Exceptional Aging: Identifying Modifiers of Alzheimer's Disease Trajectories

项目摘要/摘要 预防阿尔茨海默病(AD)痴呆症有两个主要组成部分：预防 阿尔茨海默病的病理(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“异常衰老”假说，其中一些受试者(&gt；85 岁)没有明显的ADP，由于对这两种ADP的保护因素，认知正常 以及一生中认知能力的下降。这是基于这样一种想法，即环境、 生活方式和遗传因素在大多数人中随着年龄的增长引发AD痴呆的发病，但 “特殊老年人”受到保护。将这些知识转化为成功的个性化预防 和治疗试验，重要的是确定保护因素的简约组(S)以及如何确定 个人的表现优于平均人口轨迹，即“异常年龄”。我们的中央 假说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 种群轨迹，取决于个体的基因组变异、生活方式的丰富和血管 健康。这项提案的目的是应用这里提出的统一理论框架来确定 对ADP和认知功能减退的重要保护因素：一项基于人群的抽样和迁移 通过使用两个独立的用户发现“异常衰老”的路径走向个性化医疗 数学模型(关联规则挖掘和结构方程模型)。 我们将利用现有的以人口为基础的纵向梅奥诊所研究的基础设施 老龄化(MCSA)(60-90岁的人)，收集淀粉样蛋白(PIB)和tau的成像替代物 (Tau PET)、神经心理学检查、丰富生活方式(中年认知和体力活动)和载脂蛋白E 基因状态。我们还将利用罗切斯特流行病学项目(REP)，该项目保持着全面的 病历-链接系统(自1965年起)，从电子病历中提取附加信息 记录：纵向实验室检查(血脂检查)，血压，药物，体重指数，心脏和心脏疾病的诊断 在淀粉样蛋白和tau扫描前长达20年的代谢状况(CMC)。最后，我们将添加一个 ADP、相关神经退行性疾病和衰老相关基因变异的全面筛查 采用最新的基于SNP的阵列(NeuroX2)。

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).