Educational attainment and sex modulate clinical outcomes in genetic frontotemporal dementia
Year: 2026
Type: article
Abstract: Individuals with autosomal dominant frontotemporal dementia (FTD) exhibit considerable variability in disease onset and progression. Both modifiable and non-modifiable factors—such as sex, educational attainment or geographic region of residence—may contribute to this heterogeneity, potentially through their influence on cognitive reserve. The aim of the present study was to investigate the role of cognitive reserve modulators within the Genetic Frontotemporal dementia Initiative (GENFI) cohort. To this end, we used functional MRI (i.e. spatial chronnectome measures) and neurodegenerative markers (i.e. plasma neurofilament light chains levels) to determine disease stage using a Discriminative Event-Based Model (DEBM). We then examined how potential modulators influence the relationship between disease stage and cognitive performance. We analysed a total of 711 participants, including 106 patients with genetic FTD, 325 presymptomatic mutation carriers and 280 non-carriers healthy controls. Female participants showed a weaker association between disease stage and cognitive performance compared to males (P < 0.001), with difference becoming progressively more pronounced across symptomatic stages. Educational attainment exhibited a similar effect: individuals with higher education demonstrated an attenuated association compared to those with secondary or primary schooling (P < 0.001), with differences already detectable at prodromal disease stages. The effect of geographical region of residence was associated with education levels, but appeared to have an indirect and less strong influence. In summary, sex and educational attainment significantly affect the development and maintenance of cognitive reserve in individuals with genetic FTD. These findings underscore the importance of identifying disease-modifying interventions since the presymptomatic stages of the disease.
Source: Brain Communications
Authors: Enrico Premi, Damiano Archetti, Alberto Redolfi, Valeria Bracca, Valentina Cantoni, Armin Iraji, Vince D Calhoun, Sonia Bellini, Roberta Ghidoni, Roberto Gasparotti, Arabella Bouzigues, Lucy L Russell, Phoebe H Foster, Eve Ferry-Bolder, John C van Swieten, Lize C Jiskoot, Harro Seelaar, Raquel Sanchez-Valle, Robert Laforce, Caroline Graff, Daniela Galimberti, Rik Vandenberghe, Alexandre de Mendonça, Giuseppe Di Fede, Isabel Santana, Alexander Gerhard, Johannes Levin, Benedetta Nacmias, Markus Otto, Maxime Bertoux, Thibaud Lebouvier, Simon Ducharme, Christopher R Butler, Isabelle Le Ber, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, James B Rowe, Matthis Synofzik, Fermin Moreno, Henrik Zetterberg, Jonathan D Rohrer, Barbara Borroni, the GENetic Frontotemporal dementia Initiative (GENFI), Rhian Convery, Martina Bocchetta, David Cash, Sophie Goldsmith, Kiran Samra, David L Thomas, Thomas Cope, Maura Malpetti, Antonella Alberici, Emanuele Buratti, Andrea Arighi, Chiara Fenoglio, Vittoria Borracci, Maria Serpente, Tiziana Carandini, Emanuela Rotondo, Giacomina Rossi, Giorgio Giaccone, Pietro Tiraboschi, Paola Caroppo, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robert Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Liset de Boer, Julie de Houwer, Rick van Minkelen, Yolande Pijnenburg, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Enrico Fainardi, Stefano Chiti, Mattias Nilsson, Henrik Viklund, Melissa Taheri Rydell, Vesna Jelic, Abbe Ullgren, Elena Rodriguez-Vieitez, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Tiago Costa-Coelho, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ioana Croitoru, Mikel Tainta, Myriam Barandiaran, Patricia Alves, Benjamin Bender, David Mengel, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Maxime Montembeault, Raffaella Lara Migliaccio, Ninon Burgos, Daisy Rinaldi, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sonja Schönecker, Alexander Maximilian Bernhardt, Anna Stockbauer, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Vincent Deramecourt, João Durães, Marisa Lima, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso, João Lemos
