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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

基本信息

批准号：
10188368
负责人：
NIR J BARZILAI
金额：
$ 124.45万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188368
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Ashkenazim Biochemical Biological Biological Assay 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 Prevention 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 dementia risk effective therapy exome exome sequencing functional outcomes gene interaction genetic manipulation genetic variant high dimensionality high risk longevity gene molecular marker molecular phenotype multidimensional data multidisciplinary new therapeutic target novel offspring potential biomarker preservation prospective protein metabolite resilience response stressor success therapeutic target therapy development

项目摘要

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.

项目概要/摘要：以前的研究工作，重点是确定阿尔茨海默病（AD）的风险，导致了有效的治疗。这导致人们越来越重视弹性因素，尽管有AD的风险因素，但个体仍保持无病状态。百岁老人是人口丰富的AD弹性，因为许多人保持正常的认知，尽管达到了先进的实际年龄，但寿命是AD的主要风险因素，或者是高风险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和其他年龄相关疾病侵害的弹性因素通过研究德系犹太人的基因同质人群，确定了与认知功能保护有关的弹性基因型。在我们过去多学科研究的成功基础上，包括综合网络方法，我们将测试的假设，个人与特别长寿的人拥有独特的基因型，导致他们对痴呆症的恢复力，两项已建立的长寿研究：（1）长寿基因项目（LGP），一项横断面队列研究，百岁老人，谁在95岁时保留了认知功能，和对照组;（2）LonGenity，一项针对百岁老人后代的独立纵向研究，基因组和年龄匹配的无长寿父母史的对照组（计划n=1400，平均年龄75岁），前瞻性随访神经认知评估的发生率认知能力下降和AD该提案旨在整合来自这两个领域的高级数据，长寿队列，包括基因型，全外显子组测序，生化，临床和神经认知特征，并对其进行询问，以确定认知弹性基因利用：（1）基因-基因交互作用分析和（2）基于网络的整合分析。顶部通过这些综合方法发现的候选者将被验证其关联性，在两个人类群体和神经元细胞模型中，携带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基因型和介导认知弹性的分子网络。鉴定这些因素在弹性人口有可能加快发展，有效治疗AD。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deep post-GWAS analysis identifies potential risk genes and risk variants for Alzheimer's disease, providing new insights into its disease mechanisms.

DOI：
10.1038/s41598-021-99352-3
发表时间：
2021-10-15
期刊：
Scientific reports
影响因子：
4.6
作者：
Wang Z;Zhang Q;Lin JR;Jabalameli MR;Mitra J;Nguyen N;Zhang ZD
通讯作者：
Zhang ZD

PGA: post-GWAS analysis for disease gene identification.

PGA：疾病基因鉴定的 GWAS 后分析。

DOI：
10.1093/bioinformatics/btx845
发表时间：
2018
期刊：
Bioinformatics (Oxford, England)
影响因子：
0
作者：
Lin,Jhih-Rong;Jaroslawicz,Daniel;Cai,Ying;Zhang,Quanwei;Wang,Zhen;Zhang,ZhengdongD
通讯作者：
Zhang,ZhengdongD

The role of dietary patterns and exceptional parental longevity in healthy aging.

饮食模式和父母的超长寿命在健康老龄化中的作用。