3RD PLACE, LITERATURE REVIEW TRACK: Interplay of Microglia and the Glymphatic System in Alzheimer’s Disease: A Systematic Review

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by memory loss, cognitive decline, and pathological amyloid-β (Aβ) and tau protein accumulation. In 2021, the World Health Organization (WHO) reported over 57 million people worldwide living with dementia, with AD as the most common form. While most research has focused on the overproduction of these toxic proteins, mounting evidence suggests that impaired brain-wide clearance mechanisms may also drive disease progression. Understanding the cellular processes behind this impaired clearance is critical to the development of effective interventions. Recent studies highlight the glymphatic system—a glial-dependent fluid clearance pathway—and microglia, the brain’s immune cells, as key regulators of protein clearance and neuroinflammation. Intriguingly, some studies indicate a bidirectional relationship: microglial activity may regulate glymphatic efficiency, while glymphatic dysfunction may in turn exacerbate microglial inflammation. This systematic literature review synthesizes findings from animal models and human studies to better understand the dynamic interplay between microglia and the glymphatic system in AD. We first describe microglia and the glymphatic system and then their role in AD, following with an exploration of how microglial activation shapes, and is shaped by, impaired glymphatic function. We also evaluate how these processes interact in disease models and human brain tissue. Finally, we discuss dual-targeting strategies that may restore clearance and reduce neuroinflammation, while acknowledging limitations in translating animal model findings to clinical therapies.