Objective: This study aims to investigate whether single-nucleotide polymorphisms (SNPs) of the Aquaporin-4(AQP4) gene were related to abnormal protein accumulation (α-synuclein), glymphatic dysfunction (DTI-ALPS), and motor symptoms in Parkinson’s disease patients.

Background: The glymphatic system is involved in clearing waste from the brain through aquaporin-4 (AQP4) water channels.

Method: A total of 136 newly diagnosed, drug-naive Parkinson’s disease patients at HY stage ≤ 2 were included in this study. Whole-genome sequencing data were analyzed. SNP pruning parameters were as follows: window size 10, increment 5, and variance inflation factor 2, resulting in a final set of 11 SNPs.[Figure1][Table1] TheDTI analysis along the perivascular space (DTI-ALPS) index was computed to evaluate glymphatic function by measuring the diffusivity of water molecules in the direction of the PVS1.[Figure2]

Linear regression models were independently applied to examine the association between AQP4 genotype and CSF α- synuclein, DTI-ALPS index, and UPDRS-III score, adjusting age, sex, and disease duration and educational level . A partial correlation analysis was conducted to explore the association between the DTI-ALPS index and UPDRS-III scores. Furthermore, we examined whether AQP4 genotypes moderate the relationship between DTI-ALPS and UPDRS-III scores.

Results: AQP4-rs1058427 was associated with a lower DTI-ALPS index (β = -0.07, p = 0.04), while AQP4- rs7240333 was linked to higher UPDRS-III scores (β = 5.19, p < 0.01). A significant negative correlation was observed between the DTI-ALPS index and UPDRS-III scores (r = -0.23, p < 0.01)[Figure3]. The effect of DTI-ALPS on UPDRS-III scores differs depending on the AQP4-rs1058427 status[Figure4]. Specifically, the negative association between DTI-ALPS and UPDRS-III scores was stronger in individuals with the rs1058427_HET genotype.(β = -26.33, p < 0.01).

Conclusion: 1.This study suggests that specific genetic variations of AQP4 are associated with glymphatic dysfunction and motor symptom severity in Parkinson’s disease, while no significant relationship was found with CSF α-synuclein accumulation. 2.The rs1058427_HET genotype moderates the effect of glymphatic dysfunction on motor symptoms, indicating a potential genetic influence the clinical manifestations of Parkinson’s disease.

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Table1

Figure2

Figure3

Figure4

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-aquaporin-4-polymorphisms-on-glymphatic-function-and-motor-symptoms-in-parkinsons-disease/