Disease-modifying effects of <i>TMEM106B</i> in genetic frontotemporal dementia: a longitudinal GENFI study

Common variants within TMEM106B are associated with risk for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). The G allele of the top single nucleotide polymorphism, rs1990622, confers protection against FTLD-TDP, including genetic cases due to GRN mutations or C9orf72 hexanucleotide repeat expansions. However, the effects of interaction between TMEM106B-rs1990622 and frontotemporal dementia (FTD) mutations on disease endophenotypes in genetic FTD are unknown. This longitudinal cohort study was embedded within the GENetic Frontotemporal dementia Initiative (GENFI). We included 518 participants from 222 families [209 non-carriers; 222 presymptomatic carriers (C9orf72 = 79; GRN = 101, MAPT = 42); 87 symptomatic carriers (C9orf72 = 45; GRN = 29; MAPT = 13)] followed for up to 7 years. Using linear mixed-effects models, we examined the effects of a triple interaction between TMEM106B-rs1990622G allele dosage (additive model: 0, 1 or 2 alleles) and autosomal dominant FTD mutations with clinical status, and time from baseline on (i) grey matter volume using a voxel-based analysis; (ii) serum neurofilament light chain (NfL) levels; and (iii) cognitive and behavioural measures. Mean age of participants was 47.9 ± 13.8 years, 58.1% were female and 61% had at least one G allele. C9orf72: rs1990622G allele dosage was associated with less atrophy within the right occipital region in presymptomatic carriers at baseline, and reduced atrophy rate within putamen and caudate nucleus, right frontotemporal regions, left cingulate and bilateral insular cortices in symptomatic carriers over time; lower NfL levels in presymptomatic carriers at baseline; better executive functions and language abilities in presymptomatic carriers; and maintained overall cognitive functions and behaviour in symptomatic carriers over time. GRN: rs1990622G allele dosage was associated with reduced grey matter atrophy rate within the right temporal and occipital regions in presymptomatic carriers, and within the right frontal cortex and insula over time in symptomatic carriers; lower serum NfL levels over time in presymptomatic carriers and lower NfL levels at both baseline and over time in symptomatic carriers; and better global cognitive performance at baseline and higher attention/processing speed scores over time in symptomatic carriers. MAPT: rs1990622G allele dosage was associated with reduced grey matter atrophy rate within the right inferior frontal gyrus in symptomatic carriers, but no effects on serum NfL or cognitive/behavioural measures. TMEM106B-rs1990622G allele dosage showed protective effects on multiple endophenotypes predominantly in GRN and C9orf72 groups. Therefore, TMEM106B genotype should be assessed in clinical trials, particularly of GRN- and C9orf72-related genetic FTD, due to its modifying effects on biomarker, imaging, cognitive and clinical outcomes.

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Journal
Brain
Published
2025-04-22
DOI
https://doi.org/10.1093/brain/awaf019
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1
Primary Topic
Amyotrophic Lateral Sclerosis Research
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article
Field-Weighted Citation Impact
1.39

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article

Disease-modifying effects of TMEM106B in genetic frontotemporal dementia: a longitudinal GENFI study

Mattias Nilsson, Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai et al.
1 citations
Brain
Amyotrophic Lateral Sclerosis Research
1.39
article

Disease-modifying effects of TMEM106B in genetic frontotemporal dementia: a longitudinal GENFI study

Mattias Nilsson, Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai, Ron Keren, Kiran Samra, Koen Poesen, Olivier Colliot, John Cornelis Van Swieten, Maura Malpetti, Alexander Bernhardt, Robert Bartha, Stefano Chiti, Rick van Minkelen, Carolina Maruta, Caroline Graff, Ekaterina A. Rogaeva, Philip Van Damme, Giacomina Rossi, Alazne Gabilondo, Andrea Arighi, Liset de Boer, Valentina Bessi, Maria Carmela Tartaglia, Jaume Olives, Tobias Christoph Langheinrich, Enrico Premi, James Benedict Rowe, Albert Lladó, Timothy Rittman, Giorgio Giaccone, Alexander Gerhard, Lucia Giannini, Alexis Brice, Christopher Robert Butler, Roberto Gasparotti, María Serpente, Matthis Synofzik, Emanuele Buratti, Vesna Jelić, Linn Öijerstedt, Lisa Graf, Johannes Levin, Saira Saeed Mirza, Johanna Krüger, Gemma Lombardi, Aurélie Funkiewiez, Alexandre de Mendonça, Jolina Lombardi, Eve Ferry‐Bolder, Mircea Balasa, Sandra E. Black, Anna Stockbauer, David M. Cash, João Durães, David Mengel, Camilla Ferrari, Thomas Cope, Sara Prioni, Raquel Sánchez‐Valle, Sonja Schönecker, Veronica Redaelli, Rosa Rademakers, Núria Bargalló, Harro Seelaar, Jackie M. Poos, Aitana Sogorb‐Esteve, Sergi Borrego‐Écija, Pietro Tiraboschi, Frederico Simões do Couto, Grégory Kuchcinski, Andrew D. Paterson, Phoebe H. Foster, Florence Pasquier, Benjamin Bender, Anne Bertrand, Tiago Costa-Coelho, Arabella Bouzigues, Lize Corrine Jiskoot, Daisy Rinaldi, Enrico Fainardi, Dario Saracino, Cristina Polito, Martina Bocchetta, Annick Vogels, Antonella Alberici, Vittoria Borracci, Lucy Louise Russell, Jonathan D. Rohrer, Maurice Pasternak, Markus Otto, Rik R. Vandenberghe, Maxime Bertoux, Jan De Houwer, Elizabeth C. Finger, Patricia Alves, Valentina Cantoni, Mathieu Vandenbulcke, Ioana Croitoru, Adeline Rollin, Chiara Fenoglio, Melissa Taheri Rydell, Ana Verdelho, Henrik Viklund, Catharina Prix, Miguel Tábuas‐Pereira, Marisa Lima, Henrik Zetterberg, Vincent Deramecourt, Maria João Leitão, Maria Rosário Almeida, Thibaud Lebouvier, Mario Masellis, Emanuela Rotondo, Fermín Moreno, Robert Laforce, David Lee Thomas, Olivia Wagemann, Rhian S. Convery, Tiziana Carandini, Giuseppe Di Fede, João M. Lemos, Barbara Borroni, Pedro Rosa‐Neto, Sarah Anderl‐Straub, Isabelle Le Ber, Miguel Castelo-Branco, Myriam Barandiarán, Yolande A.L. Pijnenburg, Mikel Tainta, Daniela Galimberti, Sara Berman Mitchell, Sandro Sorbi, Rose Bruffaerts, Simon Ducharme, Gabriel Miltenberger, Sònia Afonso, Anna Antonell, Christen Shoesmith, Sophie Goldsmith, Agnès Camuzat, Sabrina Sayah, Paola Caroppo, Isabel Santana, Janne M. Papma, Benedetta Nacmias, Maxime Montembault
article en
1 citations

