Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a world-wide healthcare crisis among older adults. Sex, aging, and apolipoprotein E (APOE) genotype are among the most impactful risk factors for AD. Sleep is beneficial for memory and changes with age. We aimed to test whether sex and APOE (ε4-carriers/non-carriers) interact to impact sleep-dependent memory consolidation (SDMC).

Methods: We tested 67 older adults (41 women, 25 ε4-carriers, mean±SD; 61.8±6.1 years). Participants encoded word-pairs in the evening, were tested immediately, then underwent overnight in-lab polysomnography, and performed a delayed test in the morning. SDMC was computed as a difference score (morning-evening). Time spent in non-rapid eye movement (NREM) sleep stages, and electroencephalography (EEG) spectral power in frontal canonical frequency bands during NREM sleep, were quantified. ANOVA, independent t-tests, and bivariate correlation analyses were employed in the study.

Results: A sex × APOE interaction predicted SDMC (p = 0.02). Post hoc analysis revealed no difference between male ε4-carriers and non-carriers (p = 0.36), but among women, ε4-non-carriers exhibited increased deterioration (more forgetting) compared to ε4-carriers (p = 0.02). Additionally, male ε4-carriers had worse memory retention than female ε4-carriers (p = 0.01). Further analysis showed that female ε4-carriers spent more time in N3 sleep (p = 0.01), correlating with better SDMC (r = 0.72, p = 0.02), while male ε4-carriers spent more time in N2 sleep (p = 0.04), also linked to better SDMC (r = 0.68, p = 0.03). Fisher r-to-z transformation indicated significant differences in these associations (p = 0.01). Regardless of sex, among ε4 non-carriers, no significant associations were found between theta, alpha, slow-sigma, fast-sigma during NREM sleep and memory (all ps>0.17). Among ε4-carriers, male participants showed no significant associations (all ps>0.54), whereas females exhibited positive associations between memory and theta (r = 0.80, p = 0.005), alpha (r = 0.82, p = 0.004), slow-sigma (r = 0.85, p = 0.002), and fast-sigma (r = 0.77, p = 0.009).

Conclusion: Our study reveals that the interplay of sex and APOE affects sleep patterns and memory consolidation in older adults. Notably, distinct non-rapid eye movement (NREM) sleep stages impact Slow Delta and Theta Modulation (SDMC) differently in male and female APOE ε4-carriers. While enhanced sleep quality may mitigate APOE and sex-related cognitive decline in later life, considering sex-related differences in memory benefits from sleep is crucial for older adults at high risk for AD.