Sex differences in default mode network connectivity in healthy aging adults

Abstract

Women show an increased lifetime risk of Alzheimer's disease (AD) compared to 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 increased connectivity with age in posterior DMN nodes and decreased connectivity in the medial prefrontal cortex. Differences were most prominent in the decades surrounding menopause. Seed-based analysis revealed increased connectivity in women from the posterior cingulate to angular gyrus and parahippocampal gyrus, which correlated with neuropsychological measures of declarative memory. 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

“…Women rely upon specific DMN edges for memory performance; connections between the bilateral pIPL and the two greatest hubs of the DMN, the mPFC and the PCC/precuneus are the strongest predictors. Our prior work suggests that women have relatively increased within-DMN connectivity compared with men, particularly in posterior nodes and particularly during perimenopausal decades (Ficek-Tani et al ., In press). Reliance upon intra-DMN edges for memory performance likely has its advantages: we and others have shown that DMN connectivity, particularly between posterior nodes, correlates with memory task performance (Fredericks et al ., 2019; Natu et al ., 2019; Kang et al ., 2021; Vanneste et al ., 2021; Ficek-Tani et al ., In press), and the literature consistently demonstrates that women outperform men across the lifespan in tests of verbal episodic memory (Bleecker et al ., 1988; Herlitz, Nilsson and Bäckman, 1997; Golchert et al ., 2019).…”

“…This work adds to the growing literature suggesting that women rely more on the DMN than do men both at rest and during memory task performance. At rest, women have relatively higher DMN connectivity (Biswal et al ., 2010; Scheinost et al ., 2015; Cavedo et al ., 2018; Ritchie et al ., 2018; Ficek-Tani et al ., In press), with higher posterior DMN connectivity particularly during the menopausal decades (Ficek-Tani et al ., In press); this increased connectivity correlates with better performance on tests of short-term memory (Fredericks et al ., 2019; Natu et al ., 2019; Kang et al ., 2021; Vanneste et al ., 2021; Ficek-Tani et al ., In press). This profile is similar to individuals with preclinical (amyloid-β +) or elevated genetic risk (e.g.…”

“…See Bookheimer et al (2019) for full exclusion criteria. As described previously (Ficek-Tani et al ., In press), we implemented additional exclusion criteria based on motion (see below for details), missing data, and anatomical abnormalities. After exclusion, the remaining sample size was n=579 (330 female; 249 male).…”

“…Using Wilcoxon rank sum tests, we determined no differences in mean FFD between female and male subjects across all seven scan types ( Supplementary Table 1 ). Linear, quadratic, and cubic drift, a 24-parameter model of motion (Satterthwaite et al ., 2013), mean cerebrospinal fluid signal, mean white matter signal, and global signal were regressed from the data as described in (Ficek-Tani et al ., In press).…”

“…Prior research assessing sex differences in the aging brain has demonstrated that healthy aging women show lower segregation of functional networks (i.e., more cross-hemispheric/-module connections) (Ingalhalikar et al ., 2014). Women have relatively higher DMN connectivity overall (Biswal et al ., 2010; for the Women’s Brain Project and the Alzheimer Precision Medicine Initiative et al ., 2018; Ritchie et al ., 2018), and demonstrate higher connectivity than men in posterior DMN nodes, which relates to short-term memory performance (Ficek-Tani et al ., In press).…”