Resilience to Alzheimer's disease in humans with exceptional longevity

项目摘要/摘要： 以前的研究集中在确定阿尔茨海默病(AD)的风险上，但没有 导致了有效的治疗。这导致了人们对弹性因素的日益认识，这些因素使得 尽管存在阿尔茨海默病的风险因素，但个人仍应保持无病状态。百岁老人是一种 AD恢复力丰富的人群，因为许多人在整个一生中保持正常认知 寿命，尽管达到了较高的年龄，这是AD的主要风险因素，或 高危AD相关基因携带者。十多年来，我们的研究小组一直在 重点关注保护百岁老人免受AD和其他与年龄有关的疾病的复原力因素 通过研究德系犹太人的遗传同质性群体和 确定了与认知功能保护有关的弹性基因类型。 在我们过去多学科研究的成功基础上，将我们的方法扩展到 包括整合的网络方法，我们将测试以下假设 超凡的长寿拥有独特的基因类型，导致对痴呆症的韧性 两项公认的长寿研究：(1)长寿基因项目(LGP)，一个横断面队列 在95岁时保持认知功能的百岁老人和对照组；(2)LonGenity， 一项对百岁老人后代的独立、纵向研究，这些百岁老人的后代长寿丰富 基因组和没有父母长寿病史的年龄匹配的对照组(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 认知功能减退和阿尔茨海默病。本提案旨在将这两个项目的高级数据进行整合 长寿队列，包括基因分型、外显子全测序、生化、临床和 神经认知特征，并对其进行询问，以努力识别认知弹性基因 应用：(1)基因-基因互作分析和(2)基于网络的综合分析。顶层 使用这些综合方法发现的候选人将被验证其关联性 在两个人类队列和神经细胞模型中具有弹性，这将被设计成 保护AD-Resilience基因型别。通过利用综合计算方法来 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 验证调节认知复原力的基因类型和分子网络。身份识别 这些因素在有弹性的人群中具有加速发展的潜力 阿尔茨海默病的有效疗法。

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.