Sex Difference in General Cognition Associated with Coupling of Whole-brain Functional Connectivity Strength to Cerebral Blood Flow Changes During Alzheimer’s Disease Progression

Abstract

Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disorder that results in irreversible cognitive impairments. Nonetheless, there are numerous sex-dependent differences in clinical course. We examined potential contributions of neurovascular coupling deficits to sex differences in AD progression. T1-weighted three-dimensional structural magnetic resonance images, functional blood oxygen level dependent and arterial spin labeling images were acquired from 50 AD patients (28 females), 52 amnesic mild cognitive impairment patients (31 females), and 59 healthy controls (36 females). Short- and long-range functional connectivity strength (FCS) and cerebral blood flow (CBF) values were calculated for all participants. Then, the CBF/FCS coupling ratio, which represented the amount of blood supply per unit of connectivity strength, was calculated for each voxel. Two-way ANOVA was performed to identify group × sex interactions and main effects of group. Correlation analysis was used to assess associations between CBF/FCS ratios and Mini-Mental State Examination (MMSE). There were significant group × sex interaction effects on short-range coupling ratios of right middle temporal gyrus, left angular gyrus, left inferior orbital frontal gyrus, and left superior frontal gyrus as well as on the long-range coupling ratios of right middle temporal gyrus, left precuneus, left posterior cingulate cortex, and left angular gyrus. There were significant negative correlations between MMSE scores and CBF/FCS ratios for all regions with significant group × sex interactions among female patients, while positive correlations were found among male patients. Our results demonstrate significant sex differences in neurovascular coupling mechanisms associated with cognitive function during the course of AD.