Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease

阿尔茨海默病认知弹性的综合网络建模

• 批准号: 10170187
• 负责人: MICHELLE E EHRLICH
• 金额: $ 121.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170187
• 关键词: Academic Medical Centers; Activities of Daily Living; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Autopsy; Biological Models; Biology; Brain; Caenorhabditis elegans; Categories; Cessation of life; Clinical; Clinical Data; Cognitive; DNA sequencing; Data; Data Set; Dementia; Deterioration; Development; Disease; Elderly; Gene Proteins; Genes; Genetic; Genotype-Tissue Expression Project; Goals; Human; Immunocompetence; Individual; Lead; Maps; Measurable; Memory; Memory Loss; Messenger RNA; Methods; Mitochondria; Modeling; Molecular; Molecular Profiling; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathologic; Persons; Population; Prefrontal Cortex; Prevention strategy; Proteins; Proteomics; Research; Risk Factors; Scientist; Senile Plaques; Signal Pathway; Structure; System; Testing; Tissue Sample; Variant; aging brain; brain tissue; cohort; differential expression; epigenetic marker; genetic variant; high dimensionality; human very old age (85+); in vivo Model; medical schools; molecular scale; mouse model; network models; non-demented; novel; prevent; resilience; transcriptomics

Project Summary Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles. Clinically, AD patients present with progressive memory decline followed by deterioration of other cognitive domains and activities of daily living. Advanced age is the greatest risk factor. No effective method is available for preventing and/or treating this devastating disease. However, certain individuals of the elder population (≥ 85 years) remain cognitively intact, including some with substantial plaques and neurofibrillary tangle burdens, the two pathological hallmarks for fully symptomatic AD. The mechanisms of cognitive resilience and protection against AD in these elderly persons remain elusive. This proposal brings together scientists and postmortem human brain tissue samples from two major AD-research centers (the Icahn School of Medicine at Mount Sinai and the Rush University Medical Center) and aims to systematically identify and validate genetic variants, genes, proteins, and molecular networks underlying cognitive resilience to AD risk and proposes to build a comprehensive unbiased signaling pathway map underlying cognitive resilience to AD. Towards this end, we will develop an AD resilient cohort comprised of genetic, transcriptomic and proteomic data in the prefrontal cortex from a large number of brains in four categories: 1) very old (age of death (AoD) ≥ 85) AD-resilient, 2) young (AoD < 85) healthy, 3) very old (AoD ≥85) AD and 4) young (AoD < 85) AD. We will perform systems genetics and integrative network biology analyses on the large-scale high-dimensional molecular profiling data to identify genetic variants, genes, proteins, and molecular networks underlying cognitive resilience to AD risk. We will systematically validate key drivers of the molecular networks underlying the cognitive resilience to AD using two diverse (C. elegans and mouse) model systems. We will validate the structures of AD-resilient molecular networks for building a data- driven, comprehensive signaling pathway map underlying cognitive resilience to AD risk. In particular, we will test the hypotheses that enhanced mitochondrial function and immune competence as well as their underlying molecular networks confer cognitive resilience. Our study will not only present a global landscape of the interplays among genetic variants, mRNAs and proteins responsible for cognitive resilience to AD but also pinpoint critical network structures and key drivers that can potentially lead to development of novel prevention strategies in combating AD.

项目总结