Associations of Mitochondrial DNA Alterations with Alzheimer's Disease Related Brain Health

线粒体 DNA 改变与阿尔茨海默病相关大脑健康的关联

基本信息

批准号：
10724103
负责人：
Yang Pan
金额：
$ 9.66万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724103
关键词：
Acceleration Adult Affect Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Articulation Award Bioenergetics Biology Black Populations Blood Blood Pressure Body mass index Brain Cardiac health Cephalic Cerebrovascular Circulation Cerebrum Childhood Clinical Cognition Cohort Studies DNA copy number Data Dementia Development Diagnosis Early Diagnosis Elderly Epidemiology Functional Magnetic Resonance Imaging Functional disorder Funding Genomics Genotype Glucose Growth Health Heart Homeostasis Impaired cognition Knowledge Life Life Cycle Stages Linear Regressions Link Lipids Measurement Measures Mediating Mediation Mendelian randomization Mentors Meta-Analysis Methods Mitochondria Mitochondrial DNA Modeling Molecular Mutation Neurobiology Organ Participant Photons Play Population Prevalence Prevention Renal function Research Resources Risk Factors Role Sampling Scanning Syndrome Testing Time Training Trans-Omics for Precision Medicine United States National Institutes of Health Validation Variant White Matter Hyperintensity Work aging brain apolipoprotein E-4 brain health brain magnetic resonance imaging brain research brain tissue cardiometabolism cardiovascular disorder risk career cognitive function drug development early detection biomarkers effective therapy epidemiologic data follow-up genome wide association study global health health data heteroplasmy improved innovation insight middle age mitochondrial DNA alteration mitochondrial DNA mutation mitochondrial dysfunction multiple omics neurocognitive test novel marker novel strategies prevent preventive intervention programs prospective risk stratification statistics tomography tool

项目摘要

ABSTRACT Dementia is a major global health challenge that lacks effective treatment and early diagnosis tools. Alzheimer’s disease (AD) comprises 70% of all dementia syndromes. The Lancet Commission recently urged a life-course model of AD prevention, providing impetus for the development of scalable early biomarkers. Mitochondria play a critical bioenergetic role in maintaining physiologic homeostasis, particularly for high energy demand organs, like the brain. Mitochondrial DNA (mtDNA) copy number (mtDNA-CN), a quantitative indicator of mitochondrial function, is strongly associated with AD in older adults. Growing evidence also implicates mtDNA mutation load, or mtDNA heteroplasmy (mtDNA-Het), in AD. Despite the accumulating evidence for a key role of these blood indicators in cognitive decline and AD in older adults, there is a paucity of research examining their relationships in midlife, a critical time when preventive interventions may be most effective. Moreover, the relationships between these mtDNA alterations and early emerging AD-related neurobiological substrates is unclear. While cardiovascular disease (CVD) risk factors have also been associated with mtDNA alterations, the temporal associations are not fully discerned. Whether mtDNA alterations could mediate the well-known but less well understood associations of heart and brain health is unknown. Our central hypothesis is that mtDNA alterations are associated with cognitive decline and AD-related neurobiological substrates in midlife and mediate the associations of early life CVD risk factors with midlife brain health. To test this hypothesis, we will leverage life- long measures of CVD risk factors and two midlife measures of cognitive function in the full Bogalusa Heart Study (BHS) cohort (N=1,298; 850 whites and 448 Blacks), along with AD-related neurobiological substrates from brain magnetic resonance imaging (MRI) and photon emission tomography (PET) scans available in a large subsample at midlife (N=700). Within the BHS, we further propose measurement of mtDNA alterations at two midlife time-points. Our well-powered validation effort will be conducted among diverse participants from the Trans-Omics for Precision Medicine program (N=3,724) with existing data. These resources will allow us to examine the prospective and temporal associations of mtDNA alterations with cognitive decline (Aim 1) and neurobiological substrates in midlife (Aim 2); and assess prospective and temporal associations of early life CVD risk factors with mtDNA and investigate mediating effects of mtDNA on associations of childhood CVD risk factors with midlife brain health (Aim 3). Our work could have broad impacts on population-wide and targeted efforts to curb dementia, informing drug development and risk stratification. The K99 training will allow me to conduct the first study examining prospective associations of midlife mtDNA with cognitive decline. Mentored by a team of experts in epidemiology, genomics, and neurobiological aging and led by my primary mentor Dr. Kelly, this award will undoubtedly accelerate my career independence in multi-omics research of brain aging.

抽象的痴呆症是缺乏有效治疗和早期诊断工具的全球主要健康挑战。阿尔茨海默氏症疾病（AD）占所有痴呆综合征的70％。柳叶刀委员会最近敦促一场生命课预防AD的模型，为开发可扩展的早期生物标志物提供动力。线粒体发挥在维持生理稳态的生物稳态方面，尤其是对于高能量需求器官，喜欢大脑。线粒体DNA（mtDNA）拷贝数（mtDNA-CN），线粒体的定量指标功能与老年人的AD密切相关。越来越多的证据也会实现mtDNA突变负荷， AD中的MtDNA异质性（mtDNA-HET）。尽管积累了这些血液的关键作用的证据老年人认知能力下降和AD的指标，研究他们的关系很少在中年，预防干预措施可能最有效的关键时期。而且，关系这些mtDNA改变与早期新兴广告相关的神经生物学底物之间尚不清楚。心血管疾病（CVD）危险因素也与mtDNA改变有关关联并没有完全辨别。 mtDNA的改变是否可以介导已知但良好的良好了解心脏和大脑健康的关联是未知的。我们的中心假设是mtDNA改变与中年的认知能力下降和与广告相关的神经生物学底物有关早期生命的关联CVD风险因素与中年大脑健康。为了检验这一假设，我们将利用生活 - 长期测量CVD危险因素和两种中年的认知功能测量研究（BHS）队列（n = 1,298; 850个白人和448个黑人）以及与AD相关的神经生物学底物从大脑磁共振成像（MRI）和光子发射断层扫描（PET）扫描中年的大子样本（n = 700）。在BHS中，我们进一步提出了MTDNA改变的测量两个中年的时间点。我们能力良好的验证工作将在潜水员参与者中进行具有现有数据的精密医学计划（n = 3,724）的跨词（n = 3,724）。这些资源将使我们能够检查mtDNA改变与认知能力下降的前瞻性和临时关联（AIM 1）和中年的神经生物学底物（AIM 2）；并评估早期生活的前瞻性和临时关联 MTDNA的CVD风险因素并研究mtDNA对儿童期CVD风险关联的中介作用中年大脑健康的因素（AIM 3）。我们的工作可能会对整个人群产生广泛的影响，并针对努力遏制痴呆症，为药物开发和风险分层提供信息。 K99培训将使我能够进行第一项研究，研究中年生命麦芽孢子的前瞻性关联随认知能力下降。由由我的主要导师博士领导的流行病学，基因组学和神经生物学衰老专家团队凯利（Kelly），该奖项无疑将加速我在大脑衰老多摩克研究中的职业独立性。