The Glymphatic system: A key mechanism linking sleep to brain health and diseases

Sleep is increasingly recognized as a fundamental regulator of brain homeostasis, yet the mechanisms linking sleep to neurological health have only recently begun to emerge. The glymphatic system, a brain-wide perivascular transport network, has provided a mechanistic framework connecting sleep physiology with brain health and disease. Accumulating evidence indicates that glymphatic activity is markedly enhanced during sleep through coordinated regulation of vasomotion, norepinephrine oscillations, aquaporin-4 polarization, extracellular space expansion, respiration, and meningeal lymphatic drainage. Conversely, chronic sleep disruption impairs glymphatic transport, promotes the accumulation of neurotoxic metabolites, and contributes to neuroinflammation, thereby accelerating the progression of diverse neurological disorders. In this review, we integrate recent advances in glymphatic biology from structural organization and transport mechanisms to sleep-dependent regulation and emerging neuroimaging approaches. We critically evaluate current evidence supporting glymphatic dysfunction in neurodegenerative diseases, traumatic brain injury, cerebrovascular disorders, psychiatric disorders, brain tumors, and ocular diseases, highlighting sleep-related impairment as a common mechanistic denominator. Particular emphasis is placed on the translational potential and limitations of non-invasive imaging biomarkers, including DTI-ALPS, dynamic contrast-enhanced MRI, diffusion MRI, PET, and emerging multimodal techniques. We also discuss major controversies surrounding glymphatic physiology, including the relative contributions of bulk flow and diffusion, species-specific differences, and the challenges of validating human imaging biomarkers. Finally, we propose a conceptual sleep-glymphatic-disease axis that integrates current mechanistic knowledge with clinical translation. Understanding how sleep regulates glymphatic function may provide new opportunities for disease prevention, biomarker development, and therapeutic intervention across a broad spectrum of brain disorders.