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Both modifiable and non-modifiable factors\u2014such as sex, educational attainment or geographic region of residence\u2014may 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 &amp;lt; 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 &amp;lt; 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.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag262","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:18:00Z","timestamp":1785755880000},"source":"Crossref","is-referenced-by-count":0,"title":["Educational attainment and sex modulate clinical outcomes in genetic frontotemporal dementia"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-6963","authenticated-orcid":false,"given":"Enrico","family":"Premi","sequence":"first","affiliation":[{"name":"Stroke Unit, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili , Brescia 25123 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Archetti","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroinformatics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli 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London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy L","family":"Russell","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe H","family":"Foster","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve","family":"Ferry-Bolder","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"van 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