Our study explores the complex association between sleep quality and Alzheimer's disease (AD) risk, focusing on the moderating role of the APOE ε4 allele.

Linear regression models, linear mixed-effects models, and Cox proportional hazard models were conducted in 321,905 non-demented participants from UK Biobank (UKB, mean age = 56.49, mean follow-up: 12.3 years) and 1,598 non-demented participants (mean age = 73.19, mean follow-up: 3.90 years) from Alzheimer's Disease Neuroimaging Initiative (ADNI). The interaction terms of sleep by APOE ε4 status were added in all analyses and stratified analyses were further performed. Separate proteomic analyses combined with bioinformatic analyses were conducted to elucidate the potential biological mechanisms of sleep-by-APOE ε4 interaction.

Poor sleep quality was associated with worse cognition (all P < 0.01), faster hippocampal atrophy (all P < 0.05), and increased AD risk (HR = 1.05 in UKB; HR = 1.37 in ADNI, all P < 0.05). Notably, the APOE ε4 allele intensified the effects of poor sleep on cognitive decline, hippocampal atrophy, and AD risk (all P for interaction < 0.05). Good sleep, however, mitigated these effects. Proteomic analyses suggested that growth differentiation factor 15 (GDF15)-enriched pathways may underlie these interactions.

APOE ε4 moderates the relationships of sleep quality with AD, possibly via the GDF15-enriched pathways. Adhering to good sleep patterns might attenuate the risk of AD especially for those with high genetic susceptibility.