Aquaporin‑4 polarization and glymphatic function in Alzheimer's disease: Mechanisms, modulators, and therapeutic strategies.

Although Alzheimer's disease (AD) is traditionally viewed as a disorder of cerebral amyloid‑β (Aβ) accumulation, emerging evidence has shifted attention toward impaired clearance mechanisms as a primary driver of sporadic disease. Central to this paradigm shift is the glymphatic system and its obligate facilitator, aquaporin‑4 (AQP4), whose polarized localization at astrocytic endfeet is essential for efficient interstitial solute clearance. Loss of AQP4 polarization, termed depolarization, is consistently observed in AD mouse models as a driver of glymphatic failure and in human postmortem tissue as a correlate of protein aggregation. This review synthesizes current understanding of the molecular and cellular mechanisms that govern AQP4 polarization. We discuss the dystrophin‑associated protein complex as the primary anchoring machinery, the role of orthogonal array particle assembly and isoform switching, and the impact of post‑translational modifications. We also examine how diverse factors, including proteases, kinase signaling pathways, circadian modulators, pathological proteins, astrocyte phenotypes, and lifestyle interventions, converge to regulate AQP4 polarity. Finally, we evaluate emerging therapeutic strategies that target this axis, including pharmacological AQP4 facilitators, upstream polarity regulators such as PERK inhibitors, and non‑invasive approaches like 40 Hz gamma stimulation and exercise. By repositioning AQP4 polarization as a modifiable homeostatic checkpoint, we propose that restoring perivascular AQP4 localization represents a biologically sound strategy to enhance endogenous brain clearance and modify AD progression.