The glymphatic-lymphatic axis: known pathways, open questions, and emerging roles in neurodegeneration

The discovery of the glymphatic system and meningeal lymphatic vessels has transformed our understanding of brain fluid homeostasis and central-peripheral communication, highlighting the critical role of cerebrospinal fluid in brain clearance. While substantial progress has been made in defining the structural components and physiological regulators of brain clearance, major uncertainties remain regarding (1) how these systems interact as an integrated physiological network, (2) how they fail in disease, and (3) whether they can be therapeutically manipulated. In this review, we first summarize the anatomical and physiological organization of the glymphatic-lymphatic axis, with particular emphasis on its regulatory mechanisms in light of rapid advances in this field. We then discuss how the glymphatic-lymphatic axis functionally integrates with peripheral immune and metabolic systems and describe how impairment of these clearance pathways is associated with the accumulation of pathological proteins, neuroinflammation, and vascular dysfunction and may contribute to the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Finally, we discuss emerging therapeutic strategies and biomarkers targeting the glymphatic-lymphatic axis. By redefining the central-peripheral crosstalk, the glymphatic-lymphatic axis provides a unifying framework for understanding brain clearance, neurodegeneration, and future therapeutic interventions.