Glymphatic dysfunction is associated with neurodegenerative diseases and brain tumors, leading to impaired waste clearance and immune modulation.
Impaired glymphatic function can lead to the accumulation of neurotoxic proteins such as amyloid-β, tau, and α-synuclein in Alzheimer's and Parkinson's diseases.
Factors contributing to glymphatic dysfunction include loss of polarization, reduced arterial pulsatility, genetic risks, and sleep disturbances.
Neuroimaging biomarkers like the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and choroid plexus volume (CPV) can quantify glymphatic function and correlate with clinical decline.
In brain tumors, mechanical compression and lactate-driven acidosis obstruct perivascular fluid transport, leading to a reduced ALPS index that correlates with tumor grade and survival.
Emerging therapies aimed at restoring function include pharmacological interventions, non-invasive techniques, and surgical approaches.
Simplified
Dysfunction of the (GS), a brain-wide waste clearance pathway dependent on polarized aquaporin-4 () water channels on astrocytic endfeet, is increasingly recognized as a critical mechanism in both neurodegenerative diseases and brain tumors. In Alzheimer's (AD) and Parkinson's (PD) diseases, impaired glymphatic function leads to the accumulation of neurotoxic proteins, including amyloid-β (Aβ), tau, and α-synuclein (α-syn). Contributing factors include loss of AQP4 polarization, reduced arterial pulsatility, genetic risks (e.g., APOE4, FAM171A2 mutations), and sleep disturbances. These functional impairments can be quantified using neuroimaging biomarkers such as the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and choroid plexus volume (CPV), which correlate with pathological burden and clinical decline, though the direct physiological interpretation of these metrics requires further validation. Conversely, in glioblastoma and other brain tumors, mechanical compression and lactate-driven acidosis obstruct perivascular fluid transport, promoting an immunosuppressive tumor microenvironment that limits T-cell infiltration and confers therapeutic resistance. Here, too, glymphatic dysfunction is reflected by a reduced ALPS index, which correlates with tumor grade, peritumoral edema, and survival. Emerging therapeutic strategies aimed at restoring GS function include pharmacological interventions (e.g., circadian regulators, AQP4 modulators), non-invasive techniques (e.g., cervical lymphatic stimulation, gamma stimulation, exercise), and surgical approaches (e.g., lymphatic-venous anastomosis). Advances in multimodal MRI and artificial intelligence (AI)-enhanced analytics further support novel diagnostic capabilities. This review highlights the dual role of the GS across neurological disorders and underscores its potential as a therapeutic target for enhancing waste clearance and immune modulation. However, significant challenges remain, including the validation of human biomarkers, elucidating bidirectional tumor-glymphatic crosstalk, and translating preclinical discoveries into clinical practice.
Key numbers
40–60%
Reduction in CSF–ISF exchange efficiency in AD
Efficiency of CSF–ISF exchange is reduced due to dysfunction.
30%
Decrease in glymphatic clearance efficiency in PD
Efficiency is reduced due to obstruction by α-synuclein aggregates.
30–50%
Increase in glymphatic clearance efficiency from pharmacological modulation
Pharmacological interventions can enhance glymphatic clearance.
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Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
