Meningeal lymphatic dysfunction in Alzheimer's disease: molecular mechanisms, clinical implications, and future perspectives.

Abstract

The meningeal lymphatic system has recently emerged as a critical regulator of brain homeostasis, facilitating cerebrospinal fluid drainage, metabolic waste clearance, and immune cell trafficking. Accumulating evidence now implicates meningeal lymphatic dysfunction as a pivotal contributor to the pathogenesis of Alzheimer's disease (AD). This review critically evaluates current neuroimaging techniques for assessing meningeal lymphatic function in humans, highlighting their technical limitations in capturing dynamic pathological changes specific to AD. We summarize recent advances demonstrating that meningeal lymphatic impairment exacerbates key AD hallmarks-including amyloid-β (Aβ) and tau deposition, neuroimmune dysregulation, and myelin degradation-collectively accelerating disease progression. Building on these insights, we systematically analyse emerging therapeutic strategies aimed at enhancing meningeal lymphatic function, such as pharmacological approaches (e.g., vascular endothelial growth factor C (VEGF-C)-mediated lymphangiogenesis), physical interventions (e.g., transcranial photobiomodulation), and surgical techniques (e.g., cervical lymphaticovenous anastomosis). However, significant challenges remain, including the scarcity of direct human evidence linking meningeal lymphatic dysfunction to AD and the lack of standardized, noninvasive assessment tools. To address these gaps, we propose future fundamental and clinical research directions for meningeal lymphatic vessels and AD. By bridging mechanistic insights with translational applications, this review highlights the role of the meningeal lymphatic system as a promising yet underexplored target for AD modification.