ArticleMolecular neurodegeneration2025
Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.
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Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- LR11/SorLA and its role in cardiovascular disease.International journal of cardiology. Heart & vasculature · 2026Review
- SORL1 variant links endosomal amyloid precursor protein mis-sorting to axonal transport defects and neuronal dysfunction.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Alzheimer's disease: genetic background in the era of next-generation sequencing technologies.Brain communications · 2026Review
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Authors and funding
106 authors.
Olav M Andersen *Department of Biomedicine, Aarhus University, Aarhus, Denmark. o.andersen@biomed.au.dk.
Matthijs W J de Waal *Department of Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.ORCID 0000-0001-6746-4326
Giulia MontiDepartment of Biomedicine, Aarhus University, Aarhus, Denmark.
Niccolo TesiDepartment of Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Anne Mette G JensenDepartment of Biomedicine, Aarhus University, Aarhus, Denmark.
Christa de GeusClinical Genetics, Human Genetics, Amsterdam UMC, Amsterdam, The Netherlands.
Rosalina van SpaendonkGenome Analysis Laboratory, Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Maartje VogelGenome Analysis Laboratory, Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Shahzad AhmadDepartment of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Najaf AminDepartment of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Philippe AmouyelUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, LabEx DISTALZ-U1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Gary W BeechamThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Céline BellenguezUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, LabEx DISTALZ-U1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Claudine BerrUniv Montpellier, Inserm, INM (institute for Neurosciences of Montpellier), Montpellier, France.
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Anne BolandUniversité Paris-Saclay, CEA, Centre National de Recherche En Génomique Humaine, Evry, France.
Paola BossùExperimental Neuro-Psychobiology Laboratory, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
Femke BouwmanAmsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
Jose BrasDivision of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.
Camille CharbonnierDepartments of Genetics and CNRMAJ, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, F-76000, France.
Jordi ClarimonMemory Unit, Neurology Department and Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Sant Quintí 77-79, Barcelona, 08041, Spain.
Carlos CruchagaPsychiatry Department, Washington University School of Medicine, St Louis, MO, USA.
Antonio DanieleDepartment of Neuroscience, Catholic University of Sacred Heart, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Jean-François DartiguesUniversity Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France.
Stéphanie DebetteUniversity Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France.
Jean-François DeleuzeUniversité Paris-Saclay, CEA, Centre National de Recherche En Génomique Humaine, Evry, France.
Nicola DenningUKDRI at Cardiff, School of Medicine, Cardiff University, Cardiff, UK.
Anita L DeStefanoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Oriol Dols-IcardoMemory Unit, Neurology Department and Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Sant Quintí 77-79, Barcelona, 08041, Spain.
Cornelia M van DuijnDepartment of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Lindsay A FarrerDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Maria Victoria FernándezPsychiatry Department, Washington University School of Medicine, St Louis, MO, USA.
Wiesje M van der FlierAmsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
Nick C FoxUK Dementia Research Institute at UCL, London, UK.
Daniela GalimbertiUniversity of Milan, Milan, Italy.
Emmanuelle GeninUniv Brest, Inserm, EFS, CHU Brest, UMR 1078, GGB, Brest, F-29200, France.
Johan J P GilleGenome Analysis Laboratory, Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Benjamin Grenier-BoleyUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, LabEx DISTALZ-U1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Detelina GrozevaDivision of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
Yann Le GuenQuantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA.
Rita GuerreiroDivision of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.
Jonathan L HainesDepartment of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Clive HolmesClinical and Experimental Science, Faculty of Medicine, University of Southampton, Southampton, UK.
Holger HummerichMRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, UK.
M Arfan IkramDepartment of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
M Kamran IkramDepartment of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Amit KawaliaDivision of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Robert KraaijDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
Jean-Charles LambertUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, LabEx DISTALZ-U1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Marc LathropMcGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
Afina W LemstraAmsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
Alberto LleóMemory Unit, Neurology Department and Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Sant Quintí 77-79, Barcelona, 08041, Spain.
