. A. ; Pijnenburg, Y. A. L. ; Piras, F. ; Quenez, O. ; Ramirez, A.DZNE* ; Raybould, R. ; Redon, R. ; Reinders, M. J. T. ; Richard, A.-C. ; Riedel-Heller, S. G. ; Rivadeneira, F. ; van Rooij, J. G. J. ; Rousseau, S. ; Ryan, N. S. ; Sanchez-Juan, P. ; Schellenberg, G. D. ; Scheltens, P. ; Schott, J. M. ; Seshadri, S. ; Sie, D. ; Sims, R. ; Sistermans, E. A. ; Sorbi, S. ; van Swieten, J. C. ; Tijms, B. ; Uitterlinden, A. G. ; Visser, P. J. ; Wagner, M.DZNE* ; Wallon, D. ; Wang, L.-S. ; Williams, J. ; Yokoyama, J. S. ; Zarea, A. ; van der Lee, S. J. ; Olsen, J. G. ; Hulsman, M. ; Holstege, H.

2025
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s13024-025-00907-z

Abstract: 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.

Keyword(s): Age at onset ; Alzforum mutation database ; Alzheimer’s disease ; Disease risk ; Domain-mapping disease-mutations ; Genetics ; Penetrance ; Rare variants ; SORL1 ; SORLA

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Contributing Institute(s):

1. Neuropsychology (AG Wagner)
2. Patient Studies (Bonn) (Patient Studies (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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