Liu Lingyun, Zeng Qingze, Luo Xiao, Hong Hui, Fang Yi, Xie Linyun, Zhang Yao, Lin Miao, Wang Shuyue, Li Kaicheng, Liu Xiaocao, Zhang Ruiting, Chen Yanxing, Yang Yunjun, Huang Peiyu
Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Hum Brain Mapp. 2025 Mar;46(4):e70171. doi: 10.1002/hbm.70171.
We investigated whether aquaporin-4 (AQP4) single-nucleotide polymorphisms (SNPs) influence Alzheimer's disease (AD) progression through changes in the glymphatic system. We included 242 non-dementia 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-ALPS), in both cross-sectional and longitudinal data. We investigated whether AQP4-related 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-positive group (SNPtime: β = -0.0040, t(46.25) = -2.062, p = 0.045, 95% CI = -0.0078 ~ -0.0001), whereas the rs9951307 minor allele carrier showed a faster FW increase in the amyloid-negative group (SNPtime: β =0.0033, t(81.19) = 2.245, p = 0.027, 95% CI = 0.0004 ~ 0.0062). The higher FW was associated with faster cognitive decline at follow-ups. 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.
我们研究了水通道蛋白4（AQP4）单核苷酸多态性（SNP）是否通过类淋巴系统的变化影响阿尔茨海默病（AD）的进展。我们纳入了242名非痴呆参与者，并选择了先前显示与AD相关的6个SNP。我们在横断面和纵向数据中分析了AQP4 SNP与类淋巴标志物之间的关联，包括扩大的血管周围间隙（PVS）、白质自由水（FW）以及沿血管周围间隙的扩散张量成像分析（DTI-ALPS）。我们研究了与AQP4相关的类淋巴标志物是否与AD病理进展和认知障碍相关，以及它们是否介导AQP4 SNP与AD进展之间的关系。基线时，AQP4 SNP与类淋巴标志物之间无关联。AQP4 SNP rs72878794次要等位基因状态的携带者在淀粉样蛋白阳性组中FW增加较慢（SNP时间：β = -0.0040，t(46.25) = -2.062，p = 0.045，95% CI = -0.0078 ~ -0.0001），而rs9951307次要等位基因携带者在淀粉样蛋白阴性组中FW增加较快（SNP时间：β = 0.0033，t(81.19) = 2.245，p = 0.027，95% CI = 0.0004 ~ 0.0062）。随访时较高的FW与更快的认知衰退相关。AQP4 SNP影响间质液积聚，导致AD患者认知衰退但不影响淀粉样蛋白沉积。需要进一步研究以阐明连接AQP4 SNP与AD进展的途径。
