Association Between Aquaporin-4 Single Nucleotide Polymorphisms And Parkinson’s Disease

Background: Parkinson’s disease(PD)is one of the most common neurodegenerative disorders,abnormal aggregation of α-synuclein lies at the core of its pathology.Besides,aggregation of amyloid-β(Aβ)and tau contributes to cognitive decline in PD.Insufficient clearance of neurotoxic proteins is closely linked to the onset and progression of this disease.Glymphatic system is a glial-dependent interstitial fluid circulatory system that is dedicated to drain waste proteins and metabolic waste.Cerebrospinal fluid is propelled from the periarterial compartment to the interstitial space and then mixed with interstitial solutes and emptied along the veins.Aquaporin-4(AQP4)at the astrocytic end feet facilitates the exchange process and plays a critical role in brain waste removal.Previous studies in animal models demonstrated that knockout of Aqp4 substantially increases the accumulation of α-synuclein and amyloid.In human patients,single nucleotide polymorphisms(SNP)of AQP4 are associated with amyloid burden and rate of cognitive decline in the spectrum of Alzheimer’s dementia.Therefore,it is likely that genetic variations of AQP4 are also predictive of disease severity and rate of progression in PD as they alter the clearance efficacy of neurotoxic proteins by the glymphatic system.Methods: Using a landmark large-scale,multicenter,longitudinal observational study,the Parkinson’s Progression Markers Initiative,the current study pruned AQP4 SNPs from whole genome sequencing data by linkage disequilibrium-based pruning.The current study explored the association between AQP4 SNP and rate of motor and cognitive decline in Caucasian patients with PD(N = 382)and healthy controls(N = 180)by linear mixed model and Cox proportional hazards model.In addition,this study indirectly evaluated the efficacy of the glymphatic system with cerebrospinal fluid biomarkers,amyloid in vivo imaging with PET,and MRI-visible enlarged perivascular space,and tested the hypothesis that AQP4 SNP are closely linked to these glymphatic markers.Furthermore,the association between AQP4 SNP and disease severity in southern Chinese Han patients(N = 244)was examined in a cross-sectional cohort.Result: AQP4 SNPs that were investiged in the current study were not associated with either disease risk or motor symptom severity in PD.In Caucasian patients with PD,AQP4 rs162009(AA/AG vs.GG)was associated with slower declination to dementia(HR = 0.473,95% CI = 0.234 ~ 0.957),better performance in attention and working memory(letter number sequencing: p = 0.006;symbol digit modalities: p = 0.006),lower amyloid burden in putamen(p = 0.012)and anterior cingulate(p = 0.048).In the subgroup of patients with higher rapid eye movement behavior screening questionnaire score,rs162009 was protective of amyloid aggregation(with higher Aβ42 level in cerebrospinal fluid: p = 0.017).In addition,this variant was associated with lower burden of enlarged perivascular space(basal ganglia: p < 0.001,centrum semiovale: p = 0.008,midbrain: p = 0.039).This variant was also associated with higher semantic fluency test performance in healthy controls(p = 0.016).In Chinese Han patients,this variant was associated with better sleep quality(Parkinson’s disease sleep scale: p = 0.024).In caucasian patients,rs68006382(GG/GA vs.AA)was associated with accelerated conversion to MCI(HR = 1.973,95% CI = 1.246 ~ 3.123),worse performance in attention and working memory(letter number sequencing: p = 0.003;symbol digit modality test: p = 0.002),and executive function(semantic fluency test: p = 0.001).In Chinse Han patient,this genotype was marginally associated with worse sleep quality(Pittsburgh Sleep Quality Index: p = 0.071).In Chinese Han patients,rs9951307(AA/AG vs.GG)was marginally associated with better cognition(MMSE: p = 0.072;auditory verbal learning test – recognition: p = 0.016;semantic fluency test: p = 0.077),which was consistent with previous observation in AD that this variant was protective of cognitive decline.Conclusion: The current study provides novel evidence that genetic variations of AQP4 and subsequent alterations of glymphatic efficacy likely contributes to cognitive decline in PD.AQP4 rs162009 is likely a novel genetic prognostic marker of cognitive decline in PD.