Peripheral microRNA signature in genetic frontotemporal dementia—findings from the GENFI initiative
Year: 2026
Type: article
Study design: Observational Study
Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by significant clinical and genetic heterogeneity, with approximately 40% of cases linked to hereditary genetic mutations, including MAPT, GRN, and C9ORF72. Recently, microRNAs (miRNAs) have emerged as key regulators of cellular processes related to neurodegeneration and as potential biomarkers for FTD. However, their relevance in presymptomatic stages remains poorly understood. We conducted a miRNA expression analysis using TaqMan OpenArray® panels on blood samples collected from 171 individuals, including symptomatic mutation carriers (SMC), presymptomatic carriers (PMC), and healthy non-carriers (NC). Dysregulated miRNAs were validated and bioinformatic tools were used to identify potential associated molecular pathways. In C9ORF72, miR-20b-5p and miR-223-5p were significantly upregulated in SMC (fold regulation over NC: 2.418 p = 0.0336 and 7.829 p < 0.0264 respectively) and PMC (5.518, p < 0.0001 and 3.941, p < 0.0001 respectively). In GRN mutation carriers, miR-28-3p was altered in both SMC and PMC (fold regulation over NC: 1.484 p < 0.050 and 3.287, p < 0.050). In MAPT mutation carriers, miR-28-5p, miR-192-3p, miR-25-3p, and miR-532-3p were altered only in SMC (fold regulation over NC: 1.496 p < 0.050, 1.911 p = 0.006, 1.468 p < 0.05, and 0.728 p < 0.05). Bioinformatic analysis revealed enrichment of pathways related to neurodegeneration and synapse impairment. These results suggest that miRNA expression levels are deregulated in mutated SMC, in C9ORF72 and GRN PMC. Notably, miR-20b-5p, miR-223-5p, and miR-28-3p were increased in preclinical stages of the disease, supporting their role as early biomarkers for C9ORF72-FTD and GRN-FTD. Conversely, alterations in MAPT carriers appeared only in symptomatic stages, suggesting a different involvement in disease progression.
Source: GeroScience
Authors: Chiara Fenoglio, Maria Serpente, Marina Arcaro, Tiziana Carandini, Luca Sacchi, Manuela Pintus, Vittoria Borracci, Giulia Giudici, Marta Rigoni, Paola Muti, Laura Ghezzi, Arabella Bouzigues, Lucy L. Rusell, Phoebe H. Foster, Eve Ferry-Bolder, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Raquel Sánchez Valle, Robert Laforce, Caroline Graff, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tiraboschi, Isabel Santana, Alexander Gerhard, Johannes Levin, Florence Pasquier, Simon Ducharme, Isabelle Le Ber, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, James B. Rowe, Matthis Synofzik, Fermin Moreno, Barbara Borroni, Andrea Sacconi, Jonathan D. Rohrer, Andrea Arighi, Daniela Galimberti, GENetic Frontotemporal dementia Initiative (GENFI), Antonella Alberici, Sónia Afonso, Patricia Alves, Sarah Anderl-Straub, Anna Antonelli, Mircea Balasa, Myriam Barandiaran, Nuria Bargalló, Robert Bartha, Benjamin Bender, Alexander Maximilian Bernhardt, Maxime Bertoux, Anne Bertrand, Valentina Bessi, Sandra Black, Giorgio Bocca, Martina Bocchetta, Sergi Borrego-Ecija, Alexis Brice, Rose Bruffaerts, Valentina Cantoni, Paola Caroppo, David Cash, Miguel Castelo-Branco, Olivier Colliot, Rhian Convery, Thomas Cope, Tiago Costa-Coelho, Ioana Croitoru, Agnès Camuzat, Liset de Boer, Julie de Houwer, Vincent Deramecourt, João Durães, Giuseppe Di Fede, Camilla Ferrari, Graziana Florio, Marta Frascotti, Morris Freedman, Aurélie Funkiewiez, Alazne Gabilondo, Roberto Gasparotti, Giorgio Giaccone, Lucia Giannini, Sophie Goldsmith, Lisa Graf, Vesna Jelic, Ron Keren, Johanna Krüger, Gregory Kuchcinski, Tobias Langheinrich, Thibaud Lebouvier, Maria João Leitão, João Lemos, Marisa Lima, Albert Lladó, Gemma Lombardi, Jolina Lombardi, Maura Malpetti, Carolina Maruta, David Mengel, Gabriel