The Glymphatic and Meningeal Lymphatic Systems: Gatekeepers of Brain Health in Aging and Neurodegeneration

The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.