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

摘要 痴呆症是一个重大的全球健康挑战，缺乏有效的治疗和早期诊断工具。阿尔茨海默氏症 阿尔茨海默病(AD)占所有痴呆综合征的70%。《柳叶刀》委员会最近敦促人们 AD预防模型，为可扩展早期生物标志物的发展提供动力。线粒体发挥作用 在维持生理动态平衡方面的关键生物能量作用，特别是对高能量需求的器官， 比如大脑。线粒体DNA(MtDNA)拷贝数(mtDNA-CN)是线粒体的一个定量指标 功能，与老年人的阿尔茨海默病密切相关。越来越多的证据也牵涉到线粒体DNA突变， 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起到了关键作用 关于老年人认知能力下降和阿尔茨海默病的指标，研究它们之间的关系的研究还很少 在中年，这是预防干预可能最有效的关键时期。此外，这些关系 这些线粒体DNA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。而当 心血管疾病(CVD)的危险因素也与线粒体DNA的改变有关， 人们还没有完全辨别出它们之间的联系。线粒体DNA改变是否可以调节众所周知但不太清楚的 已知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 与中年的认知衰退和AD相关的神经生物学底物有关，并介导 早期心脑血管疾病危险因素与中年脑健康的关系。为了验证这一假设，我们将利用生命- Bogalusa心力衰竭患者心血管疾病危险因素的长期测量和认知功能的两种中年测量 研究(BHS)队列(N=1,298；850名白人和448名黑人)，以及与AD相关的神经生物学底物 来自脑磁共振成像(MRI)和光子发射断层扫描(PET)扫描，可在 中年大样本(N=700)。在BHS内部，我们进一步建议在以下位置测量mtDNA改变 两个中年时点。我们强大的验证工作将在不同的参与者中进行， TRANS-OMICS for Precision Medicine计划(N=3,724)与现有数据。这些资源将使我们能够 研究线粒体DNA改变与认知功能下降的前瞻性和时间性关联(目标1)和 中年的神经生物学基础(目标2)；以及评估早期生活的前瞻性和时间性联系 心血管疾病危险因素与线粒体DNA的关系及线粒体DNA在儿童心血管疾病风险关联中的中介作用 影响中年大脑健康的因素(目标3)。我们的工作可能会对全人口和有针对性的 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，考察中年线粒体DNA与认知能力下降之间的关系。指导者 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老化多组学研究方面的职业独立。

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.