Early Life Cardiovascular Disease Risk Factors, Epigenetic Age Acceleration, and Alzheimer's Disease Related Brain Health

摘要 痴呆症是一个主要的全球健康挑战，阿尔茨海默病（AD）占痴呆症病例的70%。 由于AD没有有效的治疗选择，柳叶刀委员会最近强调了迫切的需要 有效地预防AD的终生发生。表观遗传年龄加速（EAA）或DNA甲基化增加 基于DNA m的年龄相对于实足年龄，被确定为AD相关性的强有力的生物标志物。 老年人的神经生物学基质和认知功能。同样，我们的初步数据 证明了EAA和中年认知功能之间的联系，这是大脑健康的关键时期， 亚临床病理学首先出现，痴呆症的预防可能是最有效的。我们和其他人的作品 还确定了心血管疾病（CVD）风险因素与EAA之间的关联，表明 EAA可以帮助解释早期心脏和中年大脑健康之间的复杂联系。尽管有这些 有趣的数据，儿童期CVD危险因素与成年期EAA之间的前瞻性关联仍然存在， 不建立未知和时间关联。此外，还缺乏研究， EAA与中年认知功能减退及AD相关神经生物学底物的关系。我们 假设EAA与中年认知能力下降和神经生物学底物有关， 介导早期CVD风险因素与这些中年大脑健康终点的关联。为了验证这一 假设，我们将利用博加卢萨心脏研究（BHS）的丰富资源，包括终身 CVD危险因素的测量，成年期全基因组DNAm的三次重复测量，以及中年期的两次重复测量。 对1,298名BHS参与者（850名白人）进行了为期11年的随访， 448名美国人）。此外，来自3 T磁共振成像的中年AD相关神经生物学底物 核磁共振成像（MRI）和淀粉样蛋白光子发射断层扫描（PET）扫描也可在 随机抽取350名BHS参与者。作为持续访视周期（2020-2024）的一部分，我们建议进行MRI检查 在另一个350名BHS参与者的随机子样本中， 50名参与者，沿着在整个BHS队列中进行额外的全基因组DNA m测量。有了这些数据， 我们将评估早期生命CVD危险因素与EAA（目标1）的前瞻性和时间相关性; EAA与认知功能（目标2）和神经生物学底物的11年变化的相关性， 中年（目标3）;并分析EAA对儿童CVD危险因素与 中年脑健康终点（目标4）。中年大脑健康的分子特征可能具有广泛的 影响，从改善风险分层和亚表型的努力，以查明 用于药物开发的分子靶点。确定EAA的CVD危险因素前体可能表明最佳的 预防EAA及其脑相关后遗症的策略。

ABSTRACT Dementia is a major global health challenge, and Alzheimer’s disease (AD) comprises 70% of dementia cases. Because AD has no effective treatment options, the Lancet Commission recently emphasized the critical need for effective, life-course prevention of AD. Epigenetic age acceleration (EAA), or increased DNA methylation (DNAm)-based age relative to chronological age, was identified as a powerful biomarker of AD-related neurobiological substrates and cognitive function in older adults. Likewise, our preliminary data demonstrated associations between EAA and cognitive function in midlife, a critical epoch in brain health when subclinical pathology first emerges, and dementia prevention may be most effective. Works by us and others have also identified associations between cardiovascular disease (CVD) risk factors and EAA, suggesting that EAA could help to explain the intricate link between early life heart and midlife brain health. Despite these intriguing data, prospective associations between childhood CVD risk factors and EAA in adulthood remain unknown and temporal associations are not established. In addition, there is a paucity of research examining the relationships of EAA with midlife cognitive function decline and AD-related neurobiological substrates. We hypothesize that EAA is associated with cognitive decline and neurobiological substrates in midlife and mediates the associations of early life CVD risk factors with these midlife brain health endpoints. To test this hypothesis, we will leverage the rich resources of the Bogalusa Heart Study (BHS), including life-long measures of CVD risk factors, three repeated measures of genome-wide DNAm in adulthood, and two midlife measures of cognitive function over 11-years follow-up in the full cohort of 1,298 BHS participants (850 whites and 448 African Americans). Furthermore, midlife AD-related neurobiological substrates from 3T magnetic resonance imaging (MRI) and amyloid photon emission tomography (PET) scans are also available in a random subsample of 350 BHS participants. As part of the on-going visit cycle (2020-2024), we propose MRI in another random subsample of 350 BHS participants, amyloid PET scans in another random subsample of 50 participants, along with an additional genome-wide DNAm measure in the full BHS cohort. With these data, we will assess prospective and temporal associations of early life CVD risk factors with EAA (Aim 1); examine the associations of EAA with 11-year changes in cognitive function (Aim 2) and neurobiological substrates in midlife (Aim 3); and analyze the mediating effects of EAA on associations of childhood CVD risk factors with midlife brain health endpoints (Aim 4). The molecular characterization of midlife brain health may have broad implications, ranging from the improvement of risk stratification and sub-phenotyping efforts to the pinpointing of molecular targets for drug development. Identifying CVD risk factor precursors to EAA might suggest optimal strategies to prevent EAA and its brain-related sequelae.