Abstract

Common variants within TMEM106B are associated with risk for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). The G allele of the top single nucleotide polymorphism, rs1990622, confers protection against FTLD-TDP, including genetic cases due to GRN mutations or C9orf72 hexanucleotide repeat expansions. However, the effects of interaction between TMEM106B-rs1990622 and frontotemporal dementia (FTD) mutations on disease endophenotypes in genetic FTD are unknown. This longitudinal cohort study was embedded within the GENetic Frontotemporal dementia Initiative (GENFI). We included 518 participants from 222 families [209 non-carriers; 222 presymptomatic carriers (C9orf72 = 79; GRN = 101, MAPT = 42); 87 symptomatic carriers (C9orf72 = 45; GRN = 29; MAPT = 13)] followed for up to 7 years. Using linear mixed-effects models, we examined the effects of a triple interaction between TMEM106B-rs1990622G allele dosage (additive model: 0, 1 or 2 alleles) and autosomal dominant FTD mutations with clinical status, and time from baseline on (i) grey matter volume using a voxel-based analysis; (ii) serum neurofilament light chain (NfL) levels; and (iii) cognitive and behavioural measures. Mean age of participants was 47.9 ± 13.8 years, 58.1% were female and 61% had at least one G allele. C9orf72: rs1990622G allele dosage was associated with less atrophy within the right occipital region in presymptomatic carriers at baseline, and reduced atrophy rate within putamen and caudate nucleus, right frontotemporal regions, left cingulate and bilateral insular cortices in symptomatic carriers over time; lower NfL levels in presymptomatic carriers at baseline; better executive functions and language abilities in presymptomatic carriers; and maintained overall cognitive functions and behaviour in symptomatic carriers over time. GRN: rs1990622G allele dosage was associated with reduced grey matter atrophy rate within the right temporal and occipital regions in presymptomatic carriers, and within the right frontal cortex and insula over time in symptomatic carriers; lower serum NfL levels over time in presymptomatic carriers and lower NfL levels at both baseline and over time in symptomatic carriers; and better global cognitive performance at baseline and higher attention/processing speed scores over time in symptomatic carriers. MAPT: rs1990622G allele dosage was associated with reduced grey matter atrophy rate within the right inferior frontal gyrus in symptomatic carriers, but no effects on serum NfL or cognitive/behavioural measures. TMEM106B-rs1990622G allele dosage showed protective effects on multiple endophenotypes predominantly in GRN and C9orf72 groups. Therefore, TMEM106B genotype should be assessed in clinical trials, particularly of GRN- and C9orf72-related genetic FTD, due to its modifying effects on biomarker, imaging, cognitive and clinical outcomes.

BrainVol. 148(8)
Western University (CA), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Sunnybrook Health Science Centre (CA), University Health Network (CA), Karolinska University Hospital (SE), University of Lisbon (PT), Inserm (FR), University of Toronto (CA), University of Milan (IT), Universität Ulm (DE), Hong Kong University of Science and Technology (HK), Université de Lille (FR), University of Cambridge (GB), Douglas Mental Health University Institute (CA), Sahlgrenska University Hospital (SE), Hospital for Sick Children (CA), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Health Sciences Centre (CA), Baycrest Hospital (CA), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), University of Manchester (GB), Sorbonne Université (FR), University of Oxford (GB), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Assistance Publique – Hôpitaux de Paris (FR), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Don Carlo Gnocchi Foundation (IT), BioClinicum (Russia) (RU), UK Dementia Research Institute (GB), Donostiako Unibertsitate Ospitalea (ES), Hertie Institute for Clinical Brain Research (DE), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), Ferrari (Italy) (IT), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Université Laval (CA), Krembil Research Institute, University of Florence (IT), University College London (GB), Imperial College London (GB), McGill University (CA), Universitat de Barcelona (ES), University of Coimbra (PT), University of Brescia (IT), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), University of Gothenburg (SE), KU Leuven (BE)
Wellcome Trust, Weston Brain Institute, Sunnybrook Foundation, National Institute for Health and Care Research, Department of Health and Social Care, University of Cambridge, University College London, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, University of Toronto, Hjärnfonden, Vetenskapsrådet, Alzheimerfonden, Stichting Dioraphte, Alzheimer Nederland, Canadian Institutes of Health Research, Medical Research Council, Instituto de Salud Carlos III, NIHR Cambridge Biomedical Research Centre
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Amyotrophic Lateral Sclerosis Research
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