Abstract:

Objective: To investigate the correlation between serum uric acid (SUA) and cognitive function as well as cerebrospinal fluid (CSF) pathological biomarkers in patients with Alzheimer's disease (AD), and to analyze its potential role in the pathophysiological process of AD. Methods: Two independent AD cohorts were recruited from the West China Hospital, Sichuan University between January 2023 and January 2025. The Cohort 1 (cognitive cohort, n=329) included patients with AD confirmed by amyloid β-protein (Aβ)-PET or CSF pathological biomarkers. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Frontal Assessment Battery (FAB), and the association between SUA and cognitive function was evaluated. The Cohort 2 (CSF cohort, n=149) consisted of patients with AD confirmed by CSF pathological biomarkers, in whom CSF levels of Aβ₄₂, Aβ₄₀, phosphorylated tau (p-tau), total tau (t-tau), α-synuclein (α-Syn), and neurofilament light chain (NfL) were measured to investigate the association between SUA and CSF pathological biomarkers. Correlation analysis, multiple linear regression analysis, causal mediation analysis, and interaction analysis were performed to explore the associations among SUA, cognitive function, and CSF pathological biomarkers. Results: In the Cohort 1, correlation analysis showed that SUA was positively correlated with MMSE (r=0.139, P=0.022), MoCA (r=0.198, P=0.001), and FAB (r=0.138, P=0.023) in AD patients. Multiple linear regression analysis showed that SUA was linearly correlated with MoCA in AD patients (standardized partial regression coefficient=0.144, P=0.014). In the Cohort 2, correlation analysis showed that SUA was negatively correlated with CSF Aβ₄₂(r_s= -0.169, P=0.047). Multiple linear regression showed that when FAB was included, SUA was linearly correlated with CSF Aβ₄₂(standardized partial regression coefficient= -0.188, P=0.045). Causal mediation analysis showed that CSF Aβ₄₂did not mediate the associations between SUA and MMSE, MoCA and FAB (P > 0.05, for all), and the effects of SUA on cognitive function were mainly direct effect (MMSE: P=0.004; MoCA: P=0.002; FAB: P=0.000). Interaction analysis showed that CSF Aβ₄₂had significant main effect on MMSE (standardized partial regression coefficient=0.191, P=0.015), MoCA (standardized partial regression coefficient=0.195, P=0.014), and FAB (standardized partial regression coefficient=0.167, P=0.033); SUA had a significant main effect on FAB (standardized partial regression coefficient=0.199, P=0.021); however, the interaction term between SUA and CSF Aβ₄₂was not statistically significant with MMSE, MoCA and FAB (P > 0.05, for all), suggesting that the effect of SUA on cognitive function was not moderated by Aβ₄₂. Conclusions: Higher SUA is associated with better cognitive function in AD patients and with lower CF Aβ₄₂, and no significant mediation or interaction effects were found between two associations.

Key words: Alzheimer disease, Cerebrospinal fluid, Biomarkers, Uric acid, Serum, Amyloid beta-peptides, Cognition disorders, Mediation analysis

摘要：

目的: 探讨血清尿酸与阿尔茨海默病患者认知功能及脑脊液病理学标志物的关联性，分析其在阿尔茨海默病病理生理学过程中的潜在作用。方法: 纳入2023年1月至2025年1月四川大学华西医院收治的2个独立阿尔茨海默病队列：队列一（认知队列，329例）经β-淀粉样蛋白（Aβ）-PET或脑脊液病理学标志物确诊，采用简易智能状态检查量表（MMSE）、蒙特利尔认知评价量表（MoCA）及额叶功能评价量表（FAB）评估认知功能，分析血清尿酸与认知功能的关联性；队列二（脑脊液队列，149例）经脑脊液病理学标志物确诊，测定脑脊液Aβ₄₂、Aβ₄₀、磷酸化tau蛋白、总tau蛋白、α-突触核蛋白及神经丝轻链，分析血清尿酸与脑脊液标志物间的关联性。相关分析、多元线性回归分析、因果中介分析以及交互作用分析探索血清尿酸、认知功能和脑脊液病理学标志物间的关联性。结果: 队列一：相关分析显示，血清尿酸与MMSE评分（r=0.139，P=0.022）、MoCA评分（r=0.198，P=0.001）、FAB评分（r=0.138，P=0.023）呈正相关；多元线性回归分析显示，血清尿酸与MoCA评分呈线性回归关系（标准化偏回归系数=0.144，P=0.014）。队列二：相关分析显示，血清尿酸与脑脊液Aβ₄₂呈负相关（r_s= -0169，P=0.047）；多元线性回归分析结果显示，当纳入FAB评分时血清尿酸与脑脊液Aβ₄₂呈线性回归关系（标准化偏回归系数= -0.188，P=0.045）。因果中介分析显示，脑脊液Aβ₄₂在血清尿酸与MMSE、MoCA和FAB评分之间的关联中未发挥中介作用（均P > 0.05），血清尿酸对认知功能的效应主要为直接效应（MMSE评分：P=0.004；MoCA评分：P=0.002；FAB评分：P=0.000）。交互作用分析显示，脑脊液Aβ₄₂对MMSE评分（标准化偏回归系数=0.191，P=0.015）、MoCA评分（标准化偏回归系数=0.195，P=0.014）及FAB评分（标准化偏回归系数=0.167，P=0.033）具有显著主效应；血清尿酸对FAB评分具有显著主效应（标准化偏回归系数=0.199，P=0.021）；而血清尿酸和脑脊液Aβ₄₂的交互项与MMSE、MoCA和FAB评分均无统计学意义（均P > 0.05），提示血清尿酸对认知功能的影响并未受到Aβ₄₂水平的调节。结论: 较高的血清尿酸水平不仅与阿尔茨海默病患者较好的认知功能相关，而且与较低的脑脊液Aβ₄₂水平相关，并且二者关联之间不存在显著的中介或交互作用。

关键词: 阿尔茨海默病, 脑脊髓液, 生物标记, 尿酸, 血清, 淀粉样β肽类, 认知障碍, 中介分析

CLC Number: 

• R741