Sleep disorders and blood-brain barrier dysfunction: Mechanisms, biomarkers, and therapeutic implications for neurocognitive decline

This review systematically examines the relationship between sleep disorders (including obstructive sleep apnea, chronic insomnia, and sleep deprivation) and bloodbrain barrier (BBB) dysfunction, as well as the implications for neurocognitive decline. Accumulating evidence indicates that disturbed sleep impairs BBB integrity through multiple mechanisms, including oxidative stress, neuroinflammation, pericyte dysfunction, gut microbiota dysbiosis (NLRP3 inflammasome pathway), and circadian disruption. Among sleep disorders, obstructive sleep apnea shows the strongest direct human evidence of BBB injury, whereas evidence for chronic insomnia remains largely indirect. Notably, hippocampal BBB breakdown may serve as an early marker of cognitive dysfunction, partly independent of classical amyloid-β and tau pathology. The review also evaluates candidate biomarkers (e.g., CSF/serum albumin ratio, soluble PDGFRβ, dynamic contrast-enhanced MRI) and discusses current therapeutic strategies—treating the underlying sleep disorder (CPAP, CBT-I) remains the most direct approach, while mechanism-based interventions (NLRP3 inhibitors, probiotics/butyrate, chronotherapy) are still at preclinical or early exploratory stages. This review identifies key knowledge gaps, including the lack of validated BBB biomarkers in sleep disorders and limited evidence for reversibility of BBB injury after treatment.