Advancements in Therapy for Alzheimer’s Disease Based on the Cerebral Lymphatic System

Background: Conventional therapeutic interventions for Alzheimer’s disease (AD) are limited by multiple drawbacks, including anticholinesterase inhibitors, glutamate receptor antagonists, intestinal flora regulators and Aβ-targeting monoclonal antibodies, which only achieve modest symptomatic relief, are accompanied by notable adverse events (e.g., intracerebral hemorrhage, cerebral edema) and have suboptimal clinical efficacy. In recent years, the cerebral lymphatic system, consisting of the glial lymphatic system (GLS) and meningeal lymphatic vessels (MLVs), has been identified as a key mediator of amyloid β-protein (Aβ) clearance and a critical driver of AD pathogenesis. Lymphatic dysfunction in this system precedes and exacerbates Aβ deposition and cognitive decline in AD patients, revealing the close association between cerebral lymphatic system impairment and AD progression. Purpose: This study aims to focus on the emerging therapeutic advancements for AD targeting the cerebral lymphatic system, moving beyond the conventional symptomatic treatments and Aβ-centric interventions. It also intends to systematically summarize the relevant mechanisms of the cerebral lymphatic system in AD and the diverse therapeutic strategies targeting this system, thus providing a framework for developing innovative clinical interventions for AD. Methods: This study adopted a review approach, systematically collating and analyzing existing research on the cerebral lymphatic system and AD, including the cerebral lymphatic pathway of Aβ clearance, the pathological consequences of lymphatic impairment in AD, and various therapeutic strategies targeting the cerebral lymphatic system that have been reported in current studies. Results: The review identified and summarized multiple categories of effective therapeutic strategies targeting the cerebral lymphatic system for AD, covering pharmacological agents (VEGF-C, traditional Chinese medicines, oxytocin), photobiotherapies (808 nm near-infrared light, 40 Hz multisensory stimulation), physiotherapies (aerobic exercise, rTMS), gene therapy (DSCR1 upregulation), and surgical interventions (lymphatic-venous anastomosis). All these strategies are designed to optimize cerebral lymphatic function and thereby enhance Aβ drainage in the brain. Conclusion: Optimizing cerebral lymphatic function to enhance Aβ drainage is a viable, disease-modifying therapeutic direction for AD. This therapeutic approach targeting the cerebral lymphatic system can serve as a complementary or alternative method to current symptomatic or Aβ-targeted treatments for AD, and also provides a theoretical and practical framework for the development of innovative clinical interventions for the disease. Keywords: Alzheimer’s disease, glial lymphatic system, Meningeal lymphatic vessels, amyloid β-protein, therapy