AQP4-mediated glymphatic clearance: Sleep, neurodegeneration, and the translational gap

One-third of adults in industrialized societies are chronically sleep-deprived. If current evidence linking sleep disruption to glymphatic failure extends to human populations, this may represent not merely a productivity concern but a significant and underappreciated risk factor for neurodegeneration at the population scale. The glymphatic system, a brain-wide perivascular network that clears soluble amyloid-beta, tau, alpha-synuclein, and other neurotoxic metabolites through astrocytic aquaporin-4 water channels, operates predominantly during slow-wave sleep and is impaired when sleep is disrupted. Glymphatic dysfunction has been documented across Alzheimer's disease, Parkinson's disease, traumatic brain injury, and normal aging, with evidence from animal models and post-mortem and neuroimaging studies suggesting self-amplifying cycles in which impaired clearance may accelerate protein accumulation, though causal directionality in humans remains to be established prospectively. This review synthesizes the current mechanistic understanding of glymphatic biology, the bidirectional relationship between sleep disruption and neurotoxic protein accumulation, and emerging evidence that chronic conditions that suppress slow-wave sleep, including obstructive sleep apnea, chronic obstructive pulmonary disease, and tinnitus, represent plausible but largely untested glymphatic risk factors for neurodegeneration that warrant prospective investigation. We critically evaluate therapeutic strategies targeting glymphatic enhancement, including slow-wave sleep augmentation, aquaporin-4 restoration, noradrenergic tone reduction, and cerebrospinal fluid flow augmentation, and argue that the absence of validated non-invasive glymphatic biomarkers remains a major translational limitation that warrants systematic prioritization.