Reconstructing cerebral lymphatic clearance: an emerging target in the Alzheimer's disease therapeutic pipeline

Neurotoxic protein accumulation is widely recognized as a key feature of Alzheimer's disease (AD), and increasing evidence indicates that impaired brain clearance associated with dysfunction of the meningeal lymphatic and glymphatic may contribute to this process. Disruption of these pathways may weaken homeostatic mechanisms and facilitate amyloid‑β and tau buildup. This review considers lymphatic reconstruction as a potential therapeutic direction aimed at modestly improving clearance efficiency. We summarize current findings from pharmacological approaches targeting aquaporin-4 or vascular endothelial growth factor C signaling, non-invasive methods such as photobiomodulation and focused ultrasound, and emerging surgical or lifestyle interventions designed to enhance drainage. Early clinical attempts, including deep cervical lymphovenous anastomosis (dCLVA), provide preliminary proof of concept but require careful validation. Progress in this field also depends on developing sensitive, non-invasive imaging markers and defining appropriate intervention windows. By situating lymphatic modulation within the broader AD drug-development landscape, we highlight its possible role within multimodal therapeutic strategies.