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: 10264842
• 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/10264842
• 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; 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; Phase; Population; Positron-Emission Tomography; Presenile Alzheimer Dementia; 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摘要 阿尔茨海默病生物标志物 - 唐氏综合症 (ABC-DS) 计划的首要主题是 表征唐氏综合症 (DS) 中的阿尔茨海默病 (AD) 并确定其是否具有病理性 进展与迟发性 AD (LOAD) 相当，因此可以为重点关注的转化研究提供信息 所有 AD 患者的预防和治疗。患有 DS 的人在中年时患 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.A 已提出 LOAD 的假设模型，其中包括早期淀粉样蛋白 (A) 沉积，随后是 tau (T) 沉积，然后是神经变性 (N) (AT(N))。炎症和脑血管疾病（CVD）更常见 常见于患有 DS 的成人，可能会修改 AT(N) 框架。项目 1 利用 ABC- 收集的成果 DS 核心可追踪患有 DS 的成人从临床上未受 AD 影响到进展的转变 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 AD 成人 DS 进展的影响，如果不同，以何种方式进展。第二个优先事项是确定 AD 风险和 某些危险因素会改变进展。目标 1 检查 AT(N) 框架的以下方面： 症状性认知能力下降（MCI-DS/痴呆）的发展。我们假设早期的变化 淀粉样蛋白 (A) 之后是神经原纤维病理变化 (T)，然后是神经变性变化 (N)。 我们预测导致 DS 症状性认知能力下降的事件总体顺序与 AD 类似。 其他处于 AD 风险的人群，但这些事件发生的时间跨度将存在数量差异 发生。目标 2 检查改变认知能力下降风险或进展的选定因素的贡献 （MCI-DS/痴呆）和 AT(N) 框架中导致 DS 的个体差异。我们假设 炎症变化和脑血管疾病 (CVD) 会改变淀粉样蛋白和 tau 蛋白沉积的风险。 此外，我们假设性和常见的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 检查了有助于内部的选定因素： 与项目 2 和 3 合作，研究 AD 脆弱性的人口变异性。该项目的结果可以 致力于在这一高危人群中以及更广泛的 AD 领域发现有效的干预措施。