Exceptional Aging: Identifying Modifiers of Alzheimer's Disease Trajectories

项目概要/摘要 预防阿尔茨海默病（AD）痴呆有两个主要组成部分： 阿尔茨海默病病理学（ADP -淀粉样蛋白和tau蛋白）和对认知障碍的保护， ADP（认知储备）。在这里，我们提出了一个“异常老化”的假设，其中一些受试者（>85 年龄30岁）没有显著的ADP，并且由于对ADP和ADP的保护因素，认知正常 和认知能力的下降。这是基于这样的想法， 生活方式和遗传因素在大多数个体中随着年龄的增长触发AD痴呆的发作， “特殊年龄”受到保护。将这些知识转化为设计成功的个性化预防 和治疗试验，重要的是要确定一套简约的保护因素， 个体能够超越平均群体轨迹，即，“异常年龄”。我们的中央 一个假设是，每个人的淀粉样蛋白，tau蛋白和认知的轨迹将偏离平均水平 人口轨迹，这取决于个人的基因组变异，生活方式丰富，和血管 健康本建议的目的是应用这里提出的统一理论框架来确定 在基于人群样本和移动中对抗ADP和认知下降的重要保护因素 通过使用两种独立的方法发现“异常衰老”的途径， 数学模型（关联规则挖掘和结构方程模型）。 我们将利用现有的基于人群的纵向马约临床研究的基础设施， 老化（MCSA）（60-90岁的个体），收集淀粉样蛋白（PiB PET）和tau蛋白的成像替代物 (tau PET）、神经心理学检查、生活方式丰富（中年认知和体力活动）和APOE 基因状态我们还将利用罗切斯特流行病学项目（REP），该项目保持了一个全面的 医疗记录链接系统（自1965年以来），从电子医疗记录中提取额外信息。 记录：纵向实验室检查（血脂）、血压、药物、BMI和心脏病诊断， 在淀粉样蛋白和tau扫描之前长达20年的代谢条件（CMC）。最后，我们将添加一个 全面筛查与ADP、相关神经退行性疾病和衰老相关的遗传变异 使用最新的基于SNP的阵列（NeuroX 2）。

PROJECT SUMMARY / ABSTRACT Protection against Alzheimer's disease (AD) dementia has two main components: protection against Alzheimer's disease pathology (ADP – amyloid and tau) and protection against cognitive impairment despite ADP (cognitive reserve). Here, we propose an “exceptional aging” hypothesis, where some subjects (>85 years of age) have no significant ADP and are cognitively normal due to protective factors against both ADP and cognitive decline across the lifespan. This is based on the idea that a combination of environmental, lifestyle, and genetic factors trigger the onset of AD dementia in the majority of individuals as they age but “exceptional agers” are protected. To translate this knowledge to design successful personalized prevention and treatment trials, it is important to identify the parsimonious set(s) of protective factors and how certain individuals are able to outperform the average population trajectories, i.e., “exceptionally age”. Our central hypothesis is that each individual's trajectory of amyloid, tau, and cognition will deviate from the average population trajectories, depending on the individual's genomic variation, lifestyle enrichment, and vascular health. The aim of this proposal is to apply the unified theoretical framework proposed here to identify important protective factors against ADP and cognitive decline in a population-based sample and move towards personalized medicine by discovering paths to “exceptional aging” using two independent mathematical models (association rule mining and structural equation models). We will utilize the existing infrastructure of the population-based, longitudinal Mayo Clinic Study of Aging (MCSA) (individuals aged 60-90 years) which collects imaging surrogates of amyloid (PiB PET) and tau (tau PET), neuropsychological exams, lifestyle enrichment (midlife cognitive and physical activity), and APOE gene status. We will also utilize the Rochester Epidemiology Project (REP) which maintains a comprehensive medical records-linkage system (since 1965), to abstract additional information from the electronic medical records: longitudinal lab tests (lipid panel), blood pressure, medications, BMI, and diagnosis of cardiac and metabolic conditions (CMCs) up to 20 years before the amyloid and tau scans. Lastly, we will add a comprehensive screen of genetic variation related to ADP, related neurodegenerative disorders, and aging with the latest SNP-based array (NeuroX2).