Interaction effect of sex and diagnosis on functional connectivity within the default network in healthy controls, mild cognitive impairment and Alzheimer Disease

Abstract

AbstractBackgroundAge and sex are major risk factors for late onset Alzheimer’s disease (AD). Almost 70% of AD patients are women, but reasons for sex disparities are not well understood. One potential avenue of inquiry is investigation of default network (DN) functional connectivity (FC) differences between men and women.MethodWe studied amyloid positive individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), clinically diagnosed as healthy elderly controls (HCs), Mild Cognitive Impairment (MCI) and AD, with resting‐state functional Magnetic Resonance Imaging available at the diagnostic and cognitive testing visit (Table 1). We selected seven regions of interest (ROIs) in the DN (Figure 1), including bilateral angular gyrus (ANG), calcarine (CAL), precuneus (PCUN), medial orbital frontal gyrus (ORBmed) and bilateral middle occipital gyrus (MOG). Pearson’s correlation characterized FC between ROIs. Linear mixed effect models adjusted for covariates (education, handedness, presence of apolipoprotein [APOE] ε4 and intra‐subject effect), and analysis of variance (ANOVA) evaluated the effects of diagnosis, sex and their interaction, using Bonferroni correction.ResultsANOVA showed significant differences between diagnostic groups in FC of left ANG – PCUN/CAL and bilateral MOG – CAL. Significant diagnosis by interaction effects were observed in FC especially at the level of posterior‐ventral DN. Specifically, between ANG‐CAL, and PCUN‐MOG (Table 2). Post‐hoc analysis demonstrated distinct effect sizes and/or opposite direction effects in women compared to men (Figure 2). Left ANG – CAL and left ANG – PCUN connectivity had medium effect (|d| >0.5) for men in the MCI versus HC comparison, although small effect (|d| <0.2) across sexes. The discrepancies between women and men were observed in the AD versus MCI comparison, such as the left ANG – left MOG and right ANG – CAL, where they show an opposite direction of FC.ConclusionsOur study found that the sex differences in DN FC did not remain consistent across the clinical AD spectrum. Instead, significant sex by diagnosis interaction effects suggest that treating sex as a covariate overlooks sex‐specific pathological changes in brain FC.