Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

Olav M. Andersen; Matthijs W.J. de Waal; Giulia Monti; Niccolo Tesi; Anne Mette G. Jensen; Christa de Geus; Rosalina van Spaendonk; Maartje Vogel; Shahzad Ahmad; Najaf Amin; Philippe Amouyel; Gary W. Beecham; Céline Bellenguez; Claudine Berr; Joshua C. Bis; Anne Boland; Paola Bossù; Femke Bouwman; Jose Bras; Camille Charbonnier; Jordi Clarimon; Carlos Cruchaga; Antonio Daniele; Jean François Dartigues; Stéphanie Debette; Jean François Deleuze; Nicola Denning; Anita L. DeStefano; Oriol Dols-Icardo; Cornelia M. van Duijn; Lindsay A. Farrer; Maria Victoria Fernández; Wiesje M. van der Flier; Nick C. Fox; Daniela Galimberti; Emmanuelle Genin; Johan J.P. Gille; Benjamin Grenier-Boley; Detelina Grozeva; Yann Le Guen; Rita Guerreiro; Jonathan L. Haines; Clive Holmes; Holger Hummerich; M. Arfan Ikram; M. Kamran Ikram; Amit Kawalia; Robert Kraaij; Jean Charles Lambert; Marc Lathrop; Afina W. Lemstra; Alberto Lleó; Richard M. Myers; Marcel M.A.M. Mannens; Rachel Marshall; Eden R. Martin; Carlo Masullo; Richard Mayeux; Simon Mead; Patrizia Mecocci; Alun Meggy; Merel O. Mol; Benedetta Nacmias; Adam C. Naj; Valerio Napolioni; J. Nicholas Cochran; Gaël Nicolas; Florence Pasquier; Pau Pastor; Margaret A. Pericak-Vance; Yolande A.L. Pijnenburg; Fabrizio Piras; Olivier Quenez; Alfredo Ramirez; Rachel Raybould; Richard Redon; Marcel J.T. Reinders; Anne Claire Richard; Steffi G. Riedel-Heller; Fernando Rivadeneira; Jeroen G.J. van Rooij; Stéphane Rousseau; Natalie S. Ryan; Pascual Sanchez-Juan; Gerard D. Schellenberg; Philip Scheltens; Jonathan M. Schott; Sudha Seshadri; Daoud Sie; Rebecca Sims; Erik A. Sistermans; Sandro Sorbi; John C. van Swieten; Betty Tijms; André G. Uitterlinden; Pieter Jelle Visser; Michael Wagner; David Wallon; Li San Wang; Julie Williams; Jennifer S. Yokoyama; Aline Zarea; Sven J. van der Lee; Johan G. Olsen; Marc Hulsman; Henne Holstege

doi:10.1186/s13024-025-00907-z

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

Olav M. Andersen^*
, Matthijs W.J. de Waal
, Giulia Monti
, Niccolo Tesi
, Anne Mette G. Jensen
, Christa de Geus
, Rosalina van Spaendonk
, Maartje Vogel
, Shahzad Ahmad
, Najaf Amin
, Philippe Amouyel
, Gary W. Beecham
, Céline Bellenguez
, Claudine Berr
, Joshua C. Bis
, Anne Boland
, Paola Bossù
, Femke Bouwman
, Jose Bras
, Camille Charbonnier

