Educational attainment and sex modulate clinical outcomes in genetic frontotemporal dementia
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, , 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 LemosAbstract
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.