Sex differences in default mode network connectivity in healthy aging adults

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.