Resilience to Alzheimer's disease in humans with exceptional longevity

人类对阿尔茨海默病的抵抗力特别长

• 批准号: 9439529
• 负责人: NIR J BARZILAI
• 金额: $ 124.45万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9439529
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Ashkenazim; Biochemical; Biological; Biological Assay; Biological Preservation; Biology; CETP gene; Cell model; Cells; Centenarian; Chronology; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cognitive; Complex; Cross-Sectional Studies; Data; Dementia; Development; Disease; Elements; Engineering; Environmental Risk Factor; Etiology; Evaluation; Family; Female; Genes; Genetic; Genome; Genotype; Healthcare Systems; Human; Impaired cognition; Incidence; Independent Living; Individual; Inherited; Insulin-Like Growth Factor I; Interdisciplinary Study; Intervention; Lipids; Longevity; Longitudinal Studies; Mediating; Methodology; Methods; Mission; Molecular; Mutation; Network-based; Neurocognitive; Neurons; Parents; Pathway interactions; Pharmacology; Phenotype; Population; Positioning Attribute; Prevalence; Preventive Intervention; Property; Public Health; Recording of previous events; Request for Proposals; Research; Resistance; Resources; Risk Factors; Scientist; Signal Pathway; Testing; United States; United States National Institutes of Health; Validation; Work; age related; aging brain; aging population; apolipoprotein E-4; base; cognitive function; cohort; effective therapy; exome; exome sequencing; functional outcomes; gene interaction; genetic manipulation; genetic variant; high dimensionality; high risk; longevity gene; molecular marker; molecular phenotype; multidisciplinary; new therapeutic target; novel; offspring; potential biomarker; prospective; protein metabolite; resilience; response; stressor; success; therapeutic target; therapy development

Project Summary/Abstract: Prior research efforts that focused on identifying the risks for Alzheimer's disease (AD) have not resulted in effective treatments. This led to a growing appreciation of resilience factors that allow individuals to remain disease-free despite having risk factors for AD. Centenarians are a population enriched with AD resilience, as many maintain normal cognition throughout their lifespan despite achieving advanced chronological age, a major risk factor for AD, or being carriers of high-risk AD associated genotypes. For over a decade our research group has focused on resilience factors that protect centenarians against AD and other age-related diseases by studying the genetically homogenous population of Ashkenazi Jews and has identified resilient genotypes that have been implicated in preservation of cognitive function. Building on our past success of multidisciplinary research and expanding our methodologies to include integrative network approaches we will test the hypothesis that individuals with exceptional longevity possess unique genotypes that result in resilience to dementia in two established longevity studies: (1) Longevity Genes Project (LGP), a cross sectional cohort of centenarians, who at age 95 had preserved cognitive function, and controls; (2) LonGenity, an independent, longitudinal study of offspring of centenarians, who are enriched with longevity genomes, and age-matched controls without parental history of longevity (planned n=1400, mean age 75) that are followed prospectively with neurocognitive assessments for the incidence of cognitive decline and AD. This proposal aims to integrate high-level data from these two longevity cohorts that includes genotypes, whole exome sequencing, biochemical, clinical and neurocognitive profiles and to interrogate it in an effort to identify cognitive resilience genes using: (1) gene-gene interaction analysis and (2) network-based integrative analysis. The top candidates discovered with these integrative approaches will be validated for their association with resilience in two human cohorts and in neuronal cell models that will be engineered to harbor the AD-resilience genotypes. By utilizing integrative computational approaches to analyze high-dimensional data, cell models, as well as validation cohorts, we aim to identify and validate genotypes and molecular networks that mediate cognitive resilience. Identification of these factors in resilient human populations has the potential to expedite the development of effective therapies for AD.

项目摘要/摘要： 旨在确定阿尔茨海默氏病（AD）风险的事务研究工作尚未 导致有效的治疗。这导致了对弹性因素的越来越欣赏，允许 尽管有AD的危险因素，但个人仍保持无病。百岁老人是一个 人口丰富了广告弹性，因为许多人在整个过程中保持正常认知 寿命尽管达到了高级年代年龄，广告的主要危险因素或 高风险AD相关基因型的载体。十多年来，我们的研究小组拥有 专注于保护百岁老人免受AD和其他年龄有关的弹性因素 通过研究Ashkenazi犹太人的遗传同质种群，并具有疾病 鉴定出与认知功能保存有关的弹性基因型。 以我们过去的多学科研究成功为基础，将我们的方法扩展到 包括综合网络方法，我们将检验以下假设 特殊的寿命具有独特的基因型，可在 两项已建立的寿命研究：（1）寿命基因项目（LGP），横截面队列 一百岁女性的认知功能和控制； （2）长度， 一项独立的纵向研究，对百岁老人的后代，丰富了长寿 基因组和年龄匹配的对照没有父母的寿命（计划n = 1400， 平均年龄75）前瞻性地进行发病率的神经认知评估 认知能力下降和广告。该建议旨在整合这两个的高级数据 寿命人群包括基因型，整个外显子组测序，生化，临床和 神经认知概况并审问它以识别认知弹性基因 使用：（1）基因 - 基因相互作用分析和（2）基于网络的集成分析。顶部 通过这些综合方法发现的候选人将为他们的关联得到验证 在两个人类人群和神经元细胞模型中具有韧性 藏有广告弹性基因型。通过利用集成计算方法 分析高维数据，细胞模型以及验证队列，我们​​旨在识别和 验证介导认知弹性的基因型和分子网络。识别 这些弹性人群中的这些因素有可能加快 AD的有效疗法。