Plasma and CSF Biomarkers that Predict Risk for Symptomatic Alzheimer Disease

项目2：项目概要/摘要 脑淀粉样变性是必要的，但不足以发展为症状性阿尔茨海默病（AD）。 脑淀粉样变性患者是否以及何时发展为症状性AD可能取决于多种因素， 其他生物、人口、社会和环境因素的影响。除了脑淀粉样变性，许多其他 病理生理过程参与AD并可能潜在地影响症状性AD的发展， 包括tau蛋白病、突触功能障碍、神经元损伤/死亡、星形细胞增多/小胶质细胞增生和炎症。 人口因素，包括种族和健康的社会决定因素，包括歧视和 逆境，不良的早期生活经历，当前的压力和社会支持，以及邻里水平 缺点，也可以在改善症状发作中发挥作用。在这项研究中，血浆和脑脊液 (CSF)将测量代表AD病理生理学不同方面的生物标志物，并用于预测 症状性AD的发作。人口因素和SDOH的影响将被检查，以确定 这些因素改变了症状性AD的表达，并可能是某些人群中AD患病率差异的基础。 例如非洲裔美国人。流体生物标志物将用于检查潜在的机制， 哪些人口学因素和SDOH对症状性AD有影响。人口因素是否 和SDOH影响AD的病理进展也将被探索。此外，为了更好地理解 炎症在AD中的复杂作用，已经分析了高通量蛋白质组学数据以鉴定血浆 以及与炎症相关的CSF蛋白，其在无症状脑淀粉样变性和症状性AD中改变。 因为这些炎症的候选生物标志物与炎症的候选生物标志物相比具有不同的生物学功能， 目前在我们的队列中研究的生物标志物，一个或多个候选生物标志物可以提供新的见解， AD生物学和潜在地改进AD诊断。此外，将所有液体生物标志物与成像进行比较， 炎症和tau蛋白病的测量（项目1），肠道微生物组和肠道功能（项目3），以及 身体活动和心血管风险因素（项目4）。这些分析将更好地表征流体 生物标志物，并可指示由肠道微生物组改变的病理生理过程， 肠道功能、体力活动和心血管危险因素。总体而言，本项目将使用流体生物标志物， 更好地了解复杂的生物，人口，社会和环境因素，调解 脑淀粉样变性与症状性AD的关系。

Project 2: Project Summary/Abstract Brain amyloidosis is necessary but insufficient for the development of symptomatic Alzheimer disease (AD). Whether and when an individual with brain amyloidosis develops symptomatic AD likely depends on a myriad of additional biological, demographic, social and environmental factors. Besides brain amyloidosis, many other pathophysiological processes are involved in AD and could potentially affect development of symptomatic AD, including tauopathy, synaptic dysfunction, neuronal injury/death, astrocytosis/microgliosis and inflammation. Demographic factors including race and social determinants of health (SDOH), including discrimination and adversity, adverse early-life experiences, current stress and social support, and neighborhood level disadvantages, could also play a role in modifying symptom onset. In this study, plasma and cerebrospinal fluid (CSF) biomarkers that represent diverse aspects of AD pathophysiology will be measured and used to predict the onset of symptomatic AD. The effects of demographic factors and SDOH will be examined to identify factors that modify expression of symptomatic AD and may underlie the disparities in AD prevalence in certain populations, such as African Americans. Fluid biomarkers will be used to examine the potential mechanisms by which demographic factors and SDOH exert their influence on symptomatic AD. Whether demographic factors and SDOH affect the pathological progression of AD will also be explored. Additionally, to better understand the complex role of inflammation in AD, high throughput proteomic data have been analyzed to identify plasma and CSF proteins related to inflammation that change in asymptomatic brain amyloidosis and symptomatic AD. Because these candidate biomarkers of inflammation have different biological functions compared to the biomarkers currently studied in our cohort, one or more candidate biomarkers may provide novel insights into AD biology and potentially improve AD diagnostics. Further, all fluid biomarkers will be compared with imaging measures of inflammation and tauopathy (Project 1), the gut microbiome and gut function (Project 3), and physical activity and cardiovascular risk factors (Project 4). These analyses will better characterize the fluid biomarkers and may indicate the pathophysiological processes that are modified by the gut microbiome and gut function, physical activity, and cardiovascular risk factors. Overall, this Project will use fluid biomarkers to better understand the complex biological, demographic, social and environmental factors that mediate the relationship between brain amyloidosis and symptomatic AD.