Glymphatic system impairment in neurological disorders: potential mechanisms and therapeutic targets

The glymphatic system is a brain-wide metabolic clearance pathway, orchestrating the removal of neurotoxic wastes via glial-dependent perivascular networks. Mediated by polarized aquaporin-4 (AQP4) channels on astrocytic end-feet, this macroscopic system drives the convective exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF), establishing a functional coupling between the central nervous system (CNS) and the adaptive immune system. Emerging evidence highlights that glymphatic dysfunction act as both a consequence and a driver of numerous neurological disorders. Neurological pathologies, including neuroinflammation and gliovascular remodeling, compromise the structural and functional integrity of glymphatic architectures. Conversely, glymphatic dysfunction exacerbates neurotoxic wastes accumulation, accelerates disease progression, and perpetuates a pathological positive-feedback loop. Despite growing recognition of this bidirectional relationship, the precise mechanisms remain incompletely understood, and targeted therapeutic strategies are still lacking. In this review, we map the functional architecture of this pathway, from periarteriolar CSF influx to perivenous efflux, and dissect its dependence on critical modulators including sleep-wake rhythms, arterial pulsatility, and aging. Furthermore, we explore novel therapeutic interventions, ranging from AQP4-targeted pharmacological modulation to non-invasive physical approaches, and evaluate their potential to shift clinical paradigms from symptomatic management to disease modification.