The Glymphatic–Venous Axis in Brain Clearance Failure: Aquaporin-4 Dysfunction, Biomarker Imaging, and Precision Therapeutic Frontiers

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The identification of brain clearance failure as a precursor to a large variety of neurodegenerative diseases has shifted fluid dynamics from a secondary to a tertiary target of brain health. The identification of the glymphatic system, detailing cerebrospinal fluid entry along perivascular spaces and exit via perivenous and meningeal lymphatic pathways, provided a challenge to previous diffusion models and established aquaporin-4-dependent astroglial polarity as a governing principle of solute transport. Multiple lines of evidence now support a coupled glymphatic-venous axis, wherein vasomotion, venous outflow, and lymphatic drainage are functionally interrelated. Failure of any axis will cascade and affect the entire axis, linking venous congestion, aquaporin-4 disassembly, and meningeal lymphatic failure to protein aggregation, neuroinflammation, edema, and intracranial hypertension. Specific lines of evidence from diffusion tensor imaging along vascular spaces, clearance MRI, and multi-omic biomarkers can provide a measure of transport. Therapeutic strategies are rapidly advancing from experimental strategies to translational approval, including behavioral optimization, closed-loop sleep stimulation, vascular and lymphatic therapies, focused ultrasound, pharmacological polarity recoupling, and regenerative bioengineering. Novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, suggest that clearance measures may serve as endpoints to be approved by the FDA. This review is intended to bridge relevant mechanistic and translational reviews, focusing on impaired clearance as an exploitable systems defect rather than an incapacitating secondary effect. Improving our understanding of the glymphatic-venous axis Injury may lead to future target strategies that advance cognitive resilience, alleviate disease burden, and improve quality of life. By clarifying the glymphatic-venous axis, we provide a mechanistic link between impaired interstitial clearance and the pathological accumulation of amyloid-β, tau, and α-synuclein in neurodegenerative diseases. The repair of aquaporin-4 polarity, venous compliance, and lymphatic drainage might therefore open new avenues for the diagnosis and treatment of Alzheimer's and Parkinson's disease, supplying both biomarkers of disease progression and new targets for early intervention. These translational implications not only locate clearance failure as an epiphenomenon of neurodegeneration but, more importantly, as a modifiable driver of the course of neurodegeneration.

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