Genetic and Non-Genetic Modulators of Morbidity/Disability Compression in a Large Population-Based Study of Cognitive and Physical Impairment with Emphasis on Alzheimer's Disease and Related Dementias

在一项基于大规模人群的认知和身体损伤研究中，发病率/残疾压缩的遗传和非遗传调节剂，重点是阿尔茨海默氏病和相关痴呆症

• 批准号: 10608996
• 负责人: P.J. ERIC STALLARD
• 金额: $ 77.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608996
• 关键词: Activities of Daily Living; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Arthritis; Blood; Blood Vessels; Blood specimen; Chronic Disease; Cognitive; Computer software; Constitution; Constitutional; Coupled; DNA; DNA Methylation; Data; Dementia; Diabetes Mellitus; Elderly; Epigenetic Process; FOXO3A gene; FRAP1 gene; Family Study; Fracture; Genes; Genetic; Genetic Databases; Genetic Polymorphism; Genotype; Gerontology; Health; Health Care Costs; Health Insurance Portability and Accountability Act; Health and Retirement Study; Heart Diseases; Heterozygote; Hybrid Vigor; Hypertension; IGF1 gene; Impaired cognition; Impairment; Incidence; Individual Differences; Insulin; Lewy Bodies; Life; Life Expectancy; Link; Long-Term Care; Longevity; Malignant Neoplasms; Measures; Mental Depression; Methylation; Morbidity - disease rate; Nucleotides; Obesity; Outcome Measure; Pathway interactions; Phenotype; Population; Population Study; Prevalence; Protocols documentation; Public Health; Reporting; Research; Resolution; Respondent; Risk Factors; Role; SNP array; SOD2 gene; Sampling; Signal Transduction; Signs and Symptoms; Site; Smoking; Stroke; Surveys; TP53 gene; Testing; Triage; Uncertainty; United States; Variant; Whole Blood; bead chip; biodemography; comorbidity; data cleaning; density; design; disability; disability risk; end of life; gene network; genetic analysis; genetic association; health data; improved; indexing; insight; instrumental activity of daily living; middle age; modifiable risk; mortality; non-genetic; physical inactivity; physically handicapped; public health relevance; trend

Project Summary/Abstract Life expectancy at age 65 increased steadily in the United States over the past half-century. There is great uncertainty, however, regarding the extent to which this increase was accompanied by the compression of morbidity/disability due to Alzheimer’s disease (AD), AD-related dementias (ADRD), and stroke—the leading causes of cognitive impairment (CI) among the elderly—or to heart disease, cancer, diabetes, obesity, arthritis, and fractures—the leading causes of non-cognitive disablement in basic activities of daily living (ADL) among the elderly. Given the aging of the U.S. population and the increasing costs of health care and long-term care above age 65, addressing this uncertainty is of profound public health importance. The 1982–1994 National Long Term Care Survey (NLTCS) produced the first reports of major improvements in ADL and instrumental ADL (IADL) disability rates above age 65. While ADL/IADL improvements continued through 2004 in the NLTCS, dramatically larger improvements occurred for severe cognitive impairment—including AD/ADRD—during 1984– 2004. Moreover, multiple reports from the Health and Retirement Study (HRS) indicated that the favorable trends in severe cognitive impairment continued, but at a slower pace, through 2012; similar reports from the National Health and Aging Trends Study (NHATS) provided additional independent evidence of continuing improvement during 2011–2015. We propose to conduct comprehensive analyses of genetic and non-genetic modulators of the compression of morbidity/disability in the NLTCS, HRS, NHATS, and Long Life Family Study (LLFS), using morbidity/disability criteria consistent with the HIPAA ADL and CI triggers, to test two major hypotheses: (1) that modifiable non-genetic risk factors account for the recent temporal changes in the incidence, prevalence, and continuance of cognitive and physical impairments; and (2) that constitutional genetic and epigenetic factors modulate individual differences in lifetime morbidity/disability incidence, prevalence, and continuance of cognitive and physical impairments. We will analyze the roles of modifiable non-genetic risk factors in longevity, co-morbidity, functional health (ADL/IADL), and severe cognitive impairment (Aim 1). We will complete the SNP array analysis of 2,680 biospecimen samples (918 currently done) and conduct DNA methylation analysis of 639 blood samples in the NLTCS. De-identified NLTCS genetic and epigenetic data will be released using NIAGADS protocols. We will use SNP and DNA methylation data to conduct genetic and epigenetic association analyses with phenotypes of aging, health, longevity, physical disability, and severe cognitive impairment (Aim 2). We will analyze associations of phenotypes of long healthy life with candidate polymorphisms within two highly relevant coupled gene networks—Insulin/IGF1 signaling (incl. FOXO3A and IGFR) and mTOR pathways—linked to aging and longevity across different species and associations of global and pathway-specific indices of heterozygosity with exceptionally high/low morbidity/disability risks; we will determine the roles of AD/ADRD, heart disease, cancer, stroke, and diabetes in these associations (Aim 3).

