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.

抽象的痴呆症是一项重大的全球健康挑战，缺乏有效的治疗和早期诊断工具。痴呆症 (AD) 占所有痴呆症综合征的 70%，《柳叶刀》委员会最近敦促对生命全程进行研究。 AD 预防模型，为可扩展的早期线粒体生物标志物的开发提供动力。在维持生理稳态方面发挥着关键的生物能量作用，特别是对于高能量需求的器官，就像大脑一样，线粒体DNA（mtDNA）拷贝数（mtDNA-CN）是线粒体的定量指标。功能，与老年人的 AD 密切相关，越来越多的证据也表明 mtDNA 突变负荷，尽管越来越多的证据表明这些血液发挥着关键作用，但线粒体DNA异质性（mtDNA-Het）在AD中发挥着重要作用。老年人认知能力下降和 AD 的指标，但很少有研究检验它们之间的关系中年是预防性干预措施最有效的关键时期。这些 mtDNA 改变与早期出现的 AD 相关神经生物学底物之间的关系尚不清楚。心血管疾病 (CVD) 危险因素也与 mtDNA 改变、颞叶线粒体 DNA 的改变是否可以介导众所周知但不太清楚的关联尚不完全清楚。我们的中心假设是线粒体 DNA 的改变。与中年认知能力下降和 AD 相关神经生物学底物有关，并介导早期心血管疾病危险因素与中年大脑健康的关联为了检验这一假设，我们将利用生命- 完整 Bogalusa 心脏中 CVD 危险因素的长期测量和认知功能的两项中年测量研究 (BHS) 队列（N=1,298；850 名白人和 448 名黑人），以及 AD 相关神经生物学底物脑部磁共振成像 (MRI) 和光子发射断层扫描 (PET) 扫描可在在 BHS 中，我们进一步建议测量中年时的 mtDNA 变化。我们将在来自不同参与者的两个中年时间点进行强有力的验证工作。精准医学跨组学计划 (N=3,724) 和现有数据将使我们能够检查 mtDNA 改变与认知能力下降的前瞻性和时间关联（目标 1）中年的神经生物学基础（目标 2）；并评估早期生活的前瞻性和时间关联 CVD 危险因素与 mtDNA 的关系并研究 mtDNA 对儿童 CVD 风险关联的中介作用影响中年大脑健康的因素（目标 3）。遏制痴呆症，为药物开发和风险分层提供信息 K99 培训将使我能够在指导下进行了第一项研究中年 mtDNA 与认知衰退的前瞻性关联。一个由流行病学、基因组学和神经生物学衰老方面的专家组成的团队，由我的主要导师 Dr. 凯利，这个奖项无疑将加速我在脑衰老多组学研究中的职业独立。