The glymphatic system as a brain scavenger in Alzheimer's disease: mechanisms and therapeutic implications.

Alzheimer's disease (AD), the most common neurodegenerative disorder worldwide, is increasingly recognized as a major threat to global health. Its pathogenesis remains highly complex, and effective treatments are still lacking. Recent research, however, has identified a crucial player in this process-the glymphatic system, which acts as a metabolic "scavenger" in the brain, responsible for clearing waste products such as amyloid-β (Aβ) and hyperphosphorylated tau protein. Impairment of this system leads to the accumulation of these toxic proteins, which are hallmark pathological features of AD. This review comprehensively examines how glymphatic dysfunction contributes to the aggregation of Aβ and tau, thereby driving AD progression. Astrocytes regulate fluid transport via aquaporin-4 (AQP4) water channels, while microglia modulate glymphatic efficiency through phagocytosis and neuroinflammatory signaling. These cells work in concert to maintain brain homeostasis. However, in AD, the loss of polarized AQP4 expression in astrocytes, obstruction of cerebrospinal-interstitial fluid exchange by Aβ and tau, and dysregulated microglial activation collectively accelerate disease pathology. Advances in diagnostic biomarkers-such as Aβ/tau PET imaging and CSF profiles of GFAP/sTREM2-offer promising avenues for early AD detection. Meanwhile, therapeutic strategies targeting glymphatic-astrocyte-microglia interactions, including AQP4 enhancers, TREM2 agonists, and anti-inflammatory agents, open new possibilities for treatment. By integrating insights from preclinical and clinical studies, this review underscores the vital role of the glymphatic system in early intervention, highlighting potential approaches to slow AD progression through enhanced waste clearance and immunomodulation.