| Title: |
Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease |
| Authors: |
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; van Duijn, CM |
| Publisher Information: |
BioMed Central |
| Publication Year: |
2025 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1186/s13024-025-00907-z |
| Availability: |
https://doi.org/10.1186/s13024-025-00907-z; https://ora.ox.ac.uk/objects/uuid:3b224b24-0c30-431a-8636-62f294fc1b53 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.63E528BC |
| Database: |
BASE |