The glymphatic system in neurodegenerative diseases and brain tumors: mechanistic insights, biomarker advances, and therapeutic opportunities

Dysfunction of the glymphatic system (GS), a brain-wide waste clearance pathway dependent on polarized aquaporin-4 (AQP4) 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.