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

项目摘要/摘要 在过去的半个世纪里，美国65岁的预期寿命稳步增长。有很棒的 然而，不确定这种增加在多大程度上伴随着对 阿尔茨海默病(AD)、AD相关痴呆(ADRD)和中风导致的发病率/残疾--主要 老年人认知障碍(CI)的原因--或心脏病、癌症、糖尿病、肥胖、关节炎、 和骨折-基本日常生活能力(ADL)中非认知障碍的主要原因 老年人。鉴于美国人口老龄化以及医疗保健和长期护理费用的增加 在65岁以上，解决这种不确定性对公共卫生具有深远的重要性。1982-1994年全国 长期护理调查(NLTCS)第一次报告了日常生活能力和工具性学习能力的重大改善 65岁以上的日常生活活动能力(IADL)伤残率。尽管NLTCS的ADL/IADL改进持续到2004年， 1984年期间，严重认知障碍-包括AD/ADRD-出现了显著更大的改善- 2004年。此外，来自健康和退休研究(HRS)的多份报告表明，有利的趋势 严重的认知障碍仍在继续，但速度较慢，一直持续到2012年；来自国家统计局的类似报告 健康和老龄化趋势研究(NHATS)提供了持续改善的额外独立证据 2011-2015年间。我们建议对遗传和非遗传调节因子进行全面分析。 NLTCS、HRS、NHATS和长寿家庭研究(LLFS)中发病率/残疾的压缩，使用 符合HIPAA ADL和CI触发因素的发病率/残疾标准，以检验两个主要假设：(1) 可修改的非遗传风险因素解释了最近发病率、患病率和 认知和身体损害的持续性；以及(2)体质遗传和表观遗传因素 调整终生发病率/残疾发生率、患病率和持续性的个体差异 认知和身体障碍。我们将分析可改变的非遗传风险因素在长寿中的作用， 共病、功能健康(ADL/IADL)和严重认知障碍(目标1)。我们将完成SNP 对2,680个生物样本(目前已完成918个)进行阵列分析，并对639个样本进行DNA甲基化分析 NLTCS的血样。未确认的NLTCS基因和表观遗传学数据将使用NIAGADS发布 协议。我们将使用SNP和DNA甲基化数据来进行遗传和表观遗传关联分析 有衰老、健康、长寿、身体残疾和严重认知障碍的表型(目标2)。我们会 分析健康长寿表型与两个高度相关的候选多态之间的关联 耦合基因网络-胰岛素/IGF1信号转导(包括FOXO3a和IGFR)和mTOR通路--与衰老有关 以及不同物种之间的寿命以及全球和特定路径杂合性指数的关联 具有极高/极低的发病率/残疾风险；我们将确定AD/ADRD、心脏病、 癌症、中风和糖尿病与这些关联(目标3)。

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).