Sex-modulated heterogeneity in frontotemporal dementia spans clinical phenotypes and anatomical substrates

Frontotemporal dementia (FTD) exhibits profound inter-individual heterogeneity that complicates diagnosis and intervention, yet the factors that modulate this variability remain poorly understood. Here, we examined whether biological sex serves as one such modulator, from clinical phenotypes to anatomical substrates. Using a well-characterized cohort from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (108 FTD patients and 67 healthy controls enrolled at the first visit), we quantified multidimensional heterogeneity and assessed sex effects across FTD subtypes. Permutation testing revealed that both phenotypic and anatomical heterogeneity significantly exceeded random expectation across the FTD spectrum, confirming heterogeneity as a core disease feature. Critically, heterogeneity was selectively modulated by biological sex in clinically diagnosed behavioral-variant FTD (bvFTD): males exhibited greater dispersion in phenotypic profiles and atrophy patterns, alongside stronger phenotype-anatomy coupling, effects not observed in other subtypes. Further analysis anchored this male-enhanced heterogeneity in bvFTD to a confined set of regions, whose atrophy patterns reliably discriminated sex via a logistic classifier that outperformed null models (accuracy = 72.73%, AUC = 0.821). Together, these findings position biological sex as a robust and anatomically specific modulator of heterogeneity, with effects most pronounced in bvFTD. This work advances our understanding of individual differences, providing a foundation for sex-stratified biomarkers and precision-medicine strategies.