Development and prospect of treating Alzheimer's disease using the glymphatic system.

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disorder with progressive cognitive decline and typical amyloid-&#x3b2; (A&#x3b2;) and tau pathologies, whose pathogenesis remains unclear. The glymphatic system, a core cerebral waste clearance pathway, has become a critical target for AD pathogenic research and novel therapy development. This review explores the glymphatic system's structure and function, illustrates its correlation with AD pathogenesis, summarizes targeted therapies, and highlights research limitations and future directions to facilitate AD translational research. Relevant literatures published from 2012 to 2025 were retrieved from PubMed and Web of Science databases with the combined keywords of "Alzheimer's disease", "glymphatic system", "meningeal lymphatic vessels", "A&#x3b2; clearance" and "lymphatic therapy for AD". The included literatures were systematically sorted, and the basic mechanism, therapeutic strategy and research limitations were analyzed and summarized. The glymphatic system clears 30%-50% of cerebral A&#x3b2; in rodent models via meningeal lymphatic and parenchymal pathways, yet human evidence is lacking. Glymphatic dysfunction, <i>APOE4</i> genotype, and immune imbalance promote A&#x3b2; and tau accumulation and AD progression. Several glymphatic-targeted strategies have demonstrated preclinical efficacy, with intranasal agents and photostimulation progressing into early-phase clinical trials. The glymphatic system is a promising therapeutic target for AD by improving brain waste clearance. Existing limitations include species discrepancies, unclear causal relationships and insufficient clinical data. Future research will focus on human-specific mechanisms, staged intervention strategies, and rigorous safety evaluation of targeted treatments.