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

Obstructive sleep apnea (OSA) is linked to cognitive decline and is increasingly implicated in neurodegenerative trajectories. Continuous positive airway pressure (CPAP), the most common form of positive airway pressure (PAP) used to treat OSA, improves breathing and sleep continuity, yet cognitive outcomes, as well as reports of REM sleep behavior disorder (RBD) manifestations in comorbid OSA, remain heterogeneous. In parallel, the last decade has reframed sleep as an active state for brain fluid transport, in which cerebrospinal fluid (CSF) 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, PAP (and specifically CPAP) may modulate CSF-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 CSF stroke volume under higher-pressure CPAP during wakefulness and persistent heterogeneity in cognitive outcomes. This Perspective proposes a mechanistic framework that separates (i) event suppression (restored consolidated sleep), (ii) pressure-dependent CSF/venous coupling, and (iii) 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., DTI-ALPS), and CSF/blood biomarkers to determine when, for whom, and through which pathways PAP could exert neuroprotective effects.