Miltenberger, Sara Mitchell, Maxime Montembault, Benedetta Nacmias, Mattias Nilsson, Linn Öijerstedt, Jaume Olives, Janne Papma, Yolande Pijnenburg, Koen Poesen, Cristina Polito, Jackie Poos, Enrico Premi, Sara Prioni, Catharina Prix, Veronica Redaelli, Timothy Rittman, Rosa Rademakers, Daisy Rinaldi, Ekaterina Rogaeva, Adeline Rollin, Pedro Rosa-Neto, Maria Rosario Almeida, Giacomina Rossi, Kiran Samra, Dario Saracino, Sabrina Sayah, Sonja Schönecker, Christen Shoesmith, Frederico Simões do Couto, Anna Stockbauer, Miguel Tábuas-Pereira, David Tang-Wai, Melissa Taheri Rydell, Mikel Tainta, David L Thomas, Mathieu Vandenbulcke, Philip Van Damme, Rick van Minkelen, Ana Verdelho, Henrik Viklund, Roberto Vimercati, Annick Vogels, Olivia Wagemann, Elisabeth Wlasich
Institutions: University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UCL Queen Square Institute of Neurology, University College London, Erasmus MC, Hospital Clínic de Barcelona, Fundació Clínic per a la Recerca Biomèdica, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Université Laval, CHU de Québec-Université Laval, Karolinska University Hospital, Karolinska Institutet, Universitair Ziekenhuis Leuven, KU Leuven, University of Lisbon, Fondazione IRCCS Istituto Neurologico Carlo Besta, Unidade Local de Saúde de Coimbra, Centro de Neurociências e Biologia Celular, 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, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, LabEx DISTALZ, Montreal Neurological Institute and Hospital, Douglas Mental Health University Institute, McGill University, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, 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, Centro San Giovanni di Dio Fatebenefratelli, University of Brescia, Istituti di Ricovero e Cura a Carattere Scientifico, Instituto Nazionale Tumori Regina Elena
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,890
Funders: McGill University, Wellcome Trust, Sunnybrook Research Institute, Università degli Studi di Milano, Weston Brain Institute, Brain Research UK, National Institute for Health and Care Research, University of Cambridge, University College London, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, ZonMw, Toronto Rehabilitation Institute, Eberhard Karls Universität Tübingen, Bundesministerium für Bildung und Forschung, Cambridge University Hospitals, Erasmus Medisch Centrum, Ministero della Salute, University of Toronto, Karolinska Institutet, Vetenskapsrådet, Università degli Studi di Firenze, Centre National de la Recherche Scientifique, Ludwig-Maximilians-Universität München, Universidade de Coimbra, Universidade de Lisboa, Oulun Yliopisto, Università degli Studi di Brescia, Universiteit Antwerpen, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Universität Ulm, Universiteit Hasselt, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Stichting Dioraphte, Alzheimer Nederland, Sorbonne Université, Tau Consortium, Medical Research Council, Instituto de Salud Carlos III, NIHR Cambridge Biomedical Research Centre
Awards: G1076890169, G1240843554, G139696651, G1789099517, G2076520454, G249966083, G2588154941, G2846482002, G2951265004, G3245177014, G3379762541, Restoring brain function: from cortical microcircuits to complex behaviours in neurodegenerative disease., G3584577881, G3594153814, G3630346250, G3691030594, G370598735, Diseño de biomarcadores para Demencia Fronto-temporal asociada a mutaciones en GRN, G3836382391, G3923834380, EXC 2145: Munich Cluster for Systems Neurology (SyNergy), G4014046109, G4190891609, G4665392370, G5484725842, G5870702634, G6058803565, G6077662935, G6115791316, G6368058359, G6641991021, G7053626042, G712881263, G7649985594, Human genetic studies of Alzheimer disease and other dementias, G7826725679, 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: W7153075967