Evidence map›Paper›PMID 40260680›Full record

ArticleBrain : a journal of neurology2025

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

Saira S Mirza, Maurice Pasternak, Andrew D Paterson, Ekaterina Rogaeva, Maria C Tartaglia, Sara B Mitchell, Sandra E Black, Morris Freedman, David Tang-Wai, Arabella Bouzigues and 34 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Article
  6. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

44 authors.

Saira S MirzaCentre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.ORCID 0000-0002-0973-2246
Maurice PasternakCentre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.ORCID 0000-0003-0647-172X
Andrew D PatersonProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada.ORCID 0000-0002-9169-118X
Ekaterina RogaevaTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 1A8, Canada.
Maria C TartagliaTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 1A8, Canada.
Sara B MitchellDivision of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada.
Sandra E BlackCentre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.
Morris FreedmanDivision of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada.
David Tang-WaiDivision of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada.
Arabella BouziguesDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.
Lucy L RussellDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.
Phoebe H FosterDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.
Eve Ferry-BolderDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.
Martina BocchettaDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.ORCID 0000-0003-1814-5024
David M CashDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.ORCID 0000-0001-7833-616X
Henrik ZetterbergDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.ORCID 0000-0003-3930-4354
Aitana Sogorb-EsteveDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.
John van SwietenDepartment of Neurology, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.
Lize C JiskootDepartment of Neurology, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.ORCID 0000-0002-1120-1858
Harro SeelaarDepartment of Neurology, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.ORCID 0000-0003-1989-7527
Raquel Sanchez-ValleAlzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona 08036, Spain.ORCID 0000-0001-7750-896X
Robert LaforceClinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Quebec, QC G1V 4G2, Canada.
Caroline GraffDepartment of Neurobiology, Care Sciences and Society; Center for Alzheimer Research, Division of Neurogeriatrics, Bioclinicum, Karolinska Institutet, Solna 171 65, Sweden.ORCID 0000-0002-9949-2951
Daniela GalimbertiFondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan 20122, Italy.
Rik VandenbergheLaboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven 3001, Belgium.ORCID 0000-0001-6237-2502
Alexandre de MendonçaFaculty of Medicine, University of Lisbon, Lisbon 1649-028, Portugal.
Pietro TiraboschiDipartimento Diagnostica e Tecnologia - Neurologia V, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano 20133, Italy.
Isabel SantanaFaculty of Medicine, University of Coimbra, Coimbra 3004-531, Portugal.
Alexander GerhardDivision of Psychology Communication and Human Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester M20 3LJ, UK.ORCID 0000-0002-8071-6062
Johannes LevinDepartment of Neurology, Ludwig-Maximilians Universität München, Munich 80802, Germany.ORCID 0000-0001-5092-4306
Sandro SorbiDepartment of Neurofarba, University of Florence, Florence 50139, Italy.
Markus OttoDepartment of Neurology, University of Ulm, ULM 45 89081, Germany.
Florence PasquierDivision of Neurology, Faculty of Medicine, Univ Lille, Lille 59000, France.ORCID 0000-0001-9880-9788
Simon DucharmeDouglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada.ORCID 0000-0002-7309-1113
Chris ButlerNuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford OX3 7JX, UK.
Isabelle Le BerSorbonne Université, Paris Brain Institute-Institut du Cerveau-ICM, Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpêtrière, Paris 75013, France.
Elizabeth FingerDepartment of Clinical Neurological Sciences, University of Western Ontario, London, ON N6A 3K7, Canada.
James B RoweDepartment of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 3EB, UK.
Matthis SynofzikDepartment of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany.ORCID 0000-0002-2280-7273
Fermin MorenoCognitive Disorders Unit, Department of Neurology, Hospital Universitario Donostia, Donostia, Gipuzkoa 20014, Spain.
Barbara BorroniNeurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia 15-25121, Italy.ORCID 0000-0001-9340-9814
Jonathan D RohrerDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3AR, UK.
Mario MasellisCentre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.ORCID 0000-0002-6244-2096
GENetic Frontotemporal dementia Initiative (GENFI)

Funding

Alzheimer FoundationAlzheimer Nederland and the Bluefield ProjectAlzheimer's Research UK Clinical Research Training Fellowship ARUK-CRF2017B-2Alzheimer's Society, UK AS-JF-19a-004-517Association for Frontotemporal Dementias Research Grant 2009Brain FoundationCambridge University Centre for Frontotemporal Dementia, the Medical Research Council MC_UU_00030/14Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council MR/T033371/1Canadian Institutes of Health Research (CIHR) #327387Canadian Institutes of Health Research (CIHR) MOP-327387Canadian Institutes of Health Research (CIHR) PJT-175242Carlos III Health Institute PI19/01637Centre of Brain Resilience and Recovery (CBRR)Dementia FoundationDepartment of Health and Social CareDepartment of Medicine at Sunnybrook Health Sciences Centre and the University of TorontoDeutsche Forschungsgemeinschaft German Research FoundationDioraphte Foundation 09-02-03-00EU Joint Programme-Neurodegenerative Disease Research 733051042EU Joint Programme-Neurodegenerative Disease Research Italian Ministry of HealthEU Joint Programme-Neurodegenerative Disease Research GENFI-PROX 2019-02248EU Joint Programme-Neurodegenerative Disease Research-Prefrontals Vetenskapsrådet Dnr 529-2014-7504European Reference Network for Rare Neurological Diseases (ERN-RND) 739510Fundació Marató de TV3, Spain 20143810Germany's Federal Ministry of Education and ResearchHolt FellowshipMady Browaeys Fund for Research into Frontotemporal DementiaMiriam Marks Brain Research UK Senior FellowshipMunich Cluster for Systems Neurology 390857198National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre and has received funding from an MRC Clinician Scientist Fellowship MR/M008525/1National Institute for Health Research Cambridge Biomedical Research Centre BRC-1215-20014National Institute for Health Research Cambridge Biomedical Research Centre NIHR203312Netherlands Organization for Scientific Research HCMI 056-13-018NIHRRegion StockholmSunnybrook FoundationSwedish FTD Inititative-Schörling FoundationVetenskapsrådet 2015-02926Vetenskapsrådet 2018-02754Vetenskapsrådet 2019-0224Wellcome Trust 103838Wellcome Trust 220258Weston Brain InstituteZonMw Memorabel 733 051 042ZonMw Onderzoeksprogramma Dementie 10510032120002
6 · The paper itself

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.

Indexed as

Frontotemporal DementiaMembrane ProteinsNerve Tissue ProteinsAdultAgedAtrophyC9orf72 ProteinCohort StudiesFemaleHumansLongitudinal StudiesMagnetic Resonance ImagingMaleMiddle AgedMutationPolymorphism, Single NucleotideC9orf72 ProteinC9orf72 protein, humanGRN protein, humanMembrane ProteinsNerve Tissue ProteinsProgranulinsTMEM106B protein, humanadditive modelblood-based biomarkerscognitionFTLD-TDPstructural MRITMEM106B

Identifiers

PMID40260680
PMCPMC12316011

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.