Purpose <p>The association of Obstructive Sleep Apnea (OSA) with cognitive deficits is increasingly recognized. In non-demented OSA patients, this research explored the associations among sleep architecture instability, intermittent hypoxia, and cognitive impairment, along with the potential mediating role of IL-6 and core Alzheimer’s disease biomarkers.</p> Methods <p>A total of 370 participants reporting snoring were enrolled and compledted both polysomnography and cognitive assessment. Ultimately, 299 met inclusion criteria. Sleep stage durations and transitions were extracted from hypnograms using a custom program. Blood samples were collected at ~ 7:00 AM for biochemical assays.Neuronal-derived exosomes (NDEs) were immunocaptured for the quantification of total tau (T-tau), amyloid-β (Aβ42), and phosphorylated tau (P-T181-tau) via ELISA. Mediation analysis was employed to evaluate whether inflammatory and Alzheimer’s biomarkers mediate the link between sleep disruption and cognitive performance.</p> Results <p>A comparative analysis showed significant differences in OSA patients with mild cognitive impairment, including increased sleep fragmentation, ODI, IL-6 levels, and more N1-to-wake transitions compared to controls and OSA patients without MCI. Spearman correlations revealed negative associations between cognitive scores and both N1-to-wake duration and ODI, as well as IL-6. Linear regression showed N1-to-wake duration was positively correlated with IL-6, while ODI correlated with Aβ42 and IL-6. Mediation analyses indicated IL-6 and P-T181-tau served as a partial mediator in impact of intermittent hypoxia on cognition.</p> Conclusions <p>Sleep instability, along with elevated levels of IL-6, serves as a strong predictor for cognitive impairment observed in OSA. Furthermore, IL-6 and phosphorylated T181-tau in NDEs play a mediating role in the cognitive dysfunction that arises due to intermittent hypoxia.</p>