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: 10356840
• 负责人: Hyun-Sik Yang
• 金额: $ 19.76万
• 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/10356840
• 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; 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; biomedical imaging; 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; preventive intervention; prognostication; 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.

项目总结/摘要 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病， 治疗全基因组关联支持髓系细胞在AD进展中的关键作用 研究（GWAS）显示在AD的遗传结构中骨髓细胞基因变体的强烈富集。 然而，免疫遗传变异对AD发病机制和进展的具体贡献 仍然未知。这是临床前AD的一个特别关键的知识缺口， 仍然可以防止广泛的不可逆的神经退化。为了实现我们的长期目标， 通过更好地了解免疫遗传性AD风险变异如何影响临床前AD的治疗靶点， 病理生理学，这个K23项目的目的是确定，在临床前AD，特定的AD相关 免疫遗传性AD风险导致的表型。我们的中心假设是，高免疫遗传性AD 风险预测更高的AD病理负担，改变髓样细胞基因表达，并导致更快的 临床前AD中的神经变性和认知下降。我们将利用专门针对性的多基因 风险评分，以捕捉总的免疫遗传性AD风险，并在大样本中研究我们的假设， > 4，000例临床正常（CN）老年人接受抗淀粉样蛋白治疗，治疗无症状AD（A4） 研究/淀粉样蛋白风险和神经变性的纵向评价（LEARN）筛选数据集和270 CN老年人来自哈佛老化大脑研究（HABS）。我们将通过确定 免疫原性AD风险对（1）横断面AD病理学的贡献（通过淀粉样蛋白/tau PET估计） (A4/LEARN/HABS），（2）髓样细胞基因共表达模块（HABS）的表达改变，和（3） tau病理学、神经变性和认知衰退（HABS）的纵向进展。在K23 以病人为导向的研究职业发展奖期间，候选人的短期职业目标是 过渡到独立的临床研究者，阐明遗传结构的临床意义 的AD，重点是免疫遗传学对临床前AD进展的贡献。为了实现这一目标， 候选人计划（1）获得临床前AD的神经影像学生物标志物方面的专业知识，（2）增强 基因组学/转录组学（“组学”）数据生成和分析技能，以及（3）继续接受以下培训： 生物统计学通过成功执行拟议的项目和培训，候选人将处于理想的状态。 作为一名独立的NIH资助的临床研究者，并实现长期的职业目标 领导一个合作研究项目，将组学的进步转化为个性化的解释， 和AD治疗靶点的鉴定。这位候选人很幸运，因为他处于一个理想的环境中。 研究项目和培训，获得特殊的资源和研究社区在布里格姆和 妇女医院（BWH），马萨诸塞州总医院（MGH），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）和哈佛的布罗德研究所。