Serum Uric Acid Level And Its Correlation With Cerebrospinal Fluid Biomarkers In Preclinical Alzheimer’s Disease

Background and objective:Alzheimer’s disease（AD）was a common degenerative disease of the central nervous system and has become a major global health challenge in the 21st century.However,the specific pathogenic mechanism of the occurrence and development of AD was still unclear.Amyloid plaques caused by extracellularβ-amyloid（Aβ）aggregation and neurofibrillary tangles caused by intracellular hyperphosphorylated tau protein constituted the main pathological hallmarks of AD.And this pathological change has existed as early as the preclinical stage before the appearance of cognitive impairment.Therefore,exploring the influencing factors of AD pathology in the preclinical stage was of great significance to the early prevention of AD and the exploration of pathogenic mechanisms.A growing body of evidence has indicated that serum uric acid（SUA）levels may affect the occurrence and development of AD but yielded inconsistent findings.Therefore,the relationship between SUA level and AD still needs to be further explored.This study aims to explore the changes of SUA levels and their correlations with CSF biomarkers in preclinical AD and determine whether high SUA was a potential risk factor for AD.Methods:A total of 839 cognitively intact older adults（age,mean±SD=62.16±10.93;484 males[57.69%]）were selected eventually for the present study from the Chinese Alzheimer’s Biomarker and Lifestyl E study（CABLE）who had measurements of SUA level,cerebrospinal fluid（CSF）Aβ,total tau proteins（t-Tau）,phosphorylated tau proteins（p-Tau）,and apolipoprotein E-ε4（APOE-ε4）carrier status.We divided the subjects into preclinical AD and healthy control groups according to the National Institute on Aging-Alzheimer’s Association（NIA-AA）criteria.And covariance analysis controlling for age,gender,educational levels,and APOE-ε4 status was used to explore the difference in SUA levels between the two groups.Besides,to clarify the impacts of SUA on metabolisms of CSF biomarkers of Alzheimer’s pathology（Aβ1-42,t-Tau,and p-Tau）,we explored the linear or non-linear relationship between SUA and AD CSF biomarkers and their ratios（Aβ1-42/Aβ1-40,p-Tau/Aβ1-42,and t-Tau/Aβ1-42）using multiple linear regression models or a quadratic model（y=βx²+αx+c）,respectively.Finally,we introduced interaction terms（SUA×gender,SUA×APOE-ε4 status）into the linear model to explore the potential modification effects of gender and APOE-ε4 status on the identified correlations.Results:Covariance analysis showed that SUA levels in the preclinical AD stage elevated（P=0.007）.Results from multiple linear models with age,gender,educational levels,APOE-ε4 status and China Modified-Mini-Mental State Examination（CM-MMSE）as covariates revealed that SUA was significantly linearly related to brain amyloidosis reflected by CSF indicators,including CSF Aβ1-42(β=-2.2×10^-6,P=0.017),CSF Aβ1-42/Aβ1-40(β=-1.6×10^-3,P=0.033),CSF p-Tau/Aβ1-42(β=4.4×10^-4,P=0.007),and CSF t-tau/Aβ1-42(β=4.0×10^-4,P=0.033).Sensitivity analysis further adjusted for vascular risk factors and medication history related to SUA metabolism indicating that the above results were robust.The results of the classification analysis using the quartile method and clinical criteria for the diagnosis of hyperuricemia also suggested that CSF biomarkers related to amyloidosis in hyperuricemia participants were metabolically abnormal.Regardless of the quartile method or the dichotomy method,CSF Aβ1-42 and CSF Aβ1-42/Aβ1-40 were decreased,and CSF p-Tau/Aβ1-42 and CSF t-tau/Aβ1-42were increased in hyperuricemia participants as compared with control group.We did not find a nonlinear relationship between SUA and CSF biomarkers.Besides,interaction analyses did not find modification effects of APOE-ε4 status or gender.Conclusion:This study demonstrated that SUA levels in the preclinical AD stage elevated,indicating that high SUA levels may be a risk factor for AD.High SUA levels were significantly related to the poor metabolism of brain amyloidosis reflected by CSF indicators,including CSF Aβ1-42,CSF Aβ1-42/Aβ1-40,CSF p-Tau/Aβ1-42,and CSF t-Tau/Aβ1-42.Therefore,high SUA might induce the disruption of brain Aβmetabolism,thereby increasing the risk for developing AD.