The effects of aquaporin-4 polymorphisms on glymphatic function and motor symptoms in Parkinson’s disease

Growing evidence suggests that the glymphatic system, driven by aquaporin-4 (AQP4) water channels, plays a key role in Parkinson's disease (PD). We examined the impact of specific AQP4 variants on glymphatic function using diffusion tensor imaging along the perivascular space (DTI-ALPS), and explored potential mechanisms underlying motor symptom severity and progression in PD. PD participants exhibited lower DTI-ALPS indices compared to controls. Reduced DTI-ALPS at baseline was linked to more severe motor symptoms and faster longitudinal motor decline, as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III). One specific AQP4 variant was associated with decreased DTI-ALPS and increased MDS-UPDRS III scores, with DTI-ALPS mediating this relationship at baseline and follow-up. Some variants exhibited indirect protective effects on motor symptoms via enhanced glymphatic function. These findings indicate that AQP4 polymorphisms contribute to glymphatic dysfunction and motor progression in PD, supporting strategies for disease modification.