Glymphatic Dysfunction as a Convergent Mechanism in Neurodegenerative Disease: Links to Inflammaging, Gut-Brain Signaling, and Lifestyle Modulators

The glymphatic system is a brain-wide perivascular network that facilitates cerebrospinal fluid-interstitial fluid exchange and the clearance of metabolic waste. Growing experimental and clinical evidence suggests that glymphatic dysfunction may represent a convergent upstream mechanism linking aging, neuroinflammation, and neurodegeneration. In this narrative review, we synthesize human imaging, clinical, and translational evidence implicating glymphatic dysfunction across major neurodegenerative diseases and integrate these findings with emerging data supporting its role in chronic low-grade inflammation associated with aging (inflammaging). We further discuss how alterations in the gut microenvironment may remotely influence glymphatic function and contribute to neurodegeneration through the gut–brain axis. Although supported by extensive preclinical evidence, studies in humans increasingly demonstrate impaired glymphatic function in several neurodegenerative disorders, most assessed using diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Glymphatic dysfunction is associated with cognitive decline, motor impairment, and disease progression. Aging-related alterations in astrocytic function, aquaporin-4 polarization, blood-brain barrier integrity, and perivascular fluid dynamics provide mechanistic links between inflammaging and glymphatic failure. Gut dysbiosis may further exacerbate these processes by promoting central nervous system inflammation and vascular dysfunction. Together, these findings identify the glymphatic system as a clinically relevant pathway in neurodegeneration that may be regulated by aging-associated neuroinflammatory mechanisms involving the gut-brain axis. Finally, we discuss lifestyle factors that influence glymphatic function and propose a unified framework positioning glymphatic dysfunction as a central integrator of impaired brain clearance, with potential implications for biomarker development, clinical assessment, and disease-modifying therapeutic strategies in neurodegenerative disorders.