整合型孟德尔随机化分析阐明炎症发展与阿尔茨海默病发病的因果关系  

Unveiling the causal link between inflammation and Alzheimer’s disease via integrated Mendelian randomization analysis

作　　者：陈红安 张慧琼 江南 CHEN HongAn;ZHANG HuiQiong;JIANG Nan(Key Laboratory for Green Chemical Process of Ministry of Education,School of Environmental Ecology and Biological Engineering,Wuhan Institute of Technology,Wuhan 430205,China)

机构地区：[1]武汉工程大学环境生态与生物工程学院绿色化学过程教育部重点实验室,武汉430205

出　　处：《中国科学:生命科学》2025年第4期819-828,共10页Scientia Sinica(Vitae)

基　　金：国家自然科学基金青年项目(22207091);武汉市知识创新专项-曙光计划项目(2022020801020358)资助。

摘　　要：阿尔茨海默病(Alzheimer’s disease,AD)在我国的发病率和死亡率逐年上升,严重阻碍了社会的可持续化发展.炎症发展被认为是AD发病的关键因素,但向AD转变的分子机制不清晰,故现有研究未能完全阐明两者的因果关系.为此,本文对其开展了整合型孟德尔随机化(Mendelian randomization,MR)分析.双向MR发现慢性炎症可单向转化为AD,而多变量MR进一步证明了慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是AD的特定危险因素.共定位及蛋白相互作用研究筛选出了转变的关键中介——内质网氨基肽酶1,并进一步筛选出了能用于临床检测的5种金属相关炎症因子.基于这些炎症因子的两步MR进一步证实了COPD向AD转变的高风险,并显示了这些炎症因子可作评估COPD患者是否罹患AD的重要参考,为AD的诊疗提供了潜在的标志物及治疗靶点.With the increasing incidence and mortality rates in China,Alzheimer’s disease(AD)poses a significant challenge to sustainable societal development.Inflammatory progression has been recognized as a pivotal factor in AD pathogenesis;however,the molecular mechanisms driving the transition to AD remain unveiled,leaving the causal relationship between inflammation and AD inadequately elucidated.To address this,this manuscript conducted an integrated Mendelian randomization(MR)analysis.Bidirectional MR analysis revealed that chronic inflammation can unilaterally progress to AD,while multivariable MR further identified chronic obstructive pulmonary disease(COPD)as a specific risk factor for AD.Colocalization and protein-protein interaction studies pinpointed endoplasmic reticulum aminopeptidase 1 as a critical mediator between COPD and AD,leading to the identification of five metal-associated inflammatory factors suitable for clinical detection.Two-step MR analysis based on these inflammatory factors corroborated the high risk of COPD transitioning to AD and highlighted their potential as key markers for evaluating AD susceptibility in COPD patients.These findings offer potential biomarkers and therapeutic targets for the diagnosis and treatment of AD.

关 键 词：孟德尔随机化 阿尔兹海默病 炎症 金属相关炎症因子 干扰素-Γ 

分 类 号：R749.1[医药卫生—神经病学与精神病学]