Immunogenetic contribution to the progression of preclinical Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病，缺乏有效的疾病修饰 治疗。全基因组关联支持髓系细胞在阿尔茨海默病进展中的关键作用 研究表明，在AD的遗传结构中，髓系细胞基因变异具有强烈的丰富性。 然而，免疫遗传变异在AD发病和进展中的特殊作用 仍然不为人所知。这是临床前AD的一个特别关键的知识缺口，当有效的干预 仍然可以防止广泛的不可逆转的神经退化。为了实现我们的长期目标，即确定 通过更好地了解免疫遗传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项目的目标是在临床前AD中识别特定的AD相关 免疫遗传性AD风险导致的表型。我们的中心假设是较高的免疫遗传性AD 风险预示着更高的AD病理负担，改变髓系细胞基因表达，并导致更快 临床前阿尔茨海默病的神经退行性变和认知功能减退。我们将利用一种特别有针对性的多基因 风险评分，以获取总的免疫遗传性AD风险，并在以下大样本中调查我们的假设 4,000名临床正常(CN)的老年人，来自无症状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)筛查数据集和270的研究/纵向评估 来自哈佛大学老龄化大脑研究(HABS)的老年人。我们将通过确定 免疫原性AD风险对(1)AD横断面病理(由淀粉样蛋白/tau PET估计)的贡献 (A4/LINE/HABS)，(2)髓系细胞基因共表达模块(HAB)的表达改变，以及(3) Tau病理、神经退变和认知衰退(HABS)的纵向进展。在他的K23期间 以患者为导向的研究职业发展奖获得期，候选人的短期职业目标是 过渡到独立的临床研究人员，阐明遗传结构的临床意义 阿尔茨海默病的研究，重点是免疫遗传学在临床前AD进展中的作用。为了实现这一目标， 候选人计划(1)获得临床前AD的神经成像生物标志物方面的专业知识，(2)增强 基因组学/转录学(“组学”)数据生产和分析技能，以及(3)继续他在 生物统计学。通过成功地执行建议的项目和培训，应聘者将处于理想状态 作为一名由NIH资助的独立临床研究人员，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预测 AD的治疗靶点识别。这位候选人很幸运，因为他处于理想的环境中 研究项目和培训，可获得特殊资源和布里格姆研究社区 妇女医院(BWH)、马萨诸塞州综合医院(MGH)、Martinos生物医学成像中心 麻省理工学院和哈佛大学的博德学院。

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.