Sex differences in sleep and memory relationships in older adults at risk for Alzheimer's disease

Biological sex is an important modifier of aging and Alzheimer's disease risk, yet the sleep-related mechanisms through which sex and genetic risk interact to influence memory remain poorly understood. We examined whether associations among non-rapid eye movement sleep physiology, overnight memory retention, and apolipoprotein E ϵ4 (APOE ϵ4) status, a genetic risk factor for Alzheimer's disease, differed by sex in cognitively unimpaired older adults enriched for Alzheimer's disease risk.

Eighty participants completed overnight polysomnography with high-density electroencephalography, and 65 also completed an evening encoding/immediate recall and morning delayed recall word-pair memory task.

Overnight memory retention did not differ by sex. However, exploratory analyses of the proportional overnight retention measure suggested a sex × APOE ϵ4 interaction, such that female APOE ϵ4 carriers may exhibit reduced overnight forgetting relative to female non-carriers and male carriers. Although counterintuitive, this pattern may reflect compensatory or resilience-related sleep-memory mechanisms in cognitively unimpaired women at genetic risk for Alzheimer's disease rather than a protective effect of APOE ϵ4 itself. Women spent more time in N3 sleep and had higher non-rapid eye movement delta and slow sigma power than men. Sleep-memory associations also differed by sex: greater N2 duration was more strongly associated with better overnight retention in men, whereas greater frontal slow sigma power and fronto-central fast sigma power were positively associated with retention in women. Exploratory APOE-stratified analyses suggested sex-specific differences in sleep stage-memory relationships, with more positive N2-memory associations in male than female APOE ϵ4 carriers and more positive N3-memory associations in female than male carriers; both differences remained significant after FDR correction. TFCE-corrected analyses further identified positive associations between NREM delta and sigma activity and overnight memory retention in female APOE ϵ4 carriers.

These findings highlight sex-specific patterns in NREM sleep physiology and sleep-memory relationships in cognitively unimpaired older adults at risk for Alzheimer's disease. More broadly, the results suggest that sex and APOE ϵ4 status may jointly shape the neurophysiological pathways linking sleep and memory, underscoring the importance of considering sex as a biological variable when studying sleep, cognitive aging, and Alzheimer's disease vulnerability.