Project 1: Biomarkers for Characterizing and Predicting AD in DS

项目1摘要 阿尔茨海默病生物标记物-唐氏综合症(ABC-DS)计划的一个主要主题是 描述唐氏综合征(DS)中阿尔茨海默病(AD)的特征并确定其是否具有病理性 进展与晚发性AD(负荷)相当，因此可以为专注于以下方面的翻译研究提供信息 对所有AD患者进行预防和治疗。DS患者在中年患AD的风险极高 至少在很大程度上，是由于位于Chr上的APP编码基因的终生过度表达。21.一个 已经提出了由早期淀粉样蛋白(A)沉积和随后的tau(T)组成的负荷的假设模型 沉积，然后是神经变性(N)(AT(N))。炎症和脑血管疾病(CVD)较多 在患有DS的成人中很常见，可能会修改AT(N)框架。项目1利用美国广播公司收集的成果- DS核心跟踪患有DS的成年人从临床未受AD影响到进展的转换 发生MCI-DS和随后的痴呆症。该项目将确定AT(N)框架是否具有描述性 对患有DS的成人AD进展的预测，以及如果不同，以何种方式进行。第二个优先事项是确定AD风险和 进展会受到某些风险因素的影响。目标1检查AT(N)框架关于 出现症状性认知功能减退(MCI-DS/痴呆)。我们假设早期的变化 淀粉样蛋白(A)之后是神经原纤维病变(T)，然后是神经变性(N)。 我们预测，导致DS症状性认知功能下降的总体事件序列与AD相似 其他高危AD人群，但这些事件发生的时间跨度将存在数量差异 发生。目标2考察了影响认知功能下降的风险或进展的选定因素的作用 (MCI-DS/痴呆)和AT(N)框架中导致DS的个体差异性。我们假设 炎症变化和脑血管疾病(CVD)改变了淀粉样蛋白和tau沉积的风险。 此外，我们假设性行为和常见的共生疾病(例如癫痫发作， 高脂血症、肥胖和睡眠呼吸暂停)可能导致MCI-DS发病年龄的异质性。 和/或从MCI-DS到痴呆的进展速度。目标3考察了影响内部因素的选定因素- 与项目2和项目3合作，AD漏洞的人口变异性。该项目的结果可能 帮助努力在这一高危人群和更广泛的AD中发现有效的干预措施(S)。

Project 1 Abstract An overarching theme of the Alzheimer's Disease Biomarkers-Down syndrome (ABC-DS) program is to characterize Alzheimer disease (AD) in Down syndrome (DS) and to determine if it has a pathological progression comparable to late onset AD (LOAD) and thus can inform translational research focused on prevention and treatment for all people with AD. People with DS are at extremely high risk of AD in middle age due, at least in large measure, to lifelong overexpression of the gene coding for APP, located on Chr. 21. A hypothesized model has been proposed for LOAD consisting of early amyloid (A) deposition followed by tau (T) deposition and then neurodegeneration (N) (AT(N)). Inflammation and cerebrovascular disease (CVD) are more common in adults with DS and may modify the AT(N) framework. Project 1 utilizes outcomes collected by ABC- DS Cores to follow the conversion of adults with DS from when they are clinically unaffected by AD to progression of incident MCI-DS and subsequent dementia. This project will determine if the AT(N) framework is descriptive of AD progression in adults with DS and, if different, in what way. A second priority is to determine if AD risk and progression is modified by certain risk factors. Aim 1 examines the AT(N) framework with regard to the development of symptomatic cognitive decline (MCI-DS/Dementia). We hypothesize that early changes in amyloid (A) are followed by changes in neurofibrillary pathology (T) and then changes in neurodegeneration (N). We predict the overall sequence of events that leads to symptomatic cognitive decline in DS is similar to AD in other at risk AD populations but quantitative differences will be present in the time span over which these events occur. Aim 2 examines the contribution of selected factors that modify the risk or progression to cognitive decline (MCI-DS/dementia) and in the AT(N) framework to lead to individual variability in DS. We hypothesize that inflammatory changes and cerebrovascular disease (CVD) modify the risk of amyloid and tau deposition. Furthermore, we hypothesize that sex and commonly co-occurring medical conditions (e.g. seizures, hyperlipidemia, obesity, and sleep apnea) may contribute to the heterogeneity in the age at onset of MCI-DS and/or the rate of progression from MCI-DS to dementia. Aim 3 examines select factors that contribute to within- population variability in AD vulnerability in collaboration with Projects 2 and 3. Results from this Project could contribute to efforts to discover effective intervention(s) within this high risk population and for AD more broadly.