Glymphatic and meningeal lymphatic dysfunction in Alzheimer's disease: Mechanisms and therapeutic perspectives

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition and tau pathology. Although disease-modifying therapies, such as anti-Aβ monoclonal antibodies, have been approved, their clinical efficacy remains modest and accompanied by substantial safety concerns. The glymphatic system, which is a brain-wide waste clearance network mediated by cerebrospinal fluid-interstitial fluid exchange, is critical in AD pathogenesis. Glymphatic dysfunction promotes Aβ and tau accumulation, neuroinflammation, and vascular impairment, forming a vicious cycle that drives neurodegeneration. This review elucidates the anatomical and physiological basis of the glymphatic system, its role in AD progression, and novel therapeutic strategies targeting glymphatic enhancement. Emerging interventions, including aquaporin-4 (AQP4) modulation, meningeal lymphatic regeneration, cervical deep lymphaticovenous anastomosis, and nonpharmacological approaches, are also discussed for their potential to shift AD therapeutics from symptom management to disease modification. HIGHLIGHTS: Glymphatic dysfunction drives Alzheimer's disease (AD) pathogenesis. Meningeal lymphatic decline with aging. Cervical lymphaticovenous anastomosis (LVA) as novel new intervention method for patients with AD The apolipoprotein E (APOE) ε4 allele disrupts meningeal lymphatic function, increasing AD risk via amyloid-β (Aβ) clearance deficits. Diffusion tensor imaging along the perivascular space (DTI-ALPS) and dynamic magnetic resonance imaging (MRI) enable early detection of glymphatic dysfunction, guiding pre-symptomatic AD interventions. Sleep and arterial pulsatility critically regulate glymphatic efficiency, offering non-pharmacological therapeutic avenues.

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