AUTHOR=Fang Yi , Dai Shaobing , Jin Chongyao , Si Xiaoli , Gu Luyan , Song Zhe , Gao Ting , Chen Ying , Yan  Yaping , Yin Xinzhen , Pu Jiali , Zhang Baorong 

TITLE=Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.740491

DOI=10.3389/fnagi.2021.740491

ISSN=1663-4365

ABSTRACT=<sec><title>Objective</title><p>Aquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of <italic>AQP4</italic> polymorphisms in Parkinson’s disease (PD).</p></sec><sec><title>Methods</title><p>Three-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson’s Progression Marker Initiative study were analyzed. We examined whether <italic>AQP4</italic> SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether <italic>AQP4</italic> SNPs were associated with Aβ burden as measured by <sup>18</sup>F Florbetapir standard uptake values. Furthermore, we examined if <italic>AQP4</italic> SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers.</p></sec><sec><title>Results</title><p>In patients with PD, <italic>AQP4</italic> rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aβ deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aβ42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD.</p></sec><sec><title>Interpretation</title><p>Genetic variations of <italic>AQP4</italic> and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. <italic>AQP4</italic> rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD.</p></sec>