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： 此前专注于识别阿尔茨海默病 (AD) 风险的研究工作并未取得进展。 取得了有效的治疗效果。这导致人们越来越重视弹性因素，从而使 尽管存在 AD 危险因素，但个人仍保持无病状态。百岁老人是一个 具有 AD 恢复力的人群，因为许多人在整个生命周期中都保持正常认知 尽管实际年龄较高（这是 AD 的一个主要危险因素），但其寿命仍然很长，或者 高危AD相关基因型的携带者。十多年来，我们的研究小组 重点关注保护百岁老人免受 AD 和其他与年龄相关的疾病的复原力因素 通过研究德系犹太人的基因同质群体来预防疾病，并已 确定了与认知功能保存有关的弹性基因型。 以我们过去成功的多学科研究为基础，并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： 超长的寿命具有独特的基因型，可导致对痴呆症的抵抗力 两项已建立的长寿研究：(1) 长寿基因项目 (LGP)，一个横断面队列 百岁老人在 95 岁时仍保留认知功能和控制能力； (2) 长源性， 对长寿的百岁老人后代进行的独立纵向研究 基因组和没有父母长寿史的年龄匹配对照（计划n = 1400， 平均年龄 75 岁），前瞻性地对发病率进行神经认知评估 认知能力下降和AD。该提案旨在整合这两个方面的高级数据 长寿队列，包括基因型、全外显子组测序、生化、临床和 神经认知概况并对其进行询问以识别认知弹性基因 使用：（1）基因-基因相互作用分析和（2）基于网络的综合分析。顶部 通过这些综合方法发现的候选人将对其关联进行验证 在两个人类队列和神经元细胞模型中具有复原力，这些模型将被设计为 具有 AD 恢复基因型。通过利用综合计算方法 分析高维数据、细胞模型以及验证队列，我们​​的目标是识别和 验证介导认知弹性的基因型和分子网络。鉴定 具有复原力的人群中的这些因素有可能加速人类的发展 AD 的有效治疗方法。