Jordi Clarimon, Carlos Cruchaga, Antonio Daniele, Jean François Dartigues, Stéphanie Debette, Jean François Deleuze, Nicola Denning, Anita L. DeStefano, Oriol Dols-Icardo, Cornelia M. van Duijn, Lindsay A. Farrer, Maria Victoria Fernández, Wiesje M. van der Flier, Nick C. Fox, Daniela Galimberti, Emmanuelle Genin, Johan J.P. Gille, Benjamin Grenier-Boley, Detelina Grozeva, Yann Le Guen, Rita Guerreiro, Jonathan L. Haines, Clive Holmes, Holger Hummerich, M. Arfan Ikram, M. Kamran Ikram, Amit Kawalia, Robert Kraaij, Jean Charles Lambert, Marc Lathrop, Afina W. Lemstra, Alberto Lleó, Richard M. Myers, Marcel M.A.M. Mannens, Rachel Marshall, Eden R. Martin, Carlo Masullo, Richard Mayeux, Simon Mead, Patrizia Mecocci, Alun Meggy, Merel O. Mol, Benedetta Nacmias, Adam C. Naj, Valerio Napolioni, J. Nicholas Cochran, Gaël Nicolas, Florence Pasquier, Pau Pastor, Margaret A. Pericak-Vance, Yolande A.L. Pijnenburg, Fabrizio Piras, Olivier Quenez, Alfredo Ramirez, Rachel Raybould, Richard Redon, Marcel J.T. Reinders, Anne Claire Richard, Steffi G. Riedel-Heller, Fernando Rivadeneira, Jeroen G.J. van Rooij, Stéphane Rousseau, Natalie S. Ryan, Pascual Sanchez-Juan, Gerard D. Schellenberg, Philip Scheltens, Jonathan M. Schott, Sudha Seshadri, Daoud Sie, Rebecca Sims, Erik A. Sistermans, Sandro Sorbi, John C. van Swieten, Betty Tijms, André G. Uitterlinden, Pieter Jelle Visser, Michael Wagner, David Wallon, Li San Wang, Julie Williams, Jennifer S. Yokoyama, Aline Zarea, Sven J. van der Lee, Johan G. Olsen, Marc Hulsman, Henne Holstege^*

^*Corresponding author for this work

Aarhus University
Vrije Universiteit Amsterdam
Amsterdam UMC
Delft University of Technology
University of Oxford
Université de Lille
University of Miami
Université de Montpellier
University of Washington School of Medicine
Centre National de Recherche en Génomique Humaine
IRCCS Fondazione Santa Lucia - Roma
Michigan State University
Van Andel Institute
Université de Rouen Normandie
Autonomous University of Barcelona
Instituto de Salud Carlos III
Washington University School of Medicine in St. Louis
Agostino Gemelli University Hospital Foundation IRCCS
Institut national de la santé et de la recherche médicale
University Hospital of Bordeaux
Cardiff University School of Medicine
Boston University School of Public Health
The Framingham Heart Study
Boston University School of Medicine
Boston University
University College London
University of Milan
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
Université de Bretagne Occidentale
Stanford University School of Medicine
Case Western Reserve University School of Medicine
University of Southampton
Erasmus University Rotterdam
University Hospital Cologne
McGill University
HudsonAlpha Institute for Biotechnology
University of Amsterdam
Catholic University of the Sacred Heart
Columbia University
University of Perugia
Karolinska Institutet
IRCCS Fondazione Don Carlo Gnocchi - Milano
University of Florence
UPenn School of Medicine
University of Camerino
Generalitat de Catalunya
The Germans Trias i Pujol Research Institute (IGTP) Badalona
University of Cologne
University of Texas Health Science Center at San Antonio
German Center for Neurodegenerative Diseases
University Hospital Bonn
L'Institut du Thorax Curie-Montsouris
Leipzig University
Hospital Universitario Marques de Valdecilla
Vrije Universiteit Amsterdam
Cardiff University
University of California at San Francisco
University of Copenhagen

Research output: Contribution to journal › Article › Academic › peer-review

1 Citation (Scopus)

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Abstract

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.

Original language	English
Article number	122
Journal	Molecular Neurodegeneration
Volume	20
Issue number	1
DOIs	https://doi.org/10.1186/s13024-025-00907-z
Publication status	Published - 1 Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

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Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s diseaseFinal published version, 6.05 MBLicence: CC0

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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., ... Holstege, H. (2025). Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease. Molecular Neurodegeneration, 20(1), Article 122. https://doi.org/10.1186/s13024-025-00907-z

