Sex-specific brain atrophy patterns associated with the motoric cognitive risk syndrome

Background: Females are twice as likely to be diagnosed with Alzheimer's disease (AD) as males, but the underlying mechanisms of this sex difference are not well-understood. The motoric cognitive risk (MCR) syndrome is characterized by slow gait and subjective cognitive concerns and predicts both AD and vascular dementia (VaD). The prevalence of MCR is typically similar in females and males. We have previously shown that MCR is associated with cortical atrophy in frontal, parietal, and temporal regions. Objective: The current study examined sex-specific, cortical (frontal), and subcortical (hippocampal) atrophy patterns associated with MCR. Methods: Frontal cortical thicknesses (in 11 frontal regions) and hippocampal volumes (in 12 hippocampal subfields) were quantified in 940 females (M Age = 71.03 years) and 1108 males (M Age = 71.07 years). Sex-stratified linear models were used to examine frontal cortical thicknesses and hippocampal volumes as a function of MCR—after adjusting for age, education, total intracranial volume, study site, vascular comorbidities, white matter lesion burden, and multiple comparisons (with the false discovery rate). Results: MCR-related frontal atrophy was observed (in pars orbitalis and caudal middle frontal) in males but not in females. MCR-related hippocampal atrophy (in CA1, molecular layer, GCMLDG, and Fimbria) was observed in females but not in males. Conclusions: There are sex-specific patterns of atrophy associated with MCR. Females with MCR display brain atrophy patterns more consistent with early AD, while males with MCR display atrophy patterns more consistent with VaD.