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

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 阿尔茨海默病和相关痴呆症(ADRD)影响着全球4700万人。该病的病因学 ADRD很复杂，人们对其了解不多，治疗方案也很少。ADRD有很长的临床前阶段 阶段从几年到几十年不等。因此，有可能进行早期预防和治疗干预。 通过瞄准中年的风险因素和生物机制。白细胞端粒长度缩短(LTL)和 线粒体DNA拷贝数减少(MTCN)是重要的衰老生物标志物，最近被认为与此有关 在ADRD的发病机制中起重要作用。然而，调解它们与ADRD关联的潜在机制 是不被理解的。重要的是确定中年时测量的LTL和外周MTCN是否可以预测 前瞻性研究中ADRD的风险，并评估缩短LTL的下游通路 MTCN的减少可能导致ADRD的发展。从这样的工作中发现可能会提供病因学 可能为预防和早期干预提供有针对性的途径的见解。这项R21研究将利用 现有数据来自社区动脉粥样硬化风险神经认知研究(ARIC-NCS)，NHLBI TRANS-OMICS for Precision Medicine(TOPMed)和NHGRI常见病基因组学中心(CCDG) 程序。ARIC-NCS(基线n：15,792；年龄：45-64岁)发现了2,719例30岁以上的痴呆症病例 多年的跟踪调查。我们已经获得了3,353个ARIC的LTL和白细胞MTCN(L-MTCN)的估计 参与者基于TOPMed的2次或3次全基因组测序(WGS)数据。我们的预赛 对样本的分析表明：1)中年LTL和L-MTCN与未来患痴呆的风险有关 和2)无偏蛋白质组学分析(即来自基于适体的SOMAscan v.4血浆的4931个蛋白质 蛋白质组学专家组)可以鉴定与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(n=10,193)的LTL和L-MTCN估计数 通过CCDG获得的数据。(2)评估中期测量的LTL与L-MTCN的前瞻性关联性 在整个ARIC队列中，痴呆发病率的年龄。(3)利用SOMAScan蛋白质组学数据，可用于 整个ARIC队列来自访问2和3，以进行LTL和L-MTCN的蛋白质组学分析。我们还将 对LTL的遗传多基因风险分数(PR)进行蛋白质组学分析，我们将使用 并将其归类为不同的基于基因的途径。(4)进行调解分析 评估以上(3)中确定的哪种蛋白质可能介导LTL和L-MTCN与 意外痴呆症。 本研究将利用ARIC的多组学资源来评估中年LTL和L-MTCN与 ADRD，并确定这些老化生物标记物的蛋白质组学特征与疾病的病因相关 ADRD，其广泛目标是改善ADRD的预防和治疗。