Richard M MyersHudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Marcel M A M MannensDepartment of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute Amsterdam, Amsterdam, The Netherlands.
Rachel MarshallDivision of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
Eden R MartinThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Carlo MasulloInstitute of Neurology, Catholic University of the Sacred Heart, Rome, Italy.
Richard MayeuxTaub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA.
Simon MeadMRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, UK.
Patrizia MecocciDivision of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Alun MeggyUKDRI at Cardiff, School of Medicine, Cardiff University, Cardiff, UK.
Merel O MolDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Benedetta NacmiasIRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
Adam C NajPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Valerio NapolioniQuantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA.
J Nicholas CochranHudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Gaël NicolasDepartments of Genetics and CNRMAJ, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, F-76000, France.
Florence PasquierUniv. Lille, Inserm, CHU Lille, UMR1172, Resources and Research Memory Center (MRRC) of Distalz, Licend, Lille, France.
Pau PastorUnit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
Margaret A Pericak-VanceThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Yolande A L PijnenburgAmsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
Fabrizio PirasLaboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
Olivier QuenezDepartments of Genetics and CNRMAJ, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, F-76000, France.
Alfredo RamirezDivision of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Rachel RaybouldUKDRI at Cardiff, School of Medicine, Cardiff University, Cardiff, UK.
Richard RedonUniversité de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Marcel J T ReindersDelft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
Anne-Claire RichardDepartments of Genetics and CNRMAJ, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, F-76000, France.
Steffi G Riedel-HellerInstitute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
Fernando RivadeneiraDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
Jeroen G J van RooijDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
Stéphane RousseauDepartments of Genetics and CNRMAJ, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, F-76000, France.
Natalie S RyanUK Dementia Research Institute at UCL, London, UK.
Pascual Sanchez-JuanCIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
Gerard D SchellenbergPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Philip ScheltensAmsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
Jonathan M SchottUK Dementia Research Institute at UCL, London, UK.
Sudha SeshadriFramingham Heart Study, Framingham, MA, USA.
Daoud SieGenome Analysis Laboratory, Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Rebecca SimsDivision of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
Erik A SistermansDepartment of Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Sandro SorbiIRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
John C van SwietenDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Betty TijmsAmsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
André G UitterlindenDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
Pieter Jelle VisserAmsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
Michael WagnerGerman Center for Neurodegenerative Diseases (DZNE, Bonn), Bonn, Germany.
David WallonDepartments of Genetics and CNRMAJ, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, F-76000, France.
Li-San WangPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Julie WilliamsDivision of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
Jennifer S YokoyamaMemory and Aging Center, Department of Neurology Weill Institute for Neurosciences, and Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
Aline ZareaDepartments of Genetics and CNRMAJ, Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Rouen, F-76000, France.
Sven J van der LeeDepartment of Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Johan G OlsenDepartment of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, DK2200, Denmark.
Marc HulsmanDepartment of Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Henne Holstege *Department of Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl.
Funding
Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious OrderR01AG067501 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI MAYEUX, RICHARD P, MILLER, GARY W · 2020 to 2024
$11.7MCHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5MNHLBI NIH HHS R01 HL105756NIA NIH HHS R01 AG067501
Abstract
backgroundProtein 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.
methodsTo 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.
resultsIn 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.
conclusionOur results justify a debate on whether HPV carriers should be considered for clinical counseling.
Indexed as
Alzheimer DiseaseLDL-Receptor Related ProteinsMembrane Transport ProteinsAgedAge of OnsetFemaleGenetic Predisposition to DiseaseGenotypeHumansMaleMiddle AgedMutationMutation, MissenseLDL-Receptor Related ProteinsMembrane Transport ProteinsSORL1 protein, humanAge at onsetAlzforum mutation databaseAlzheimer’s diseaseDisease riskDomain-mapping disease-mutationsGeneticsPenetranceRare variantsSORL1SORLA
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