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

• 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
• 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' s Disease; Alzheimer' 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

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.

摘要 痴呆症是一个主要的全球健康挑战，缺乏有效的治疗和早期诊断工具。阿尔茨海默 痴呆症（AD）占所有痴呆综合征的70%。《柳叶刀》委员会最近敦促， AD预防模型，为开发可扩展的早期生物标志物提供动力。线粒体游戏 在维持生理稳态，特别是对于高能量需求器官， 比如大脑线粒体DNA（mtDNA）拷贝数（mtDNA-CN），线粒体DNA拷贝数的定量指标， 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， 或线粒体DNA异质性（mtDNA-Het）。尽管越来越多的证据表明这些血液 老年人认知能力下降和AD的指标，缺乏研究它们之间的关系 中年是预防性干预可能最有效的关键时期。此外，关系 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。而 心血管疾病（CVD）的危险因素也与mtDNA的改变有关， 协会没有被充分识别。线粒体DNA的改变是否可以介导众所周知但不太好的 心脏和大脑健康之间的联系尚不清楚。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相关，并介导 早期CVD危险因素与中年大脑健康的关系。为了验证这个假设，我们将利用生命- 在完整的博加卢萨心脏中CVD危险因素的长期测量和认知功能的两个中年测量 研究（BHS）队列（N= 1，298; 850例白人和448例黑人），沿着AD相关神经生物学底物 从脑磁共振成像（MRI）和光子发射断层扫描（PET）扫描， 中年时的大型子样本（N=700）。在BHS中，我们进一步建议测量线粒体DNA的变化， 两个中年时间点我们强大的验证工作将在来自 Trans-Omics for Precision Medicine项目（N= 3，724）和现有数据。这些资源将使我们能够 研究mtDNA改变与认知能力下降的前瞻性和时间相关性（目标1）， 中年的神经生物学基质（目标2）;并评估早期生活的前瞻性和时间关联 mtDNA与CVD危险因素的关系及mtDNA对儿童CVD危险性的影响 中年大脑健康因素（目标3）。我们的工作可以对全人口产生广泛影响， 努力遏制痴呆症，为药物开发和风险分层提供信息。K99训练会让我 进行第一项研究，检查中年mtDNA与认知能力下降的前瞻性关联。辅导 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大脑衰老的多组学研究中的职业独立性。