Clinical trials to prevent Alzheimer's Disease in Down Syndrome

项目摘要/摘要 发现21三体或唐氏综合征(DS)患者有神经病理 与散发性阿尔茨海默病(AD)相同的特征在 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的人患痴呆症的终身风险超过75% 构成了世界上最大的由基因决定的AD人群。就像研究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，它也是 可能会告诉我们操纵淀粉样蛋白通路治疗的潜在益处 AD的结果。对DS人群和AD治疗领域至关重要的是 在DS患者身上进行临床试验，特别是针对淀粉样蛋白堆积的试验。 通过此应用程序，我们建议利用现有的深度和广度的专业知识 NIA资助的阿尔茨海默氏症临床试验联盟(ACTC)将在成人中进行AD临床试验 在包括阿尔茨海默氏症生物标记物在内的DS方面拥有专业知识的性能站点之间进行DS 唐氏综合症联盟(ABC-DS)。作为去年获得的NIH奖项的一部分，我们 建立了反恐委员会--DS网络，其中包括由以下方面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“试用准备阶段”期间，我们将在目标1中登记 15个地点的120名患有DS(年龄35-55岁)的成年人进入一个试验准备队列(TRC)进行收集 结果指标和生物标记物与正在进行的ABC收集的结果指标和生物标记物一致- 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生物标记物，以确定最能反映疾病进展的临床试验的终点。 在R33“临床试验”阶段，对于目标3，我们建议实施第二阶段 随机、双盲、安慰剂对照试验，评估阿司匹林的安全性和耐受性 TRC有望在个体中进行抗淀粉样蛋白治疗。在目标4中，我们将确定 该试剂对疾病修饰生物标记物证据的影响。 从根本上说，该项目将为DS人群带来AD疗法，利用 反恐委员会的基础设施，并纳入ABC-DS的经验和专门知识 Horizon 21网络。在拟议的审判之外，这将确立以下手段和方法 在这一人群中进行未来的治疗试验。此方法的潜在影响 改善患有DS的成年人和普通民众的生活怎么说都不为过。

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.