Leukocyte Telomere Length, Mitochondrial DNA Copy Number, Plasma Proteomics, and Alzheimer's Disease-related Dementia

白细胞端粒长度、线粒体 DNA 拷贝数、血浆蛋白质组学和阿尔茨海默病相关痴呆

• 批准号: 10420508
• 负责人: Weihong Tang
• 金额: $ 13.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10420508
• 关键词: Affect; Age; Aging; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Atherosclerosis Risk in Communities; Biological; Biological Markers; Complex; DNA copy number; Data; Dementia; Development; Disease; Early Intervention; Etiology; Future; Genes; Genomics; Incidence; Individual; Intervention; Lead; Length; Leukocytes; Measures; Mediating; Mediation; Mitochondrial DNA; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Neurocognitive; Participant; Pathogenesis; Pathway interactions; Peripheral; Plasma; Prevention; Preventive treatment; Prospective Studies; Proteins; Proteomics; Publishing; Resources; Risk Factors; Sampling; Trans-Omics for Precision Medicine; Visit; Work; aptamer; base; cohort; dementia risk; follow-up; genetic analysis; genome sequencing; genome wide association study; improved; insight; middle age; multiple omics; polygenic risk score; pre-clinical; preventive intervention; programs; prospective; proteomic signature; telomere; whole genome; Affect; Age; Aging; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Atherosclerosis Risk in Communities; Biological; Biological Markers; Complex; DNA copy number; Data; Dementia; Development; Disease; Early Intervention; Etiology; Future; Genes; Genomics; Incidence; Individual; Intervention; Lead; Length; Leukocytes; Measures; Mediating; Mediation; Mitochondrial DNA; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Neurocognitive; Participant; Pathogenesis; Pathway interactions; Peripheral; Plasma; Prevention; Preventive treatment; Prospective Studies; Proteins; Proteomics; Publishing; Resources; Risk Factors; Sampling; Trans-Omics for Precision Medicine; Visit; Work; aptamer; base; cohort; dementia risk; follow-up; genetic analysis; genome sequencing; genome wide association study; improved; insight; middle age; multiple omics; polygenic risk score; pre-clinical; preventive intervention; programs; prospective; proteomic signature; telomere; whole genome

Project Summary Alzheimer’s disease and related dementias (ADRD) affect 47 million individuals world-wide. The etiology of ADRD is complex and not well understood, and there are few treatment options. ADRD has a long preclinical stage ranging from years to decades. There is thus potential for early preventive and treatment interventions by targeting risk factors and biological mechanisms in midlife. Shortened leukocyte telomere length (LTL) and reduced mitochondrial DNA copy number (MTCN), important aging biomarkers, have recently been implicated in the pathogenesis of ADRD. However, the underlying mechanisms mediating their associations with ADRD are not understood. It is important to establish whether LTL and peripheral MTCN measured in midlife predict the risk of ADRD in prospective studies, and to evaluate the downstream pathways by which shortened LTL and reduced MTCN may lead to the development of ADRD. Finding from such work could provide etiologic insights that may inform targeted pathways for prevention and early intervention. This R21 study will utilize existing data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), the NHLBI Trans-Omics for Precision Medicine (TOPMed), and NHGRI Centers for Common Disease Genomics (CCDG) programs. ARIC-NCS (baseline n: 15,792; age: 45-64y) has identified 2,719 incident dementia cases over 30 years of follow-up. We have obtained estimates for LTL and leukocyte MTCN (l-MTCN) for 3,353 ARIC participants based on visits 2 or 3 whole genome sequencing (WGS) data from TOPMed. Our preliminary analysis of this sample suggests that 1) midlife LTL and l-MTCN are associated with future risk of dementia and 2) an unbiased proteomics analysis (i.e. 4,931 proteins from the aptamer-based SOMAscan v.4 plasma proteomics panel) can identify functionally relevant proteins for LTL and l-MTCN. Our objectives are to: (1) Complete the estimates for LTL and l-MTCN for the remaining ARIC participants (n=10,193) using ARIC WGS data available through CCDG. (2) Assess the prospective association of LTL and l-MTCN measured in middle age with dementia incidence in whole ARIC cohort. (3) Leverage the SOMAScan proteomics data, available for the entire ARIC cohort from visits 2 and 3, to conduct a proteomics analysis of LTL and l-MTCN. We will also conduct a proteomics analysis of genetic polygenic risk scores (PRS) for LTL, that we will derive using a published LTL GWAS and categorize into different gene-based pathways. (4) Conduct a mediation analysis to evaluate which of the proteins identified in (3) above may mediate the associations of LTL and l-MTCN with incident dementia. This study will use ARIC’s multi-omics resources to evaluate the associations of midlife LTL and l-MTCN with ADRD, and to identify proteomics signatures of these aging biomarkers that are relevant to the etiology of ADRD, with the broad objective of improving the prevention and treatment of ADRD.

项目摘要 阿尔茨海默氏病和相关痴呆症（ADRD）影响了全球4700万个人。病因 ADRD很复杂且不太了解，几乎没有治疗选择。 ADRD有一个很长的临床前 舞台范围从几年到几十年。因此，有可能进行早期预防和治疗干预措施 通过针对中年的危险因素和生物机制。缩短白细胞端粒长度（LTL）和 线粒体DNA拷贝数（MTCN），重要的老化生物标志物的减少了，最近已被暗示 在ADRD的发病机理中。但是，介导其与ADRD的关联的基本机制 不了解。重要的是确定在中年测量的LTL和外围MTCN是否预测 前瞻性研究中ADRD的风险，并评估缩短LTL的下游途径 减少MTCN可能导致ADRD的发展。从这些工作中找到可以提供病因 可能为预防和早期干预的有针对性途径提供信息的见解。这项R21研究将利用 来自社区神经认知研究（ARIC-NC）的动脉粥样硬化风险的现有数据，NHLBI 精密医学的跨词（TopMed）和NHGRI公共疾病基因组学（CCDG） 程序。 ARIC-NC（基线N：15,792；年龄：45-64Y）已确定2,719例出现30岁以上的事件痴呆症病例 多年后续行动。我们获得了3,353 ARIC的LTL和白细胞MTCN（L-MTCN）的估计值 来自TopMed的访问2或3个整个基因组测序（WGS）数据的参与者。我们的初步 该样本的分析表明1）中年LTL和L-MTCN与痴呆症的未来风险有关 和2）无偏的蛋白质组学分析（即基于APATMER的SOMASCAN v.4等离子体的4,931个蛋白质 蛋白质组学面板）可以识别LTL和L-MTCN功能相关的蛋白质。我们的目标是：（1） 使用ARIC WGS完成其余ARIC参与者的LTL和L-MTCN的估计值（n = 10,193） 通过CCDG获得的数据。 （2）评估在中间测量的LTL和L-MTCN的前瞻性关联 整个ARIC队列中痴呆症的年龄。 （3）利用Somascan蛋白质组学数据，可用于 从访问2和3进行的整个ARIC队列进行LTL和L-MTCN的蛋白质组学分析。我们也会 对LTL进行遗传多基因风险评分（PR）的蛋白质组学分析，我们将使用A得出 发表的LTL GWAS并分类为不同的基于基因的途径。 （4）进行调解分析 评估以上（3）中鉴定的哪种蛋白质可以介导LTL和L-MTCN的关联 事件痴呆症。 这项研究将使用ARIC的多摩学资源来评估中年LTL和L-MTCN的关联 ADRD，并确定与这些老化生物标志物的蛋白质组学特征 ADRD，其广泛的目标是改善ADRD的预防和治疗。