Glymphatic System Dysfunction in Alzheimer’s Disease: Insights into its Mechanisms, Diagnostic Imaging, and Therapeutic Perspectives: A Systematic Review

Introduction: The glymphatic system, a perivascular network that facilitates cerebrospinal fluid (CSF)-mediated clearance of metabolic waste, including amyloid-β (Aβ) and tau, has emerged as a critical player in the pathophysiology of Alzheimer’s disease (AD). Growing evidence suggests that an impaired glymphatic function may contribute to the onset and progression of AD by disrupting brain homeostasis and facilitating neurotoxic protein accumulation. This systematic review aims to synthesize current evidence from preclinical and clinical studies investigating the role of glymphatic system dysfunction in Alzheimer’s disease, with a focus on its imaging biomarkers, clearance mechanisms, cognitive implications, and therapeutic interventions. Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science to identify studies published up to June 2025. Thirteen eligible studies were included: five preclinical experiments, eight human imaging or biomarker studies, and one clinical trial protocol. All studies examined glymphatic system function in relation to Aβ or tau clearance, neuroimaging markers (e.g., DTI-ALPS, PVS, PET), cognitive outcomes, or therapeutic modulation (e.g., exercise, sensory stimulation). Results: Preclinical models demonstrate that impaired aquaporin-4 (AQP4) polarization and reduced CSF-interstitial fluid exchange promote Aβ accumulation and plaque formation. Human imaging studies consistently report reduced glymphatic activity in AD and mild cognitive impairment (MCI), often measured via diffusion MRI (ALPS index) and associated with increased amyloid burden, reduced cognitive performance, and altered sleep. Emerging interventions, such as aerobic exercise and 40 Hz gamma sensory stimulation, appear to enhance glymphatic clearance and reduce Aβ levels in experimental settings. A recently published trial protocol is currently evaluating the effects of exercise on glymphatic function in MCI/AD. Discussion: The current body of evidence supports a probable association between glymphatic dysfunction and Alzheimer’s disease pathology. Disruption of perivascular clearance pathways may serve as an early biomarker of AD and a novel therapeutic target. Future longitudinal and interventional studies are needed to establish causal relationships and evaluate clinical applications. Conclusion: Glymphatic system impairment plays a significant role in AD pathogenesis, contributing to the accumulation of neurotoxic proteins and cognitive decline. Therapeutic strategies targeting glymphatic function enhancement, such as lifestyle interventions and neuromodulation, hold promise for early prevention and disease modification.