An international study involving researchers from the Sant Pau Research Institute (IR Sant Pau) has demonstrated that women who are carriers of genetic mutations causing frontotemporal dementia (FTD) show a greater capacity to compensate for brain damage than men, at least in the early stages of the disease. The discovery suggests that sex is a key biological factor in the evolution of this hereditary form of dementia and opens the door to more gender-sensitive precision medicine.
The article was published in the journal Alzheimer’s & Dementia, the official publication of the Alzheimer’s Association, and is part of a series of three scientific papers on sex differences in the clinical and biological manifestations of genetic FTD. The research is part of the North American ALLFTD consortium and included collaboration from leading neuroscience and neuroimaging centers in San Francisco (UCSF) and Toronto (University of Toronto).
“What we observed is that, for the same degree of brain damage, women with FTD performed better than men in executive function and social cognition tests. This indicates they have greater cognitive and behavioral reserve,” explains Dr. Jesús García Castro, neurologist and researcher in the team led by Dr. Ignacio Illán-Gala at the Sant Pau Memory Unit and Sant Pau Research Institute (IR Sant Pau), and first author of the study.
FTD is a neurodegenerative disease still not well known to the general public, but which has gained recent attention following the diagnosis of actor Bruce Willis. Unlike Alzheimer’s, which primarily affects memory, FTD presents as personality changes, social behavior disturbances, and language or speech difficulties. It typically begins at an earlier age—between 45 and 65 years—and may lead to a progressive loss of executive functions such as judgment, empathy, or impulse control. For this reason, the study of behavioral changes is key to early detection.
Frontotemporal dementia is a rare neurodegenerative disease that usually appears between 45 and 65 years of age and severely affects personality, social behavior, and language. In about 30% of cases, it is caused by mutations in genes such as C9orf72, GRN, or MAPT, which lead to abnormal protein accumulation and progressive loss of brain tissue, especially in the frontal and temporal lobes.
Thanks to the systematic follow-up of the ALLFTD consortium, the researchers were able to analyze over 670 brain MRIs and clinical data from 394 carriers of pathogenic mutations and 279 non-carrier relatives over several years. They studied both asymptomatic individuals (presymptomatic phase) and those already diagnosed with mild cognitive impairment or dementia.
“This longitudinal design allowed us to observe how the disease evolves even before the first symptoms appear. And this is where we saw the female advantage: women showed better cognitive performance despite having greater degrees of frontal brain atrophy,” highlights Dr. García Castro.
The team used an innovative methodology known as the residual approach, which quantifies cognitive reserve: the discrepancy between a person’s actual performance and what would be expected based on their degree of neurodegeneration. This approach revealed that women, especially those carrying the C9orf72 expansion, maintained better executive and social functioning despite cortical thinning.
Statistical models also showed that this female advantage is not permanent. As the disease progresses and brain damage extends, compensatory capacity decreases, and deterioration trajectories equalize between men and women in advanced stages.
“It’s as if the female brain has more capacity to resist the disease for a time, but once a certain threshold is reached, the decline accelerates,” summarizes Dr. García Castro. “This matches what has been observed in Alzheimer’s: greater initial resilience in women, followed by faster deterioration when symptoms emerge.”
Indeed, the study observed a trend towards later symptom onset in women (up to 6.5 years on average), although this result did not reach statistical significance due to sample size.
The work has important implications for the design of clinical trials and progression prediction models in hereditary dementias. Until now, most studies had not considered sex as a differentiating variable, which may have obscured important patterns in treatment response or clinical evolution.
“Our findings reinforce the need to integrate sex and gender perspectives into precision medicine, especially in diseases like FTD, where variability is enormous even within the same genetic mutation,” notes Dr. García Castro.
The Sant Pau group, in collaboration with international partners of the ALLFTD consortium, continues to analyze other modulators of progression in genetic FTD, including immunological, hormonal, and structural markers.
The research was conducted as part of the North American ALLFTD (Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects) consortium, funded by the U.S. National Institute on Aging (NIA) and the U.S. National Institute of Neurological Disorders and Stroke (NINDS).
In addition, the work was supported by the Carlos III Health Institute through multiple projects (PI20/01473, PI23/01786, PI18/00435, PI20/01330, PI21/01395, PI21/00791, CP20/00038, PI22/00307, INT21/00073, CM21/00243 and CM23/00176), co-financed by the European Union. It also received funding from the Biomedical Research Network Centre on Neurodegenerative Diseases (CIBERNED) and the European Regional Development Fund (ERDF) under the slogan “A way to make Europe”.
At the international level, the study was supported by the Alzheimer’s Association (grants AARG-22-923680, AARF-22-924456 and GBHI ALZ UK-21-720973), the Alzheimer Society (UK), and the Global Brain Health Institute (GBHI). It also received support from the Tatiana Pérez de Guzmán el Bueno Foundation, and from the Horizon 2020 programme of the European Union.
In Catalonia, the research was promoted by the Department of Health of the Generalitat through the Strategic Plan for Health Research and Innovation (PERIS), and was supported by clinical talent contracts such as Juan Rodés and Río Hortega.
This institutional support has made it possible to carry out a large-scale multicenter study with participation from 18 centers in the United States and Canada, and consolidates Sant Pau’s leadership in advancing precision medicine in the field of neurodegenerative diseases.
Garcia Castro J, Rubio-Guerra S, Casaletto KB, Selma González J, Memel M, Vaqué-Alcázar L, Morcillo-Nieto A, Arriola-Infante J, Dols-Icardo O, Bejanin A, Belbin O, Fortea J, Alcolea D, Carmona-Iragui M, Barroeta I, Santos-Santos M, Sánchez Saudinós MB, Sala Matavera I, Heuer HW, Forsberg LK, Kantarci K, Staffaroni AM, Tartaglia C, Rankin KP, Boeve B, Boxer A, Rosen HJ, Lleó A, Illán-Gala I, ALLFTD Consortium. Sex differences in the executive and behavioral reserve of autosomal dominant frontotemporal dementia. Alzheimers Dement 2025;21:e70070. https://doi.org/10.1002/alz.70070
