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

采用多组学方法阐明阿尔茨海默病精神病的新疾病机制和生物标志物

• 批准号: 10020893
• 负责人: Julia K Kofler
• 金额: $ 48.69万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020893
• 关键词: Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Automobile Driving; Autopsy; Biological Markers; Blood; Blood specimen; Brain; Clinical; Cognition; Collection; DNA Methylation; Data; Data Set; Delusions; Dementia; Development; Disease; Disease Progression; Early identification; Etiology; Gene Expression; Genetic Fingerprintings; Genetic Polymorphism; Genetic study; Genome; Genomics; Grant; Hallucinations; Hospitalization; Impaired cognition; Individual; Intervention; Licensing; Link; Methodology; Modeling; Molecular; Molecular Disease; Molecular Genetics; Multiomic Data; Network-based; Neurobiology; Patients; Peripheral; Pharmaceutical Preparations; Prefrontal Cortex; Process; Progressive Disease; Psychotic Disorders; Regulation; Research; Research Methodology; Risk; Sampling; Schizophrenia; Series; Single Nucleotide Polymorphism; Specificity; Stratification; Stroke; Symptoms; Syndrome; Testing; Tissue Sample; United States National Institutes of Health; Variant; Work; analytical method; atypical antipsychotic; base; biomarker development; cell type; cohort; effective therapy; epigenomics; genetic profiling; genome-wide; genomic profiles; methylomics; mild cognitive impairment; mortality; multiple omics; neuroimaging; neuropathology; neuropsychiatry; new therapeutic target; novel; psychotic symptoms; symptom treatment; transcriptomics

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.

项目概要 精神病是一种使人衰弱的综合征，40-60% 的阿尔茨海默病 (AD) 患者会出现这种症状。 AD 中的精神病 (AD+P) 与更严重的病程、死亡率、住院治疗、护理人员负担相关 以及认知和功能的更快衰退。非典型抗精神病药物——最初是为治疗精神分裂症而开发的——是 广泛使用未经许可来治疗这些症状，其益处最小，危害相当大，包括 1.5- 死亡率增加 1.8 倍，中风增加 3 倍。开发安全有效的疗法 AD+P 的治疗是当务之急，这必须从更好地了解疾病机制开始。有 来自尸检、神经影像学和遗传学研究的大量证据表明，AD-P 与一种独特的 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。而且， AD+P 最有力的临床相关性之一是更快速的认知能力下降，其轨迹出现 在症状出现之前出现分歧，表明在疾病早期对个体进行分层 表明个体将出现精神病的生物标志物可以通过识别来带来临床益处 存在 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，在这个 项目中，我们将测试我们的总体假设，即 AD+P 的特点是两个方面的特定分子变化： 大脑和血液跨越了多层基因组调控。该项目的主要目的是确定 AD+P 的新疾病机制和生物标志物，通过以下具体目标； 1：识别新疾病 AD+P 涉及的机制； 2：识别血液样本中精神病症状的具体特征 患有 AD+P 的个体，并评估他们预测患有 MCI 的个体是否更有可能的潜力 发展AD； 3：阐明 AD 中的精神病症状在多大程度上与 精神分裂症 该研究汇集了独特的样本群体、尖端的方法和世界领先的专家 基因组调控、临床神经精神病学和 AD 神经病理学。该项目建立在最先进的基础上 我们之前成功的 NIH R01 资助中使用的研究方法。该项目将迈出重要一步 进一步确定 1) AD+P 的新药物靶点，2) 使用现有药物更好地治疗 AD+P，以及 3) 新的外周生物标志物可预测哪些患有 MCI 的个体将发展为 AD+P，因此更有可能 病程快速进展。