Project 1: Biomarkers for Characterizing and Predicting AD in DS

项目 1：用于表征和预测 DS 中 AD 的生物标志物

• 批准号: 10667598
• 负责人: Beau M Ances
• 金额: $ 61.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667598
• 关键词: Adult; Affect; Age; Age Years; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Back; Biological Markers; Blood; Cerebrospinal Fluid; Cerebrovascular Disorders; Chromosome 21; Clinical; Code; Collaborations; Consensus; Data; Dementia; Deposition; Development; Disease; Disease Progression; Down Syndrome; Early Diagnosis; Early Onset Alzheimer Disease; Event; Gene Expression; Gene Proteins; General Population; Genetic; Genetic Markers; Heterogeneity; Hyperlipidemia; Impaired cognition; Individual Differences; Inflammation; Inflammatory; Intellectual functioning disability; Interview; Late Onset Alzheimer Disease; Magnetic Resonance Imaging; Measures; Medical; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neuropsychology; Obesity; Outcome; Pathologic; Pathway interactions; Performance; Persons; Phase; Population; Positron-Emission Tomography; Prevention; Production; Protein Overexpression; Risk; Risk Factors; Seizures; Sleep Apnea Syndromes; Subgroup; Time; Translating; Translational Research; effective intervention; high risk; high risk population; individual variation; informant; middle age; mild cognitive impairment; neuroimaging; neuropathology; novel; overexpression; pre-clinical; precision medicine; programs; risk prediction model; sex; symposium; tau Proteins; virtual

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.

项目1摘要 阿尔茨海默氏病生物标记综合征（ABC-DS）计划的总体主题是 表征唐氏综合症（DS）中的阿尔茨海默氏病（AD），并确定其是否具有病理 与晚期AD（负载）相当的发展，因此可以为重点介绍的转化研究提供信息 所有广告患者的预防和治疗。 DS的人在中年有极高的广告风险 至少在很大程度上是由于位于Chr上的APP的基因编码的终身过表达。 21 已经提出了假设的模型，用于由早期淀粉样蛋白（a）沉积的负载，然后是tau（t） 沉积，然后是神经变性（n）（at（n））。炎症和脑血管疾病（CVD）更多 在患有DS的成年人中常见，可能会改变AT（N）框架。项目1利用ABC收集的结果 DS核心跟随成年人的DS转化，从临床上不受AD的影响到进展 事件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 DS成年人的AD进展，如果有不同的话。第二个优先事项是确定AD风险是否风险和 某些危险因素改变了进度。 AIM 1检查了AT（N）框架 症状认知下降的发展（MCI-DS/痴呆症）。我们假设早期变化 淀粉样蛋白（A）之后是神经原纤维病理学（T）的变化，然后是神经变性（N）的变化。 我们预测导致DS症状认知下降的事件的总体顺序与AD相似 其他处于风险的广告种群，但在这些事件的时间段内将存在定量差异 发生。 AIM 2检查了某些因素的贡献，这些因素改变了认知能力下降的风险或进展 （MCI-DS/痴呆症）和AT（N）框架，导致DS中的个体变异性。我们假设这一点 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，我们假设性别和通常同时发生的医疗状况（例如癫痫发作， 高脂血症，肥胖和睡眠呼吸暂停可能有助于MCI-DS发作时的异质性 和/或从MCI-D到痴呆的进展速率。 AIM 3检查了有助于内部的某些因素 与项目2和3合作，广告脆弱性的人口差异。该项目的结果可能 为在高风险人群中发现有效干预措施的努力以及更广泛的努力。