The Glymphatic system: A dynamic regulator of brain health and therapeutic target

The central nervous system (CNS) maintains homeostasis despite high metabolic activity and the apparent absence of conventional lymphatic vessels within the parenchyma. The identification of the glymphatic system-a glial-dependent perivascular network-proposes a mechanistic framework for interstitial waste clearance. This review presents a systems-level framework that views the glymphatic network as a dynamic regulator of brain homeostasis, essential for neurophysiological stability. We examine the biophysical determinants of solute transport, emphasizing the critical role of polarized aquaporin-4 (AQP4) channels and navigating the ongoing scientific debate regarding the relative contributions of convective bulk flow versus diffusion. We further analyze central regulation of clearance efficiency by the sleep-wake cycle, circadian rhythms, and state-dependent interstitial ionic fluctuations. Pathologically, we consider glymphatic dysfunction as a convergent mechanism across diverse disorders, potentially contributing to proteostasis failure in neurodegeneration, exacerbating secondary injury after stroke and trauma, linking systemic metabolic conditions to CNS impairment, and presenting emerging evidence for its role in major psychiatric disorders, including depression, bipolar disorder, and schizophrenia. Finally, we evaluate strategies to restore clearance capacity through lifestyle and pharmacological interventions; the translational potential of leveraging perivascular pathways for CNS drug delivery; and the need for developing non-invasive imaging biomarkers to enable preventative neurology. Unlike previous reviews that have largely summarized the system's anatomy and physiology, we integrate three underappreciated dimensions: (i) state-dependent neurobiological control by sleep and circadian timing; (ii) glymphatic failure as a shared systems-level mechanism across acute and chronic neurological and psychiatric disorders; and (iii) the dual translational relevance of the perivascular pathway as both a therapeutic target and a drug-delivery route.