Advances in the Treatment of Alzheimer’s Disease Based on the Glymphatic System

Alzheimer's disease (AD), characterized by the pathological accumulation of amyloid (A) plaques and hyperphosphorylated tau (p-tau) tangles, remains a major therapeutic challenge due to the limitations of conventional drug-based approaches targeting late-stage pathology.Recent advances in understanding the meningeal lymphatic system (MLS)-a critical network for brain waste clearance-have opened novel avenues for AD intervention.This review synthesizes current research on the physiological roles of the MLS, its mechanisms in clearing A and p-tau, and strategies to modulate its function for therapeutic benefit.The MLS integrates glymphatic pathways and meningeal lymphatics to facilitate the removal of neurotoxic proteins, with aquaporin-4 (AQP4)-mediated cerebrospinal fluid (CSF)interstitial fluid (ISF) exchange and lymphatic drainage to cervical nodes playing pivotal roles.Key factors influencing MLS efficiency include neuroinflammation, sleep-wake cycles, exercise, and hormonal regulation.Emerging therapeutic strategies, such as sleep optimization, physical therapies, surgical interventions (e.g., lymphaticvenous anastomosis), and nanoparticle-based drug delivery systems, demonstrate potential in enhancing A/p-tau clearance and alleviating cognitive deficits in preclinical and clinical studies.However, challenges persist, including incomplete mechanistic insights, variability in surgical outcomes, and a lack of standardized metrics for MLS evaluation.Future research should prioritize elucidating molecular crosstalk within the MLS, developing non-invasive monitoring technologies, and testing multimodal interventions in early AD stages.By bridging gaps between neurology, immunology, and bioengineering, this review underscores the transformative potential of MLS-targeted therapies in shifting AD management from symptomatic relief to disease modification.