Modulating glymphatic clearance in Alzheimer's disease: Molecular mechanisms, imaging biomarkers, and emerging...

The glymphatic system supports cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and helps clear neurotoxic proteins, including amyloid beta (Aβ) and tau. Evidence from experimental models and human observational studies links glymphatic dysfunction to Alzheimer's disease (AD), although causality in humans remains incompletely established. This review synthesizes advances in mechanisms, biomarkers, and interventions. Loss of aquaporin 4 (AQP4) polarization at astrocytic endfeet is consistently associated with reduced CSF-ISF exchange and greater Aβ and tau burden. Additional contributors, including meningeal lymphatic impairment, blood-brain barrier disruption, altered vascular pulsatility, sleep fragmentation, and perivascular structural remodeling, likely interact during early pathology. Clinically, surrogate measures such as perivascular space (PVS) enlargement and diffusion tensor-based indices including the Analysis along the perivascular space (ALPS) index provide indirect readouts of perivascular fluid behavior but are limited by intersite variability and incomplete specificity. Contrast enhanced MRI approaches can probe clearance more directly, yet they remain invasive and difficult to scale for routine use. Fluid biomarkers, including CSF AQP4 and related transport proteins, are promising but require robust analytical validation in large multicenter cohorts. Therapeutic directions include sleep and circadian optimization, vascular risk control and aerobic exercise, neuromodulation such as gamma frequency sensory stimulation, and molecular strategies targeting AQP4 anchoring, with careful attention to safety and feasibility. Standardized biomarkers and prospective longitudinal interventional trials are needed to test whether improving clearance proxies yields durable biomarker shifts and clinically meaningful benefits in AD.