Glymphatic Dysfunction as a Multisystem Pathway Linking Systemic Health Conditions to Alzheimer's Disease: Mechanisms, Risk Factors, and Therapeutic Opportunities.

The glymphatic system is a glia-associated perivascular pathway involved in cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and the transport and clearance of neurotoxic metabolites, including amyloid-β (Aβ) and tau, from the central nervous system. Growing evidence suggests that alterations in glymphatic and perivascular clearance are associated with Alzheimer's disease (AD) pathology and may contribute to the accumulation of neurotoxic proteins and neurodegeneration. This review examines the role of the glymphatic system in AD and explores how aging, sleep disturbances, hypertension, ischemic heart disease, high-fat diet, diabetes, and gut microbiome dysbiosis impair glymphatic transport. A recurring mechanism across experimental models is the loss of perivascular AQP4 polarization, while vascular, metabolic, and inflammatory conditions may converge on related perivascular and neurovascular processes that impair CSF-ISF exchange and solute handling. Neuroimaging studies using markers such as DTI-ALPS, perivascular space burden, and free-water measurements provide evidence of alterations in glymphatic-related and perivascular processes in AD and demonstrate associations with amyloid deposition, neurodegeneration, and cognitive decline. Furthermore, glymphatic dysfunction may interact with neuroinflammation and tau pathology, creating a self-reinforcing cycle that accelerates disease progression. Emerging therapeutic strategies, including continuous theta-burst stimulation, positive airway pressure therapy for obstructive sleep apnea, pharmacological enhancement of AQP4 function, and nutritional interventions, have shown potential in experimental and early translational studies to influence glymphatic-related processes and may mitigate AD-related pathology. Collectively, current findings suggest that glymphatic and perivascular clearance pathways may represent an important link between systemic health conditions and AD. Because related pathways are implicated across multiple systemic conditions, interventions targeting glymphatic and perivascular dysfunction may have broader relevance to brain health, but their clinical effects remain to be established.