Clinical trials to prevent Alzheimer's Disease in Down Syndrome

项目总结/摘要 发现患有21三体或唐氏综合征（DS）的个体具有神经病理学 与散发性阿尔茨海默病（AD）相同的特征在阿尔茨海默病中起着关键作用。 21号染色体上支持淀粉样蛋白的淀粉样前体蛋白基因的鉴定 级联假说患有DS的人一生中患痴呆症的风险超过75%， 包括世界上最大的遗传决定的AD人群。就像学习DS一样 有助于确定淀粉样前体蛋白突变在AD发病机制中的作用， 可能告诉我们操纵淀粉样蛋白通路对治疗的潜在益处 AD的结果。对于DS人群和AD治疗领域来说， 进行临床试验，特别是那些针对淀粉样蛋白积累的个人与DS。 通过这项申请，我们建议利用现有的专业知识的深度和广度， 美国国家情报局资助的阿尔茨海默氏症临床试验联盟（ACTC）在成人中进行AD临床试验 与具有DS（包括阿尔茨海默氏症生物标志物）专业知识的绩效研究中心的DS合作 唐氏综合症联盟（ABC-DS）。作为去年获得的NIH奖的一部分，我们 建立了ACTC-DS网络，其中包括由来自以下国家的领导人组成的工作组： ACTC，ABC-DS和欧洲地平线21 DS网络，以发展合作， 在DS中进行AD临床试验所需的基础设施和计划。 在本项目拟议的R61 "试验准备阶段"期间，在目标1中，我们将招募 15个研究中心的120名DS成人（年龄35 - 55岁）进入试验就绪队列（TRC），以收集 结果指标和生物标志物与正在进行的ABC中收集的指标和生物标志物相协调- DS研究（n =~400）。在目标2中，我们将确定认知测量之间的关系 和AD生物标志物，以确定最能反映疾病进展的临床试验终点。 在R33 "临床试验"阶段，为了实现目标3，我们建议实施第二阶段 一项随机、双盲、安慰剂对照试验，旨在评估 在个体中有希望的抗淀粉样蛋白治疗剂TRC。在目标4中，我们将确定 该试剂对疾病修饰生物标志物证据的影响。 从根本上说，该项目将通过利用 ACTC的基础设施，并结合ABC-DS的经验和专业知识， 地平线21网络。除了拟议的试验之外，这将建立手段和方法， 在这个人群中进行未来的治疗试验。这一做法的潜在影响 改善成年DS患者和普通人群的生活不能被夸大。

PROJECT SUMMARY/ABSTRACT The discovery that individuals with Trisomy 21, or Down syndrome (DS) have neuropathological features identical to those with sporadic Alzheimer's disease (AD) played a critical role in the identification of the amyloid precursor protein gene on chromosome 21 supporting the amyloid cascade hypothesis. People with DS have a lifetime risk for dementia in excess of 75% and comprise the world's largest population of genetically-determined AD. Just as studying DS helped identify the role of amyloid precursor protein mutations in AD pathogenesis, it is also likely to inform us of the potential benefit of manipulating the amyloid pathway on treatment outcomes in AD. It is critically important to the DS population and to the AD therapeutics field to conduct clinical trials, particularly those targeting amyloid accumulation, in individuals with DS. With this application, we propose to utilize the existing depth and breadth of expertise of the NIA-funded Alzheimer's Clinical Trial Consortium (ACTC) to conduct AD clinical trials in adults with DS across performance sites with expertise in DS including the Alzheimer's Biomarker Consortium for Down Syndrome (ABC-DS). As part of an NIH award received last year, we established the ACTC-DS network which includes working groups comprised of leaders from ACTC, ABC-DS and the European Horizon21 DS network to develop the collaborations, infrastructure and plans required to conduct AD clinical trials in DS. During the proposed R61 `Trial Readiness Phase' of the present project, in Aim 1, we will enroll 120 adults with DS (ages 35-55) across 15 sites into a trial ready cohort (TRC) to collect outcome measures and biomarkers harmonized with those being collected in the ongoing ABC- DS study (n = ~400). In Aim 2, we will determine the relationships between cognitive measures and AD biomarkers to identify endpoints for clinical trials that best reflect disease progression. During the R33 `Clinical Trial' phase, for Aim 3, we propose to implement a phase II randomized, double-blind, placebo-controlled trial to evaluate the safety and tolerability of a promising anti-amyloid therapeutic among individuals the TRC. In Aim 4, we will determine the impact of this agent on biomarker evidence of disease modification. Fundamentally, this project will serve to bring AD therapies to the DS population by leveraging the infrastructure of ACTC and incorporating the experience and expertise of the ABC-DS and Horizon21 networks. Beyond the proposed trial, this will establish the means and methods to conduct future therapeutic trials in this population. The potential impact of this approach on improving the lives of adults with DS as well as the general population cannot be overstated.