Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study

BACKGROUND: What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation. METHODS: In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method. FINDINGS: Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level. INTERPRETATION: Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed. FUNDING: Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.

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Journal
The Lancet Neurology
Published
2026-07-16
DOI
https://doi.org/10.1016/s1474-4422(26)00197-3
Citations
1
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
8.83

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article

Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study

Mattias Nilsson, Kiran Samra, Maura Malpetti, Stefano Chiti et al.
1 citations
The Lancet Neurology
Amyotrophic Lateral Sclerosis Research
8.83
article

Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study

Mattias Nilsson, Kiran Samra, Maura Malpetti, Stefano Chiti, Rick van Minkelen, Andrea Arighi, Liset de Boer, Jaume Olives, Lleras Santana, Giorgio Giaccone, M Tartaglia, María Serpente, Emanuele Buratti, Vesna Jelić, Johanna Krüger, Gemma Lombardi, Sonia Bellini, Cortes Llado A, Sara Prioni, Phoebe H. Foster, Rose Bruffaerts, Arabella Bouzigues, R Convery, Thomas Cope, Cristina Polito, Vittoria Borracci, Valentina Cantoni, Melissa Taheri Rydell, Henrik Viklund, Fenoglio Cm, Luigi Giannini, Emanuela Rotondo, Le Ber, R Keren, Tiziana Carandini, Giuseppe Di Fede, Yal Pijnenburg, Mika Kinnunen, Christopher Butler, Robart Bartha, J Levin, David Tang-Wai, Jackie Poos, Sophie Goldsmith, David Cash, Tobias Langheinrich, Raffaella Migliaccio, Christen Shoesmith, Maxime Bertoux, Sandra Black, Markus Otto, David L. Thomas, Enrico Fainardi, Sara Mitchell, Giancarlo Logroscino, Martina Bocchetta, James B Rowe, Miguel Castelo-Branco, Benedetta Nacmias, Mario Grassi, Robert Laforce, Eve Ferry-Bolder, Eino Solje, Giuliano Binetti, Mario Masellis, Anna Antonell, Daniela Galimberti, Rik Vandenberghe, Fermin Moreno, Valentina Bessi, Simon Ducharme, Lize C Jiskoot, John C van Swieten, Alexander Gerhard, Harro Seelaar, Elena Rodriguez-Vieitez, Jonathan D Rohrer, Matthis Synofzik, Raquel Sanchez-Valle, Camilla Ferrari, Alexandre de Mendonça, Ekaterina Rogaeva, Enrico Premi, Roberta Ghidoni, Veronica Redaelli, Lucy L Russell, Giacomina Rossi, Antonella Alberici, Abbe Ullgren, Roberto Gasparotti, Rosa Rademakers, Elizabeth Finger, Morris Freedman, Janne M. Papma, Julie de Houwer, Thibaud Lebouvier, Barbara Borroni, Paola Caroppo, Mircea Balasa, Caroline Graff
article en
1 citations

Abstract

BACKGROUND: What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation. METHODS: In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method. FINDINGS: Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level. INTERPRETATION: Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed. FUNDING: Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.

The Lancet NeurologyVol. 25(8)
Western University (CA), Montreal Neurological Institute and Hospital (CA), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), University of Lisbon (PT), Inserm (FR), University of Eastern Finland (FI), University of Toronto (CA), Universität Ulm (DE), Université de Lille (FR), University of Cambridge (GB), Oulu University Hospital (FI), Douglas Mental Health University Institute (CA), Universitair Ziekenhuis Leuven (BE), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), Kuopio University Hospital (FI), Innovation Engineering (Italy) (IT), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Greater Manchester STEM Centre (GB), MRC Brain Network Dynamics Unit (GB), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Don Carlo Gnocchi Foundation (IT), Essen University Hospital (DE), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), Hertie Institute for Clinical Brain Research (DE), National Hospital for Neurology and Neurosurgery (GB), VIB-KU Leuven Center for Brain & Disease Research (BE), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Université Laval (CA), University College London (GB), Universitat de Barcelona (ES), University of Coimbra (PT), University of Brescia (IT), Ludwig-Maximilians-Universität München (DE), Erasmus University Rotterdam (NL), KU Leuven (BE)
Fundació la Marató de TV3, Ontario Brain Institute, Weston Brain Institute, EU Joint Programme – Neurodegenerative Disease Research, Fondation Vaincre Alzheimer, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Hjärnfonden, Jane ja Aatos Erkon Säätiö, Vetenskapsrådet, Sigrid Juséliuksen Säätiö, Alzheimerfonden, Stichting Dioraphte, Alzheimer Nederland, Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek, Fondation Philippe Chatrier, Tau Consortium, Agenzia Italiana del Farmaco, Ministero della Salute, Jenny ja Antti Wihurin Rahasto, Instituto de Salud Carlos III, University College London Hospitals Biomedical Research Centre, NIHR Cambridge Biomedical Research Centre, Medical Research Foundation, Ministero dell'Istruzione e del Merito
Openalex Percentile: Top 2%
Amyotrophic Lateral Sclerosis Research
8.83
DOIOpen Access PDFOpenAlex
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