Genetic Resilience to the Clinical Manifestation of Dementia

描述(由申请者提供)：该项目将确定预测个人对阿尔茨海默病(AD)或脑血管疾病引起的认知障碍的恢复力的遗传因素。在尸检中，大约30%认知正常的人具有AD或脑血管疾病的病理特征。然而，到目前为止，很少有研究关注可能对这种韧性起作用的遗传因素。这项应用的目的是确定改变AD病理、脑血管疾病和认知障碍之间联系的基因变异。这项工作将利用来自全国6个数据集的数据来发现和复制这种基因-环境相互作用效应。此外，它还将使用体内生物标记物数据和体外尸检数据寻找相互作用，以提供第二层次的验证。主要假设是在初步分析中确定的相关分子途径中的基因(脂质运输、遗传稳定性和 Tau磷酸化)将预测痴呆症对病理级联反应的韧性。基于这一假设，这项应用的主要目标将识别和复制遗传变异：1)赋予tau和淀粉样蛋白相关认知功能下降的韧性；2)修改血管风险、脑血管疾病和认知功能下降之间的关系；以及3)修改AD和脑血管病理之间的关系。免费的培训计划将通过强调以下培训内容领域，使候选人具备建立专注于遗传韧性的独立研究生涯所需的技能：1)尸检方法和先进的病理学指标；2)脑脊液中量化的AD生物标志物；3)血管疾病的神经成像；以及4)AD和血管性痴呆的临床特征。导师团队由这些内容领域的专家组成，并将与范德比尔特记忆和阿尔茨海默氏症中心的跨学科培训计划以及范德比尔特大学医学中心提供的尖端计算和基因组资源相结合。这些实用和智力资源将为应聘者提供理想的培训环境。主要导师安吉拉·杰斐逊博士有很强的资助历史和支持候选人所需的所有财政资源。这些广泛的资源将使应聘者能够以助理教授的身份100%地致力于研究和职业发展。这将确保霍曼博士做好充分准备，在拟议的授权期内争取独立资金(R01)。

DESCRIPTION (provided by applicant): This project will identify genetic factors that predict individual resilience to cognitive impairment arising from Alzheimer's disease (AD) or cerebrovascular disease. At autopsy, approximately 30% of cognitively normal individuals have the pathological features of AD or cerebrovascular disease. Yet, to date very little research has focused on the genetic factors that might contribute to such resilience. The objective of this application is to identify genetic variants that modify the association between AD pathology, cerebrovascular disease, and cognitive impairment. This work will leverage data from 6 datasets across the country to both discover and replicate such gene-environment interaction effects. In addition, it will look for interactions using both in vivo biomarker data and ex vivo autopsy data n order to provide a second level of validation. The main hypothesis is that genes within relevant molecular pathways identified in preliminary analyses (lipid transportation, genetic stability, and tau phosphorylation) will predict resilience to the pathologic cascade in dementia. Based on this hypothesis, the primary aims of this application will identify and replicate genetic variants that:1) confer resilience from tau- and amyloid- related cognitive decline; 2) modify relations between vascular risk, cerebrovascular disease, and cognitive decline; and 3) modify the relationship between AD and cerebrovascular pathologies. The complimentary training plan will equip the candidate with the skills necessary to build out an independent research career focused on genetic resilience by emphasizing the following training content areas: 1) autopsy methodology and advanced metrics of pathology; 2) AD biomarkers quantified in cerebrospinal fluid; 3) Neuroimaging of vascular disease; and 4) the clinical characterization of AD and vascular dementia. The mentor team is made up of experts in each of these content areas and will be combined with the interdisciplinary training program in the Vanderbilt Memory and Alzheimer's Center and the cutting edge computational and genomic resources available at Vanderbilt University Medical Center. Together, these practical and intellectual resources will provide the ideal training environment for the candidate. The primary mentor, Dr. Angela Jefferson, has a strong funding history and all the financial resources needed to support the candidate. These extensive resources will allow the candidate to dedicate 100% protected effort as an Assistant Professor to focus on research and career development. This will ensure that Dr. Hohman is fully prepared to compete for independent funding (R01) over the course of the proposed award period.