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: 10454259
• 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/10454259
• 关键词: Adult; Affect; Age; Age of Onset; Age-Years; 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 Proteins; General Population; Genes; Genetic; Genetic Markers; Heterogeneity; Hyperlipidemia; Impaired cognition; Individual Differences; Inflammation; Inflammatory; Intellectual functioning disability; Interview; Late Onset Alzheimer Disease; Lead; Magnetic Resonance Imaging; Measures; Medical; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neuropsychology; Obesity; Outcome; Pathologic; Pathway interactions; Performance; Persons; Phase; Population; Positron-Emission Tomography; Prevention; 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; predictive modeling; programs; 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 阿尔茨海默病生物标志物-唐氏综合征（ABC-DS）计划的首要主题是 描述唐氏综合征（DS）中的阿尔茨海默病（AD），并确定其是否具有病理性 与晚发性AD（LOAD）相当的进展，因此可以为专注于以下方面的转化研究提供信息 为所有AD患者提供预防和治疗。DS患者中年患AD的风险极高 至少在很大程度上是由于位于第21染色体上的APP编码基因的终身过表达。一 已经提出了LOAD的假设模型，其由早期淀粉样蛋白（A）沉积和随后的tau（T）组成， 沉积，然后是神经变性（N）（AT（N））。炎症和脑血管疾病（CVD） 常见于DS成人，可能改变AT（N）框架。项目1利用ABC收集的结果- DS核心追踪DS成人从临床上不受AD影响到进展的转变 突发性MCI-DS和随后的痴呆症本项目将确定AT（N）框架是否是描述性的 AD在DS成人中的进展，如果不同，以何种方式。第二个优先事项是确定AD风险和 某些风险因素会影响进展。目标1审查了AT（N）框架， 出现症状性认知功能减退（MCI-DS/痴呆）。我们假设， 淀粉样蛋白（A）之后是神经病理学变化（T），然后是神经变性变化（N）。 我们预测导致DS症状性认知功能下降的事件的总体顺序与AD相似， 其他有风险的AD人群，但在这些事件发生的时间范围内将存在定量差异 发生.目标2检查了所选因素对认知能力下降风险或进展的影响 （MCI-DS/痴呆）和AT（N）框架导致DS的个体差异。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，性别和常见的共同发生的医疗条件（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进展为痴呆的速率。目标3审查有助于内部- 与项目2和项目3合作，研究AD脆弱性的人口变异性。该项目的成果可以 有助于在这一高风险人群中以及更广泛地为AD发现有效的干预措施。