@article{bbd5b47966b44f4e8f8fd6f13a860358,

title = "Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer{\textquoteright}s disease",

abstract = "Background: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer{\textquoteright}s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. Methods: To identify high-priority missense variants (HPVs), we applied {\textquoteleft}domain mapping of disease mutations{\textquoteright} 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 \textasciitilde{}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.",

author = "Andersen, \{Olav M.\} and \{de Waal\}, \{Matthijs W.J.\} and Giulia Monti and Niccolo Tesi and Jensen, \{Anne Mette G.\} and \{de Geus\}, Christa and \{van Spaendonk\}, Rosalina and Maartje Vogel and Shahzad Ahmad and Najaf Amin and Philippe Amouyel and Beecham, \{Gary W.\} and C{\'e}line Bellenguez and Claudine Berr and Bis, \{Joshua C.\} and Anne Boland and Paola Boss{\`u} and Femke Bouwman and Jose Bras and Camille Charbonnier and Jordi Clarimon and Carlos Cruchaga and Antonio Daniele and Dartigues, \{Jean Fran{\c c}ois\} and St{\'e}phanie Debette and Deleuze, \{Jean Fran{\c c}ois\} and Nicola Denning and DeStefano, \{Anita L.\} and Oriol Dols-Icardo and \{van Duijn\}, \{Cornelia M.\} and Farrer, \{Lindsay A.\} and Fern{\'a}ndez, \{Maria Victoria\} and \{van der Flier\}, \{Wiesje M.\} and Fox, \{Nick C.\} and Daniela Galimberti and Emmanuelle Genin and Gille, \{Johan J.P.\} and Benjamin Grenier-Boley and Detelina Grozeva and Guen, \{Yann Le\} and Rita Guerreiro and Haines, \{Jonathan L.\} and Clive Holmes and Holger Hummerich and \{Arfan Ikram\}, M. and \{Kamran Ikram\}, M. and Amit Kawalia and Robert Kraaij and Lambert, \{Jean Charles\} and Marc Lathrop and Lemstra, \{Afina W.\} and Alberto Lle{\'o} and Myers, \{Richard M.\} and Mannens, \{Marcel M.A.M.\} and Rachel Marshall and Martin, \{Eden R.\} and Carlo Masullo and Richard Mayeux and Simon Mead and Patrizia Mecocci and Alun Meggy and Mol, \{Merel O.\} and Benedetta Nacmias and Naj, \{Adam C.\} and Valerio Napolioni and \{Nicholas Cochran\}, J. and Ga{\"e}l Nicolas and Florence Pasquier and Pau Pastor and Pericak-Vance, \{Margaret A.\} and Pijnenburg, \{Yolande A.L.\} and Fabrizio Piras and Olivier Quenez and Alfredo Ramirez and Rachel Raybould and Richard Redon and Reinders, \{Marcel J.T.\} and Richard, \{Anne Claire\} and Riedel-Heller, \{Steffi G.\} and Fernando Rivadeneira and \{van Rooij\}, \{Jeroen G.J.\} and St{\'e}phane Rousseau and Ryan, \{Natalie S.\} and Pascual Sanchez-Juan and Schellenberg, \{Gerard D.\} and Philip Scheltens and Schott, \{Jonathan M.\} and Sudha Seshadri and Daoud Sie and Rebecca Sims and Sistermans, \{Erik A.\} and Sandro Sorbi and \{van Swieten\}, \{John C.\} and Betty Tijms and Uitterlinden, \{Andr{\'e} G.\} and Visser, \{Pieter Jelle\} and Michael Wagner and David Wallon and Wang, \{Li San\} and Julie Williams and Yokoyama, \{Jennifer S.\} and Aline Zarea and \{van der Lee\}, \{Sven J.\} and Olsen, \{Johan G.\} and Marc Hulsman and Henne Holstege",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

day = "1",

doi = "10.1186/s13024-025-00907-z",

language = "English",

volume = "20",

journal = "Molecular Neurodegeneration",

issn = "1750-1326",

publisher = "BioMed Central Ltd.",

number = "1",

}

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, JF, Debette, S, Deleuze, JF, 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, JC, 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, AC, 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, LS, Williams, J, Yokoyama, JS, Zarea, A, van der Lee, SJ, Olsen, JG, Hulsman, M & Holstege, H 2025, 'Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease', Molecular Neurodegeneration, vol. 20, no. 1, 122. https://doi.org/10.1186/s13024-025-00907-z

TY - JOUR

T1 - Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

AU - Andersen, Olav M.

