Immunogenetic contribution to the progression of preclinical Alzheimer's disease

免疫遗传学对临床前阿尔茨海默病进展的贡献

• 批准号: 9904479
• 负责人: Hyun-Sik Yang
• 金额: $ 19.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904479
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Biometry; Blood specimen; Cell physiology; Clinical; Clinical Investigator; Cognitive; Communities; Data; Data Set; Dementia; Disease; Disease Progression; Elderly; Environment; Evaluation; Foundations; Functional disorder; Funding; Future; Gene Expression; General Hospitals; Generations; Genes; Genetic Risk; Genetic Variation; Genomic Segment; Genomics; Goals; Hippocampus (Brain); Hospitals; Human; Human Genetics; Immune; Immunogenetics; Impaired cognition; Inferior; Institutes; K-Series Research Career Programs; Knowledge; Longitudinal Studies; Maps; Massachusetts; Measures; Mediating; Mentors; Microglia; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Outcome Study; Participant; Pathogenesis; Pathology; Phase; Phenotype; Play; Positioning Attribute; Positron-Emission Tomography; Preventive Intervention; Process; Production; Prognostic Marker; Research; Research Personnel; Research Project Grants; Research Training; Resources; Risk; Role; Sampling; Scientist; Technology; Temporal Lobe; Testing; Training; Translating; United States National Institutes of Health; Variant; Woman; abeta accumulation; aging brain; asymptomatic Alzheimer’s disease; base; bioimaging; career; cell type; complement pathway; differential expression; effective intervention; effective therapy; functional genomics; genetic architecture; genetic variant; genome wide association study; immune function; monocyte; neocortical; neuroimaging marker; neuroinflammation; novel; patient oriented research; peripheral blood; polygenic risk score; pre-clinical; predictive marker; prevent; prognostic; programs; risk variant; sample collection; screening; skills; tau Proteins; tau aggregation; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disorder without an effective disease-modifying treatment. The critical role of myeloid cell in the progression of AD is supported by genome-wide association studies (GWAS) that show strong enrichment of myeloid cell gene variants in the genetic architecture of AD. However, the specific contributions of the immunogenetic variations to the AD pathogenesis and progression remain unknown. This is a particularly critical knowledge gap in preclinical AD, when an effective intervention could still prevent widespread irreversible neurodegeneration. To achieve our long-term goal of to identify therapeutic targets in preclinical AD by better understanding how immunogenetic AD risk variants affect pathophysiology, the objective of this K23 project is to identify, in preclinical AD, specific AD-relevant phenotypes that result from immunogenetic AD risk. Our central hypothesis is that higher immunogenetic AD risk predicts higher AD pathology burden, alters myeloid cell gene expression, and causes faster neurodegeneration and cognitive decline in preclinical AD. We will utilize use a specifically targeted polygenic risk score to capture the aggregate immunogenetic AD risk, and investigate our hypothesis in large samples of >4,000 clinically normal (CN) older adults from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) screening dataset and 270 CN older adults from the Harvard Aging Brain Study (HABS). We will test our hypotheses by determining the contribution of immunogentic AD risk to (1) cross-sectional AD pathology (as estimated by amyloid/tau PET) (A4/LEARN/HABS), (2) altered expression of myeloid cell gene co-expression modules (HABS), and (3) longitudinal progression of tau pathology, neurodegeneration, and cognitive decline (HABS). During his K23 Patient-Oriented Research Career Development Award period, the candidate's short-term career goal is to transition to an independent clinical investigator elucidating the clinical implications of the genetic architecture of AD, with focus on immunogenetic contribution to the progression of preclinical AD. To achieve this goal, the candidate plans to (1) gain expertise in the neuroimaging biomarkers of preclinical AD, (2) enhance genomic/transcriptomic (“omics”) data production and analysis skills, and (3) continue his training in biostatistics. By successfully executing the proposed project and training, the candidate will be in an ideal position to emerge as an independent NIH-funded clinical investigator, and achieve the long-term career goal of leading a collaborative research program to translate advances in omics into personalized prognostication and therapeutic target identification in AD. The candidate is fortunate to be in an ideal environment for his research project and training, with access to exceptional resources and research community at Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH), Martinos Center for Biomedical Imaging at MGH, and the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种毁灭性的神经退行性疾病，没有有效的疾病调整 治疗。髓样细胞在AD进展中的关键作用得到了全基因组关联的支持 研究（GWAS）表明，在AD的遗传结构中，髓样细胞基因变异的强烈富集。 但是，免疫发生变化对AD发病机理和进展的特定贡献 仍然未知。当有效的干预措施时，这是临床前广告中特别关键的知识差距 仍然可以防止宽度不可逆转的神经变性。实现我们的长期目标 通过更好地了解免疫遗传AD风险变异的影响，临床前AD中的治疗靶标 病理生理学，该K23项目的目的是在临床前广告中识别特定的广告 免疫遗传AD风险导致的表型。我们的中心假设是较高的免疫原理AD 风险预测更高的AD病理学伯嫩，改变髓样细胞基因的表达，并更快地导致 临床前AD的神经变性和认知下降。我们将利用特定针对的多基因 风险评分以捕获骨料的免疫原性AD风险，并研究我们在大量样本中的假设 > 4,000名临床正常（CN）老年人来自不对称AD的抗淀粉样蛋白治疗（A4） 淀粉样蛋白风险和神经变性（学习）筛查数据集的研究/纵向评估和270 哈佛大学衰老脑研究（HAB）的CN老年人。我们将通过确定 免疫AD风险对（1）横截面AD病理学的贡献（由淀粉样蛋白/TAU PET估算） （A4/Learn/habs），（2）改变髓样细胞基因共表达模块（HAB）和（3）的表达改变 Tau病理学，神经退行性和认知下降（HAB）的纵向进展。在他的K23期间 面向患者的研究职业发展奖，候选人的短期职业目标是 过渡到独立的临床研究者，阐明了遗传结构的临床意义 AD的侧重于对临床前AD进展的免疫遗传贡献。为了实现这一目标， 候选人计划（1）在临床前AD的神经影像生物标志物中获得专业知识，（2）增强 基因组/转录组（“ OMIC”）数据生产和分析技能，（3）继续他的培训 生物统计学。通过成功执行拟议的项目和培训，候选人将是理想的 成为独立NIH资助的临床研究者的位置，并实现长期职业目标 领导协作研究计划，将OMIC的进步转化为个性化编程 和AD中的热目标识别。候选人很幸运能成为他的理想环境 研究项目和培训，可以访问Brigham和 马萨诸塞州综合医院（MGH）的妇女医院（BWH），马蒂诺斯生物医学成像中心 MGH，以及马萨诸塞州理工学院（MIT）和哈佛大学。