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We included 242 non\u2010dementia participants and chose six SNPs previously shown to be related to AD. We analyzed the associations between AQP4 SNPs and glymphatic markers, including enlarged perivascular spaces (PVS), white matter free water (FW), and diffusion tensor image analysis along the perivascular space (DTI\u2010ALPS), in both cross\u2010sectional and longitudinal data. We investigated whether AQP4\u2010related glymphatic markers are associated with AD pathology progression and cognitive impairment, and whether they mediate the relationship between AQP4 SNPs and AD progression. There was no association between AQP4 SNPs and glymphatic markers at baseline. Carriers of the AQP4 SNP rs72878794 minor allele status exhibited slower FW increase in the amyloid\u2010positive group (SNP*time: <jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.0040, t(46.25)\u2009=\u2009\u22122.062, <jats:italic>p<\/jats:italic>\u2009=\u20090.045, 95% CI\u2009=\u2009\u22120.0078\u2009~\u2009\u22120.0001), whereas the rs9951307 minor allele carrier showed a faster FW increase in the amyloid\u2010negative group (SNP*time: <jats:italic>\u03b2<\/jats:italic>\u2009=0.0033, t(81.19)\u2009=\u20092.245, <jats:italic>p<\/jats:italic>\u2009=\u20090.027, 95% CI\u2009=\u20090.0004\u2009~\u20090.0062). The higher FW was associated with faster cognitive decline at follow\u2010ups. AQP4 SNPs influence interstitial fluid accumulation, contributing to cognitive decline but not amyloid deposition in AD. Further studies are needed to clarify the pathways linking AQP4 SNPs and AD progression.<\/jats:p>","DOI":"10.1002\/hbm.70171","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T13:43:16Z","timestamp":1741700596000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Association Between Single Nucleotide Polymorphisms in the Aquaporin\u20104 Gene and Longitudinal Changes in White Matter Free Water and Cognitive Function in Non\u2010Demented Older Adults"],"prefix":"10.1002","volume":"46","author":[{"given":"Lingyun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Radiology The First Affiliated Hospital of Wenzhou Medical University  Wenzhou China"},{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingze","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyun","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou 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