AU - de Waal, Matthijs W.J.

AU - Monti, Giulia

AU - Tesi, Niccolo

AU - Jensen, Anne Mette G.

AU - de Geus, Christa

AU - van Spaendonk, Rosalina

AU - Vogel, Maartje

AU - Ahmad, Shahzad

AU - Amin, Najaf

AU - Amouyel, Philippe

AU - Beecham, Gary W.

AU - Bellenguez, Céline

AU - Berr, Claudine

AU - Bis, Joshua C.

AU - Boland, Anne

AU - Bossù, Paola

AU - Bouwman, Femke

AU - Bras, Jose

AU - Charbonnier, Camille

AU - Clarimon, Jordi

AU - Cruchaga, Carlos

AU - Daniele, Antonio

AU - Dartigues, Jean François

AU - Debette, Stéphanie

AU - Deleuze, Jean François

AU - Denning, Nicola

AU - DeStefano, Anita L.

AU - Dols-Icardo, Oriol

AU - van Duijn, Cornelia M.

AU - Farrer, Lindsay A.

AU - Fernández, Maria Victoria

AU - van der Flier, Wiesje M.

AU - Fox, Nick C.

AU - Galimberti, Daniela

AU - Genin, Emmanuelle

AU - Gille, Johan J.P.

AU - Grenier-Boley, Benjamin

AU - Grozeva, Detelina

AU - Guen, Yann Le

AU - Guerreiro, Rita

AU - Haines, Jonathan L.

AU - Holmes, Clive

AU - Hummerich, Holger

AU - Arfan Ikram, M.

AU - Kamran Ikram, M.

AU - Kawalia, Amit

AU - Kraaij, Robert

AU - Lambert, Jean Charles

AU - Lathrop, Marc

AU - Lemstra, Afina W.

AU - Lleó, Alberto

AU - Myers, Richard M.

AU - Mannens, Marcel M.A.M.

AU - Marshall, Rachel

AU - Martin, Eden R.

AU - Masullo, Carlo

AU - Mayeux, Richard

AU - Mead, Simon

AU - Mecocci, Patrizia

AU - Meggy, Alun

AU - Mol, Merel O.

AU - Nacmias, Benedetta

AU - Naj, Adam C.

AU - Napolioni, Valerio

AU - Nicholas Cochran, J.

AU - Nicolas, Gaël

AU - Pasquier, Florence

AU - Pastor, Pau

AU - Pericak-Vance, Margaret A.

AU - Pijnenburg, Yolande A.L.

AU - Piras, Fabrizio

AU - Quenez, Olivier

AU - Ramirez, Alfredo

AU - Raybould, Rachel

AU - Redon, Richard

AU - Reinders, Marcel J.T.

AU - Richard, Anne Claire

AU - Riedel-Heller, Steffi G.

AU - Rivadeneira, Fernando

AU - van Rooij, Jeroen G.J.

AU - Rousseau, Stéphane

AU - Ryan, Natalie S.

AU - Sanchez-Juan, Pascual

AU - Schellenberg, Gerard D.

AU - Scheltens, Philip

AU - Schott, Jonathan M.

AU - Seshadri, Sudha

AU - Sie, Daoud

AU - Sims, Rebecca

AU - Sistermans, Erik A.

AU - Sorbi, Sandro

AU - van Swieten, John C.

AU - Tijms, Betty

AU - Uitterlinden, André G.

AU - Visser, Pieter Jelle

AU - Wagner, Michael

AU - Wallon, David

AU - Wang, Li San

AU - Williams, Julie

AU - Yokoyama, Jennifer S.

AU - Zarea, Aline

AU - van der Lee, Sven J.

AU - Olsen, Johan G.

AU - Hulsman, Marc

AU - Holstege, Henne

PY - 2025/12/1

Y1 - 2025/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105023593220

U2 - 10.1186/s13024-025-00907-z

DO - 10.1186/s13024-025-00907-z

M3 - Article

C2 - 41327266

AN - SCOPUS:105023593220

SN - 1750-1326

VL - 20

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

IS - 1

M1 - 122

ER -

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

Abstract

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