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

摘要 并非所有具有阿尔茨海默病（AD）高遗传风险的人都会出现症状，即使是那些 达到极端老年的人（例如，90岁以上）。这一观察结果表明，遗传易感性AD是 受其他因素影响。确定这些因素，特别是那些可以改变的因素，可能会导致 有效的AD治疗和风险降低策略。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， AD相关病理在脑中的累积。这个想法得到了我们最近的博爱之心的支持 研究（FHS）调查C反应蛋白（CRP）的纵向测量，我们从中得出了一个 将慢性低度炎症（CLI）定义为慢性促炎负荷的阈值。我们发现 CLI与APOE ε4携带者AD风险增加和早期发作相关[1]。此外一些 AD风险基因影响AD风险和外周炎症。例如，PLXNA 4变体是 与AD风险相关[2]，PlxnA 4也在炎症过程中发挥作用。核心假设 这项研究的结论是，与CLI一致的遗传易感性在AD发病机制中起重要作用。 为了验证这一假设，我们将利用全面表征的FHS队列及其相关的 脑库和前瞻性系列AD相关脑MRI和生物标志物数据，以评估CLI的相关性 随着认知和大脑结构的变化，以及AD的发生，直到几十年后。 具体来说，我们将1）在存在慢性疾病的情况下，评估遗传变异与AD风险的关联。 FHS组群中的外周炎症; 2）鉴定FHS中与AD相关的血液生物标志物 AD遗传风险变异和CLI的参与者，并评估其与AD相关大脑的相关性 病理学; 3）在目的1和2中在AD相关的外周和脑之间建立的免疫相关性 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 疾病神经影像学倡议，华盛顿大学奈特阿尔茨海默病研究中心，和 韩国国家痴呆症研究中心如果我们发现AD发病率的差异是基于 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谱， 的人谁有CLI，我们的研究将提供理论基础的机制，AD遗传风险的疾病。 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。 并预防AD。

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.