A multi-omic approach to elucidate novel disease mechanisms and biomarkers for psychosis in Alzheimer’s disease

项目总结 精神病是一种经常使人衰弱的综合征，发生在40%-60%的阿尔茨海默病(AD)患者中。 阿尔茨海默病(AD+P)与更严重的病程、死亡率、住院、照顾者负担相关 认知和功能衰退的速度也更快。首次为精神分裂症开发的非典型抗精神病药物是 广泛用于治疗这些症状，益处最小，危害相当大，包括1.5- 死亡率增加1.8倍，中风增加3倍。开发安全有效的治疗方法 对于AD+P来说，必须从更好地了解疾病机制开始，这是一个紧迫的优先事项。的确有 来自尸检、神经成像和遗传学研究的大量证据表明，AD-P与明显的 神经生物学变化的概况，但对驱动病因的分子过程知之甚少。此外， AD+P最强有力的临床相关性之一是认知功能下降得更快，其轨迹出现 在症状出现之前出现分歧，表明疾病早期的个人分层 提示个体将发展成精神病的生物标记物可以通过识别 有AD+P风险的个体，并在症状出现前对其进行针对性干预。因此，在这方面 我们将测试我们的总体假设，即AD+P的特征是两个分子的特定变化 大脑和血液跨越了多层基因组调控。该项目的主要目标是确定 AD+P的新的发病机制和生物标志物，通过以下特定目的：1：识别新的疾病 AD+P中涉及的机制；2：在患者的血液样本中确定精神病症状的特定特征 AD+P患者，评估他们预测MCI患者是否更有可能 发展为阿尔茨海默病；3：阐明阿尔茨海默病的精神病症状与其机械联系的程度 精神分裂症 这项研究汇集了独特的样本队列、尖端方法和世界领先的专家 基因组调控、临床神经精神病学和阿尔茨海默病神经病理学。这个项目建立在最先进的基础上 研究方法在我们之前成功的NIH R01拨款中使用。该项目将迈出重要的一步 在确定1)AD+P的新药物靶点方面取得进展，2)更好地利用现有药物和 3)新的外周生物标志物可以预测哪些MCI患者将发展为AD+P，因此更有可能 有一个快速发展的病程。

PROJECT SUMMARY Psychosis is an often debilitating syndrome occurring in 40-60% of people with Alzheimer's disease (AD). Psychosis in AD (AD+P) is associated with a more severe disease course, mortality, hospitalization, carer burden and faster decline in cognition and function. Atypical antipsychotics – first developed for schizophrenia - are widely used off license to treat these symptoms, with minimal benefits and considerable harm, including a 1.5- to 1.8-fold increase in mortality and a 3- fold increase in stroke. The development of safe and effective therapies for AD+P is an urgent priority, which has to start with a better understanding of disease mechanisms. There is abundant evidence from post-mortem, neuroimaging and genetic studies that AD-P is associated with a distinct profile of neurobiological changes but little is known about the molecular processes driving etiology. Moreover, one of the most robust clinical correlates of AD+P is a more rapid cognitive decline the trajectory of which appears to diverge before the onset of symptoms, suggests that stratification of individuals early in the disease by biomarkers that suggest the individual will develop psychosis could bring clinical benefits by identifying individuals at risk of AD+P and targeting interventions to them before the onset of symptoms. Thus, in this project we will test our overall hypothesis that AD+P is characterized by specific molecular changes in both the brain and blood that cut across multiple layers of genomic regulation. The main aim of this project is to identify novel disease mechanisms and biomarkers of AD+P, via the following specific aims; 1: Identify novel disease mechanisms implicated in AD+P; 2: Identify specific signatures of psychotic symptoms in blood samples of individuals with AD+P and evaluate their potential to predict whether individuals with MCI are more likely to develop AD; 3: Elucidate the extent to which psychotic symptoms in AD are mechanistically linked to schizophrenia The study brings together unique sample cohorts, cutting-edge methodologies and world-leading experts in genome regulation, clinical neuropsychiatry and AD neuropathology. This project builds on the state-of-the-art research methods utilized in our previously successful NIH R01 grants. The project will provide a major step forward in identifying 1) novel drug targets for AD+P, 2) better treatment of AD+P with existing medications and 3) novel peripheral biomarkers to predict which individuals with MCI will develop AD+P and are thus more likely to have a rapidly progressive disease course.