# The Glymphatic System and Meningeal Lymphatics: Current Understandings and Future Perspectives

## TL;DR

The glymphatic-lymphatic system clears brain waste and connects to the immune system, with dysfunction linked to neurological diseases like Alzheimer's and stroke.

## Contribution

This review integrates current knowledge on the glymphatic-lymphatic axis and proposes therapeutic strategies to modulate its function.

## Key findings

- The glymphatic-lymphatic axis is critical for brain waste clearance and immune communication.
- Dysfunction of this system is linked to Alzheimer's disease, stroke, and multiple sclerosis.
- Therapeutic strategies like PBM and LVA show promise in enhancing clearance and reducing neuroinflammation.

## Abstract

The central nervous system (CNS) maintains homeostasis and immune surveillance through a recently defined brain‐wide clearance network: the glymphatic–lymphatic axis. This system couples the intramural glymphatic pathway, responsible for convective fluid transport and parenchymal waste removal, with the meningeal lymphatic vessels (MLVs), which serve as the critical efferent route to the peripheral immune system. This review delineates the structural and functional foundations of each component, their regulatory dynamics, including the roles of sleep and aging, and their synergistic interplay in maintaining fluid balance, clearing metabolic waste, and facilitating neuroimmune communication. Mounting evidence identifies the dysfunction of this integrated axis as a common pathological mechanism across a spectrum of neurological disorders. We highlight its pivotal role in three key paradigms: acute injury (stroke), chronic proteinopathy (Alzheimer's disease, AD), and autoimmune dysregulation (multiple sclerosis, MS), where impaired clearance and maladaptive immune responses are central, recurring themes. The review critically evaluates emerging translational strategies aimed at therapeutically modulating this axis, including pharmacological targets (VEGF‐C, Piezo1 agonists), noninvasive neuromodulation (photo‐biomodulation, PBM), and surgical interventions (lymphaticovenous anastomosis, LVA). This synthesis positions the glymphatic–lymphatic axis as a fundamental physiological network and a pivotal target for novel interventions, outlining key future research directions in neurology.

Brain waste clearance relies on the anatomical and functional integration of the glymphatic system and meningeal lymphatic vessels. Cerebrospinal fluid influx into the brain parenchyma occurs along periarterial spaces, a process driven by polarized aquaporin‐4 (AQP4) water channels on astrocytic endfeet. Solutes are subsequently cleared via perivenous spaces and absorbed by meningeal lymphatics, which drain them to the deep cervical lymph nodes. The efficiency of this pathway is dynamically regulated by factors including sleep, arterial pulsatility, and body posture. Dysfunction of this clearance axis impairs the removal of pathological proteins (amyloid‐β, tau), leading to their accumulation, triggering neuroinflammation, and worsening outcomes after brain injury, thereby playing a key role in neurodegenerative diseases and acute brain injury. Consequently, targeting this pathway to enhance its function represents a promising novel therapeutic direction.