Sex-dependent grey matter atrophy in Alzheimer's disease progression

Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive and functional deterioration, with mild cognitive impairment as an intermediate stage. Using high-resolution structural MRI from 332 Alzheimer's Disease Neuroimaging Initiative participants, we examined sex-specific grey matter volume (GMV) differences across healthy controls, mild cognitive impairment and Alzheimer's disease. Whole-brain parcellation into 82 regions revealed a significant group-by-sex interaction [F(164,488) = 1.42; P = 0.002; ηp² = 0.32], with 10 regions showing pronounced sex-dependent effects. GMV trajectories exhibited a clear sex-specific pattern. In healthy cohort, males and females displayed comparable GMVs. From healthy control to mild cognitive impairment, females remained relatively stable, whereas males showed a moderate decline. From mild cognitive impairment to Alzheimer's disease, however, females demonstrated steep and widespread GMV loss, contrasting with the slower, region-limited atrophy observed in males. Females also showed significantly greater reductions in key regions, including the left frontal pole during Alzheimer's disease progression [F(1,243) = 10.68; P < 0.001; ηp² = 0.14] and the right caudal middle frontal cortex during mild cognitive impairment [F(1,243) = 10.62; P < 0.001; ηp² = 0.14]. Structural differences were mirrored in behavioural associations. Females showed more widespread associations between GMV and cognitive and functional performance: higher GMV was associated with better Mini-Mental State Examination scores, whereas lower GMV was associated with greater independence on the Functional Activities Questionnaire. These findings highlight a sex-dependent vulnerability in Alzheimer's disease, with females exhibiting both more extensive atrophy and more widespread atrophy-cognition coupling across disease stages.