项目摘要/摘要 在过去的半个世纪中，美国的预期寿命在美国静静地增加了。那里很棒 然而，不确定性在通过压缩来实现这种增加的程度上 由于阿尔茨海默氏病（AD），与广告相关的痴呆症（ADRD）和中风引起的发病/残疾，这是领先的 老年人的认知障碍原因（CI），或心脏病，癌症，糖尿病，肥胖，关节炎， 和断裂 - 日常生活基本活动（ADL）中非认知残疾的主要原因（ADL） 较早的。鉴于美国人口的老龄化以及医疗保健和长期护理的成本增加 65岁以上，解决这种不确定性至关重要。 1982 - 1994年国家 长期护理调查（NLTC）产生了有关ADL和工具的重大改进的第一批报告 ADL（IADL）的残疾率高于65岁。而ADL/IADL的改进一直持续到2004年，在NLTC中， 严重的认知障碍（包括AD/ADRD）的动态改善发生了更大的改善 - 1984年 - 2004年。此外，《健康与退休研究》（HRS）的多个报告表明，有利的趋势 在严重的认知障碍中，持续的障碍持续，但在较慢的空间中，截至2012年；来自国家的类似报告 健康和衰老趋势研究（NHATS）提供了继续改进的其他独立证据 在2011 - 2015年期间。我们建议对遗传和非遗传调节剂的全面分析 使用NLTC，HRS，NHAT和长寿家庭研究（LLFS）中发病/残疾的压缩 发病/残疾标准与HIPAA ADL和CI触发器一致，以检验两个主要的假设：（1） 可修改的非遗传危险因素解释了事件，患病率和 认知和身体障碍的延续； （2）宪法遗传和表观遗传因素 调节终生发病/残疾事件的个体差异，流行和延续 认知和身体障碍。我们将分析可修改的非基因风险因素在寿命中的作用， 合并症，功能健康（ADL/IADL）和严重的认知障碍（AIM 1）。我们将完成SNP 2,680个生物测量样品（目前完成的918个）和进行DNA甲基化分析的阵列分析639 NLTC中的血液样本。将使用Niagads释放去识别的NLTC遗传和表观遗传数据 协议。我们将使用SNP和DNA甲基化数据进行遗传和表观遗传关联分析 具有衰老，健康，寿命，身体残疾和严重认知障碍的表型（AIM 2）。我们将 分析长期健康寿命的表型与两个高度相关的候选多态性 耦合基因网络 - 胰岛素/IGF1信号传导（包括FOXO3A和IGFR）和MTOR途径 - 链接到衰老 杂合性的全球和途径特定指数的不同物种的寿命和寿命 具有异常高/低的发病/残疾风险；我们将确定AD/ADRD，心脏病， 这些关联中的癌症，中风和糖尿病（AIM 3）。