Sleep quality is associated with default mode and salience network connectivity differently across age and sex.

Aging and biological sex are critical moderators of sleep quality, which contributes significantly to age-related cognitive decline and Alzheimer's disease (AD) risk. This study investigated how age and sex moderated the relationship between subjective sleep quality and resting-state functional connectivity (rsFC) within networks associated with hyperarousal and cognitive processing. Using an exploratory-confirmatory approach across two datasets (N = 95 and N = 1244), we examined connectivity of the default mode network (DMN), salience network (SN), and amygdala with the rest of the brain. Results revealed distinct age- and sex-dependent patterns: in the DMN, a three-way interaction (Age×Sex×Sleep Quality) showed that poorer sleep quality was associated with reduced DMN-superior parietal lobule (SPL) connectivity in younger women but hyperconnectivity in older women. This hyperconnectivity correlated with poorer episodic memory performance, consistent with patterns observed in preclinical AD. For the SN, an age-dependent interaction showed that poorer sleep was associated with SN-sensorimotor hyperconnectivity in younger adults-supporting the hyperarousal hypothesis-but lower connectivity in older adults, suggesting a shift toward different mechanisms, such as circadian or homeostatic decline, in late life. No significant effects were found for the amygdala or blood-based biomarkers of AD pathology, inflammation, or sex hormones. These findings highlight a selective vulnerability of the DMN to sleep impairments in older women and suggest that the neural correlates of poor sleep shift from hyperarousal in youth to neurodegenerative-like patterns in older age.