Institutions: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Centro San Giovanni di Dio Fatebenefratelli, University of Brescia, Georgia Institute of Technology, Center for Translational Research in Neuroimaging and Data Science, Inserm, Sorbonne Université, Institut du Cerveau, UCL Queen Square Institute of Neurology, University College London, Erasmus MC, Hospital Clínic de Barcelona, Universitat de Barcelona, Centre hospitalier universitaire de Québec, Université Laval, Karolinska University Hospital, Karolinska Institutet, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Universitair Ziekenhuis Leuven, KU Leuven, University of Lisbon, Fondazione IRCCS Istituto Neurologico Carlo Besta, Unidade Local de Saúde de Coimbra, University of Coimbra, University of Manchester, Klinikum Arnsberg, Stiftung Universitätsmedizin Essen, University of Duisburg-Essen, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology, Ludwig-Maximilians-Universität München, University of Florence, Universität Ulm, Université de Lille, Centre Hospitalier Universitaire de Lille, Lille Neurosciences & Cognition, Montreal Neurological Institute and Hospital, Douglas Mental Health University Institute, McGill University Health Centre, McGill University, University of Oxford, Imperial College London, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Western University, University of Toronto, Sunnybrook Health Science Centre, Sunnybrook Research Institute, University of Cambridge, Hertie Institute for Clinical Brain Research, University of Tübingen, Instituto de Salud Carlos III, Biomedical Research Networking Center on Neurodegenerative Diseases, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, University of Wisconsin–Madison, Sahlgrenska University Hospital, University of Gothenburg
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,024
Funders: McGill University, Fundació la Marató de TV3, Ontario Brain Institute, Wellcome Trust, Weston Brain Institute, EU Joint Programme – Neurodegenerative Disease Research, Brain Research UK, National Institute for Health and Care Research, University of Cambridge, University College London, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, ZonMw, Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius-Stiftung, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Hjärnfonden, Karolinska Institutet, Vetenskapsrådet, Alzheimerfonden, Stichting Dioraphte, Canada First Research Excellence Fund, Alzheimer Nederland, Centre hospitalier régional universitaire de Lille, National Institutes of Health, Tau Consortium, Canadian Institutes of Health Research, Medical Research Council, Fonds de recherche du Québec – Nature et technologies, Instituto de Salud Carlos III, Horizon 2020, NIHR Cambridge Biomedical Research Centre, Hospital Clínic de Barcelona, Canadian Institutes of Health Research - Antimicrobial Resistance Research Initiative
Awards: G1076890169, G1240843554, G1426422999, G1789099517, G1920181826, G2076520454, G2340318771, G2493601830, Defining measures of proximity to symptom onset in the GENetic Frontotemporal dementia Initiative, G2537968379, G2588154941, G2951265004, G3128737150, G3146813671, G3226649254, G3245177014, G3379762541, G3463773922, Restoring brain function: from cortical microcircuits to complex behaviours in neurodegenerative disease., G3600895423, G3691030594, Diseño de biomarcadores para Demencia Fronto-temporal asociada a mutaciones en GRN, G3836382391, G3923834380, EXC 2145: Munich Cluster for Systems Neurology (SyNergy), G4014046109, Bridging the gap: biophysical models of human frontotemporal lobar degeneration, G4190891609, G4260212813, G4665392370, G4753630297, Demencias genéticas (enfermedad de Alzheimer, demencia frontotemporal y enfermedades priónicas genéticas): cambios longitudinales y diferencias en expresión y epigenéticas con formas esporádicas, G5426136232, G5585825558, G592391772, G6115791316, Decision making and dementia: from mechanisms to clinical trials, G6368058359, G6745503199, G6749461845, MICA: Dementias Platform UK 2 - Integrated Dementia Experimental Medicine, G712881263, G7250878952, G730080581, G7345120862, G7624737488, G7649985594, G7692674602, Human genetic studies of Alzheimer disease and other dementias, G784856114, EUROPEAN RARE DISEASES RESEARCH ALLIANCE, G7998175682, G8260178993, G8347284120, G8382260133, Genetic Frontotemporal Dementia Initiative (GENFI) in Canada: Combined Investigation of Clinical, MRI, Genomic, and Epigenomic Biomarkers, G8689871703, Developing an evidence base for trials in genetic frontotemporal dementia - measures of disease onset and progression, Human genetic studies of Alzheimer disease and other dementias
OpenAlex ID: W7172439073