Sex differences in the executive and behavioral reserve of autosomal dominant frontotemporal dementia

Self-reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear.

We analyzed 394 genetic-FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI-based cortical thickness. Clinical characteristics and cortical thickness were compared between sexes. We used the residuals of linear regression models, which predict each participant's cognitive and behavioral performance levels relative to cortical thickness, as a proxy for reserve. We then modeled sex differences in longitudinal trajectories with linear mixed-effects models.

Symptomatic females with genetic FTD had lower frontal cortical thickness than males, and the C9orf72 subgroup showed lower-than-expected frontal cortical thickness for a given level of executive functioning. Differences in cognitive reserve between sexes peaked near symptom onset but diminished thereafter.

Females with genetic FTD showed higher cognitive reserve than males, suggesting that self-reported sex modulates resilience to frontotemporal neurodegeneration.

Females with genetic FTD showed higher cognitive reserve than males. Those differences were particularly pronounced in the C9orf72 and GRN subgroups. The higher cognitive reserve in females declined as the disease progressed.