Peripheral microRNA signature in genetic frontotemporal dementia—findings from the GENFI initiative

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.

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Journal
GeroScience
Published
2026-04-11
DOI
https://doi.org/10.1007/s11357-026-02214-x
Primary Topic
Amyotrophic Lateral Sclerosis Research
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article
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article

Peripheral microRNA signature in genetic frontotemporal dementia—findings from the GENFI initiative

Manuela Pintus, Alexander Bernhardt, Robert Bartha, Alazne Gabilondo et al.
GeroScience
Amyotrophic Lateral Sclerosis Research
article

Peripheral microRNA signature in genetic frontotemporal dementia—findings from the GENFI initiative

Manuela Pintus, Alexander Bernhardt, Robert Bartha, Alazne Gabilondo, Andrea Arighi, Liset de Boer, Valentina Bessi, Tobias Christoph Langheinrich, Giorgio Giaccone, Lucia Giannini, Alexis Brice, María Serpente, Vesna Jelić, Lisa H. Graf, Johanna Krüger, Gemma Lombardi, Aurélie Funkiewiez, Jolina Lombardi, Mircea Balasa, Laura Ghezzi, Marina Arcaro, João Durães, Thomas Cope, Pietro Tiraboschi, Phoebe H. Foster, Rose Bruffaerts, Paola C. Muti, Tiago Costa-Coelho, Arabella Bouzigues, Martina Bocchetta, Antonella Alberici, Andrea Sacconi, Graziana Florio, Vittoria Borracci, Maxime Bertoux, Valentina Cantoni, Luca Sacchi, Ioana Croitoru, Marisa Lima, Vincent Deramecourt, Maria João Leitão, Thibaud Lebouvier, Tiziana Carandini, Marta Rigoni, Giulia Giudici, Miguel Castelo-Branco, Myriam Barandiarán, Agnès Camuzat, Sarah Anderl-Straub, Núria Bargalló, Sergi Borrego-Écija, Sónia Afonso, Lize C. Jiskoot, Julie de Houwer, Elizabeth Finger, Gregory Kuchcinski, Eve Ferry-Bolder, Isabel Santana, Lucy L. Rusell, GENetic Frontotemporal dementia Initiative (GENFI), Alexandre de Mendonça, James B. Rowe, Matthis Synofzik, Rik Vandenberghe, Mario Masellis, Ron Keren, Jonathan D. Rohrer, Daniela Galimberti, Rhian Convery, Fermin Moreno, Johannes Levin, Olivier Colliot, Caroline Graff, Albert Lladó, Alexander Gerhard, John C. van Swieten, Sophie Goldsmith, Roberto Gasparotti, Giuseppe Di Fede, Barbara Borroni, João Lemos, Marta Frascotti, Robert Laforce, Camilla Ferrari, Simon Ducharme, Sandra Black, Giorgio Bocca, Anna Antonelli, Anne Bertrand, Florence Pasquier, Paola Caroppo, Morris Freedman, Maria Carmela Tartaglia, Patricia Alves, Raquel Sánchez Valle, Chiara Fenoglio, David Cash, Isabelle Le Ber, Benjamin Bender, Harro Seelaar
article en

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.

GeroScience
Western University (CA), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Allen Institute for Brain Science (US), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), University of Lisbon (PT), Inserm (FR), University of Toronto (CA), University of Milan (IT), Université de Lille (FR), University of Cambridge (GB), Douglas Mental Health University Institute (CA), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Health Sciences Centre (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), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), Klinikum Arnsberg (DE), Hertie Institute for Clinical Brain Research (DE), Onkologikoa (ES), National Hospital for Neurology and Neurosurgery (GB), Fundació Clínic per a la Recerca Biomèdica (ES), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Université Laval (CA), University College London (GB), McGill University (CA), University of Coimbra (PT), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Erasmus University Rotterdam (NL), KU Leuven (BE)
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
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