Could positive airway pressure enhance brain waste clearance and modify neurodegenerative risk? A perspective on sleep-dependent cerebrospinal fluid-lymphatic pathways.

Obstructive sleep apnea is linked to cognitive decline and is increasingly implicated in neurodegenerative trajectories. Continuous positive airway pressure, the most common form of positive airway pressure used to treat obstructive sleep apnea, improves breathing and sleep continuity, yet cognitive outcomes, as well as reports of rapid eye movement sleep behavior disorder manifestations in comorbid obstructive sleep apnea, remain heterogeneous. In parallel, the last decade has reframed sleep as an active state for brain fluid transport, in which cerebrospinal fluid movement, vascular and respiratory mechanics, and extracranial lymphatic drainage jointly influence the clearance of potentially neurotoxic solutes (e.g. amyloid-β). This Perspective advances a testable, conditional hypothesis: beyond correcting hypoxemia and sleep fragmentation, positive airway pressure (and specifically continuous positive airway pressure) may modulate cerebrospinal fluid-lymphatic clearance by changing upper-airway pressure gradients, intrathoracic pressure swings, craniovenous pulsatility, and extracranial lymphatic outflow mechanics. This Perspective also reviews counterevidence, including human physiologic data showing reduced cerebrospinal fluid stroke volume under higher-pressure continuous positive airway pressure during wakefulness and persistent heterogeneity in cognitive outcomes. This Perspective proposes a mechanistic framework that separates (1) event suppression (restored consolidated sleep), (2) pressure-dependent cerebrospinal fluid/venous coupling, and (3) route-dependent extracranial lymphatic outflow as partially independent modules. Finally, this Perspective outlines a focused research agenda integrating polysomnography, fast neuroimaging, perivascular transport metrics (e.g. diffusion tensor imaging-analysis along the perivascular space), and cerebrospinal fluid/blood biomarkers to determine when, for whom, and through which pathways positive airway pressure could exert neuroprotective effects.