Linking genetic subtypes of Alzheimer's disease to biological and cognitive heterogeneity

将阿尔茨海默病的遗传亚型与生物和认知异质性联系起来

• 批准号: 10330587
• 负责人: Jeremy A Elman
• 金额: $ 12.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330587
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Atrophic; Automobile Driving; Baltimore; Biological; Biological Markers; Biological Process; Biology; Brain; California; Characteristics; Cognition; Cognitive; Collaborations; Complement; Complex; Control Groups; Coupled; Data; Deposition; Dimensions; Disease; Environment; Etiology; Event; Failure; Future; Genes; Genetic; Genetic Databases; Genetic Heterogeneity; Genetic Identity; Genetic Predisposition to Disease; Genetic Risk; Goals; Grouping; Heterogeneity; Impaired cognition; Individual; Interdisciplinary Study; Intervention; Intervention Trial; K-Series Research Career Programs; Knowledge; Link; Longitudinal Studies; Measures; Memory impairment; Mentors; Methodology; Modeling; Molecular Genetics; Monitor; Nerve Degeneration; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Process; Psychiatry; Research; Research Personnel; Risk; Signal Transduction; Source; System; Testing; Therapeutic Effect; Therapeutic Intervention; Training; Twin Studies; Universities; Vietnam; Work; abeta accumulation; base; biobank; biological heterogeneity; career development; cognitive neuroscience; cohort; disorder prevention; disorder subtype; genetic association; genome wide association study; genome-wide; imaging genetics; improved; infancy; large scale data; neuroimaging; polygenic risk score; precision medicine; programs; research facility; risk variant; skills; targeted treatment; tau Proteins; therapeutic target; treatment group; treatment trial

PROJECT SUMMARY/ABSTRACT The long-term goal of the proposed career development award is to provide me with the training necessary to develop an independent research program focused on elucidating the genetic, biological and cognitive heterogeneity of Alzheimer’s disease (AD) risk. An emphasis on the genetics of biological pathways in the proposed project will complement my existing background in cognitive neuroscience and neuroimaging. The training goals are to: 1) gain training in lab management and develop a multi-disciplinary research program to study AD; 2) gain specific expertise in molecular genetics; and 3) receive training in the biological processes that contribute to AD. These training goals are mutually informative and will be achieved through a mix of formal coursework, hands-on methodological training, and informal discussion. The Psychiatry Department at the University of California, San Diego is an ideal environment in which to receive this training due to the strong presence of world-renown researchers, track record of career development, and state-of-the-field research facilities. Standard models of AD propose a characteristic sequence of pathological events that may accurately describe the progression of some, but not all individuals. However, the failure of AD treatment trials suggests that standard models are not complete. Prior studies have identified variability in domains of cognitive impairment, levels and sequence of pathological events, and the topography of atrophy and pathology in the brain. Interestingly, variability in these biological measures appears to correlate with variability in cognitive impairment. These findings provide evidence suggesting that even “typical” AD may comprise multiple disease subtypes, yet it is unclear to what extent they arise from different etiologies requiring different treatments. Genetic risk in complex diseases such as AD can be summarized using polygenic risk scores (PRSs), but these measures only consider risk along a single continuum, which may obscure different sources of genetic risk. The scientific component of the project will seek to identify genetic subtypes using multiple AD PRSs specific to biological pathways. This project will address two key questions: 1) Is the genetic etiology of AD multidimensional, and 2) how does variability in the genetic risk for AD relate to heterogenous biological and cognitive expressions of the disease? The specific aims are to: 1) determine whether there are subtypes of AD genetic risk using pathway-based PRSs; 2) test whether biological subtypes of AD are associated with different forms of AD genetic risk; and 3) examine whether cognitive impairment subtypes are associated with different forms of AD genetic risk. The project will focus on 4 large-scale studies with multiple biological, cognitive, and genetic measures: Alzheimer’s Disease Neuroimaging Initiative, Baltimore Longitudinal Study of Aging, Vietnam Era Twin Study of Aging, and UK Biobank. Characterizing the variability of disease etiology will inform efforts to develop targeted intervention strategies relevant for disease subtypes. It will also allow more accurate groupings of individuals by subtype to improve sensitivity in detecting disease and therapeutic effects.

项目总结/摘要 职业发展奖的长期目标是为我提供必要的培训， 开发一个独立的研究计划，重点是阐明遗传，生物和认知 阿尔茨海默病（AD）风险的异质性。强调了遗传学的生物学途径， 建议的项目将补充我在认知神经科学和神经影像学的现有背景。的 培训目标是：1）获得实验室管理培训，并制定多学科研究计划， 研究AD; 2）获得分子遗传学的特定专业知识; 3）接受生物过程的培训 这有助于AD。这些培训目标是相互促进的，将通过以下方式实现： 正式的课程作业、动手方法培训和非正式讨论。精神病学系， 加州大学圣地亚哥分校是一个理想的环境中接受这种培训，由于 世界知名研究人员的强大存在，职业发展的跟踪记录，以及该领域的现状 研究设施。AD的标准模型提出了一系列病理事件的特征， 准确地描述了一些人的进展，但不是所有人。然而，AD治疗试验的失败 这表明标准模型并不完整。先前的研究已经确定了认知领域的变异性， 损伤，病理事件的水平和顺序，以及萎缩和病理的地形图， 个脑袋有趣的是，这些生物学指标的变异性似乎与认知功能的变异性相关。 损伤这些发现提供的证据表明，即使是“典型的”AD也可能包括多种疾病， 亚型，但尚不清楚它们在多大程度上来自需要不同治疗的不同病因。 AD等复杂疾病的遗传风险可以使用多基因风险评分（PRS）进行总结，但 这些措施只考虑风险沿着一个单一的连续性，这可能掩盖了不同的遗传来源， 风险该项目的科学组成部分将寻求使用多种AD PRS识别遗传亚型 特定于生物途径。本项目将解决两个关键问题：1）AD的遗传病因是 多维，2）AD遗传风险的变异性如何与异质性生物学和 疾病的认知表达具体目的是：1）确定AD是否存在亚型 使用基于途径的PRS的遗传风险; 2）测试AD的生物亚型是否与不同的 AD遗传风险的形式;和3）检查认知障碍亚型是否与不同的 AD的遗传风险。该项目将重点进行4项大规模研究，涉及多种生物学、认知和 遗传测量：阿尔茨海默病神经影像学倡议，巴尔的摩老龄化纵向研究， 越南时代老龄化双胞胎研究，和英国生物银行。描述疾病病因的变异性将为我们提供信息， 努力制定与疾病亚型相关的有针对性的干预战略。它还将允许更准确的 根据亚型对个体进行分组，以提高检测疾病和治疗效果的灵敏度。