Sex differences in default mode network connectivity in healthy aging adults

Abstract

Women show an increased lifetime risk of Alzheimer’s disease (AD) compared with men. Characteristic brain connectivity changes, particularly within the default mode network (DMN), have been associated with both symptomatic and preclinical AD, but the impact of sex on DMN function throughout aging is poorly understood. We investigated sex differences in DMN connectivity over the lifespan in 595 cognitively healthy participants from the Human Connectome Project-Aging cohort. We used the intrinsic connectivity distribution (a robust voxel-based metric of functional connectivity) and a seed connectivity approach to determine sex differences within the DMN and between the DMN and whole brain. Compared with men, women demonstrated higher connectivity with age in posterior DMN nodes and lower connectivity in the medial prefrontal cortex. Differences were most prominent in the decades surrounding menopause. Seed-based analysis revealed higher connectivity in women from the posterior cingulate to angular gyrus, which correlated with neuropsychological measures of declarative memory, and hippocampus. Taken together, we show significant sex differences in DMN subnetworks over the lifespan, including patterns in aging women that resemble changes previously seen in preclinical AD. These findings highlight the importance of considering sex in neuroimaging studies of aging and neurodegeneration.

Connectome-based predictive modeling shows sex differences in brain-based predictors of memory performance

“…Edges from connectivity matrices for each subject per scan were correlated to the three aforementioned memory performance measures, totaling to seven connectivity matrices and three memory scores per subject (21 total correlated matrices). Motion and age covariates were also included in the CPM analyses to account for in-scanner head motion, age, and their interaction in our predictions, as previously done (Scheinost et al, 2021;Dufford et al, 2022;Horien et al, 2022).…”

“…To visualize sex differences at the network level, we first split the aforementioned consensus matrix into two binarized matrices (a "positive" matrix containing edge with significant positive correlations to memory and the other "negative" matrix of edges with significant negative correlations to memory) for each predictive model. Categorization of nodes by functional network was determined using the 10-network parcellation of the Shen 268node atlas (Horien et al, 2022). In this network grouping, the medial frontal (MF) network also includes some temporal and frontal nodes which often cluster with the DMN.…”

“…Inter-network edges were defined as the number of significant edges between each pair of networks normalized by the total number of edges between the same network pair. As done in previous work, we defined edges as "significant" if they appear in at least 2 out of 5 folds in 40% of 1,000 iterations of CPM to minimize noise while retaining meaningful connections (Rosenberg et al, 2016;Yip et al, 2019;Horien et al, 2022). In addition to using heatmaps to visualize the inter-network edges of both female and male groups separately, we subtracted male-group positive edges from female-group positive edges (and the same with the negative edges) across corresponding matrix cells to evaluate the inter-network sex differences.…”

Somatomotor-visual resting state functional connectivity increases after 2 years in the UK Biobank longitudinal cohort

“…22 The FC of males and females is also quantitatively different, with females having higher intra-default mode network (DMN) connectivity and males having relatively greater connectivity between the DMN and other networks, although there is a wide degree of individual variation. 23,24 Meanwhile, studies have shown that changes occur in the DMN during late middle and old age, 25 although the exact direction of change in FC does not always appear constant. 26 In addition, various studies have examined age-related changes in the cingulum 27 and medial temporal lobe.…”

“…For example, connectivity in young children is generally very high among all brain regions and decreases while becoming more modularized during and after puberty 22 . The FC of males and females is also quantitatively different, with females having higher intra-default mode network (DMN) connectivity and males having relatively greater connectivity between the DMN and other networks, although there is a wide degree of individual variation 23 , 24 . Meanwhile, studies have shown that changes occur in the DMN during late middle and old age, 25 although the exact direction of change in FC does not always appear constant 26 .…”