Characterizing the interaction of genetic vulnerabilities and chronic peripheral inflammation for AD risk

摘要 并不是所有有阿尔茨海默病(AD)高遗传风险的人都会出现症状，即使是那些 达到极高年龄(例如，90岁以上)的人。这一观察表明阿尔茨海默病的遗传易感性是 受其他因素的影响。确定这些因素，特别是那些可修改的因素，可能会导致 有效的AD治疗和降低风险的策略。我们推测外周慢性低度恶性 炎症是影响AD相关基因表达的主要因素。此外，我们假设 AD风险基因影响外周和中枢系统的促炎反应，从而加速 阿尔茨海默病相关病变在大脑中的积聚。这一想法得到了我们最近的弗雷明翰之心的支持 研究(FHS)研究C反应蛋白(CRP)的纵向测量，我们从中推导出 将慢性低度炎症(CLI)定义为慢性促炎负担的阈值。我们发现 在载脂蛋白Eε4携带者中，慢性精神分裂症与AD风险增加和较早发病相关[1]。此外，还有一些 AD风险基因同时影响AD风险和外周炎症。例如，PLXNA4的变体是 与AD风险相关[2]，PlxnA4也在炎症过程中发挥作用。中心假说 这项研究表明，遗传易损性与CLI在AD发病机制中起着重要作用。 为了验证这一假设，我们将利用全面描述的FHS队列及其关联 脑库和前瞻性AD相关脑MRI和生物标记物数据评估CLI的相关性 随着认知和大脑结构的变化，以及事件AD，长达几十年后。 具体地说，我们将1)评估在存在慢性AD的情况下，遗传变异与AD风险的关联 FHS队列中的外周炎症；2)在FHS中确定与AD相关的血液生物标志物 携带AD遗传风险变异和CLI的参与者，并评估它们与AD相关脑的相关性 病理学；3)验证AIMS 1和2中建立的AD相关外周和脑之间的关联 其他数据集中的炎症，包括阿尔茨海默病遗传联盟队列，阿尔茨海默病 疾病神经成像倡议，华盛顿大学奈特阿尔茨海默氏症研究中心，以及 韩国国家痴呆症研究中心。如果我们基于以下因素发现AD发病率的差异 特定AD相关遗传变异的携带者和非携带者之间的生物标志物图谱 对于患有CLI的人群，我们的研究将为AD遗传风险的发病机制提供理论基础。 我们预计，这项研究的结果将为开发个性化的治疗方法提供见解。 预防阿尔茨海默病。

ABSTRACT Not all persons who have a high genetic risk for Alzheimer's disease (AD) become symptomatic, even those who reach extreme old age (e.g., 90+ years old). This observation suggests that genetic vulnerability to AD is moderated by other factors. Identifying these factors, particularly those that are modifiable, could lead to effective AD treatments and risk reduction strategies. We conjecture that peripheral chronic low-grade inflammation is a major factor that influences expression of AD-related genes. Further, we hypothesize that AD risk genes affect proinflammatory reactions in both peripheral and central systems that accelerate accumulation of AD-related pathologies in the brain. This idea is supported by our recent Framingham Heart Study (FHS) investigation of longitudinal measurements of C-reactive protein (CRP) from which we derived a threshold to define chronic low-grade inflammation (CLI) as a chronic proinflammatory burden. We found that CLI was associated with increased risk and earlier onset of AD among APOE ε4 carriers [1]. In addition, some AD risk genes influence both AD risk and peripheral inflammation. For example, PLXNA4 variants are associated with AD risk [2] and PlxnA4 also has a role in inflammatory processes. The central hypothesis for this study is that genetic vulnerability in concert with CLI has an important role in AD pathogenesis. To test this hypothesis, we will capitalize on the comprehensively characterized FHS cohort and its associated brain bank and prospective serial AD-related brain MRI and biomarker data to evaluate the correlation of CLI with changes in cognition and brain structure, as well as with incident AD, up to several decades later. Specifically, we will 1) Evaluate the association of genetic variants with AD risk in the presence of chronic peripheral inflammation in the FHS cohort; 2) Identify blood biomarkers associated with AD among FHS participants with AD genetic risk variants and CLI, and evaluate their correlation with AD-related brain pathology; 3) Validate associations established in Aims 1 and 2 between AD-related peripheral and brain inflammation in other datasets including the Alzheimer Disease Genetic Consortium cohorts, the Alzheimer Disease Neuroimaging Initiative, Knight Alzheimer's Disease Research Center at Washington University, and the Korean National Center for Research in Dementia. If we find differences in the incidence of AD based on biomarker profiles between carriers and non-carriers of particular AD-associated genetic variants among persons who have CLI, our study will provide rationale for the mechanisms of AD genetic risk for the disease. We anticipate that results from this study will provide insight for developing a personalized approach for treating and preventing AD.