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The role of blood and brain 5-hydroxymethylcytosine in linking vascular risk factors to ADRD in older White and Black persons

血液和脑 5-羟甲基胞嘧啶在老年白人和黑人血管危险因素与 ADRD 之间的联系中的作用

基本信息

批准号：
10315659
负责人：
Zoe Arvanitakis
金额：
$ 327.52万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ ABSTRACT Alzheimer’s Disease (AD) is a chronic and disabling condition, the 6th leading cause of death in the US, and a major cause of personal, societal, and global burden. Yet, our understanding of pathobiologic mechanisms underlying dementia and cognitive impairment in aging remains incomplete, and this gap in knowledge hinders scientific advancement and improved clinical care and prevention. Vascular conditions such as diabetes mellitus (DM) are common, especially among minority racial groups, and recognized as increasing dementia risk. Because these factors are modifiable by treatment and lifestyle approaches, research linking vascular factors to Alzheimer’s Disease/ Alzheimer’s Disease-Related Dementias (AD/ADRD) is more important than ever. Emerging data suggests that the epigenome likely plays a role in this link, and novel methods to study the epigenome are now available. 5-hydroxymethylcytosine (5hmC) is an epigenetic modification of cytosine for which we can now measure genome-wide changes in circulating cell-free DNA (cfDNA) in blood and genomic DNA (gDNA) in tissues. Our group has developed a highly sensitive and selective analytic approach to capture and sequence 5hmC-containing DNA fragments in order to map genome-wide distributions, and have successfully used this approach to develop 5hmC scores which distinguish between patients with and without different conditions, including in recent studies of AD and DM. In response to the pressing need to better understand the pathobiologic underpinnings of AD/ADRD, we propose a collaborative project with the overall goal of elucidating epigenetic mechanisms linking vascular risk factors to AD/ADRD clinical and pathological phenotypes, in older Whites and Blacks. The proposed study will leverage available resources from two community-based cohort studies, including research participants from which to collect blood specimens, as well as extensive longitudinal clinical data and postmortem neuropathologic data, and biospecimens (e.g., frozen brain tissue samples). Among White and Black persons, we will collect new genome-wide 5hmC data to generate serum-specific (Aims 1 and 4) and brain-specific 5hmC scores (Aims 2 and 4), using discovery and validation experiments in different sets of persons, that distinguishes between persons with and without dementia. We will then link the blood and brain 5hmC data to AD/ADRD clinical and pathologic phenotypes, including incident dementia and cognitive decline (Aims 1 and 4), cerebrovascular and AD pathology (Aim 2). We will further examine if relations are differential by vascular risk factors (DM, blood pressure [BP], and body mass index [BMI]) and by other factors (e.g., sex; Aims1-4), and if generalizable to Black persons (Aim 4). Because vascular risk factors are common and modifiable, this study which will elucidate 5hmC mechanisms in AD/ADRD and vascular diseases among White and Black older persons, will fill a major gap in scientific knowledge about dementia and provide important data to inform future research and to ultimately improve clinical dementia care and prevention.

项目概要/摘要阿尔茨海默病 (AD) 是一种慢性致残性疾病，是美国第六大死因，也是个人、社会和全球负担的主要原因。然而，我们对病理生物学机制的理解衰老过程中潜在的痴呆和认知障碍仍然不完整，这种知识差距阻碍了科学进步和改善临床护理和预防。血管疾病，例如糖尿病糖尿病（DM）很常见，尤其是在少数族裔群体中，并被认为是痴呆症的增加风险。由于这些因素可以通过治疗和生活方式来改变，因此研究将血管导致阿尔茨海默病/阿尔茨海默病相关痴呆 (AD/ADRD) 的因素比曾经。新出现的数据表明表观基因组可能在这一联系中发挥着作用，以及新的研究方法表观基因组现已可用。 5-羟甲基胞嘧啶 (5hmC) 是胞嘧啶的表观遗传修饰为此，我们现在可以测量血液中循环游离 DNA (cfDNA) 的全基因组变化，组织中的基因组 DNA (gDNA)。我们的团队开发了一种高度灵敏和选择性的分析方法捕获并测序包含 5hmC 的 DNA 片段，以绘制全基因组分布图，以及已成功地使用这种方法开发了 5hmC 评分，用于区分患有和没有不同的条件，包括最近的 AD 和 DM 研究。为了响应迫切需要为了更好地了解 AD/ADRD 的病理生物学基础，我们提出了一个与阐明将血管危险因素与 AD/ADRD 临床和治疗联系起来的表观遗传机制的总体目标老年白人和黑人的病理表型。拟议的研究将利用现有资源来自两项基于社区的队列研究，包括收集血液的研究参与者标本，以及广泛的纵向临床数据和死后神经病理学数据，以及生物样本（例如冷冻脑组织样本）。在白人和黑人中，我们将收集新的全基因组 5hmC 数据，用于生成血清特异性（目标 1 和 4）和大脑特异性 5hmC 评分（目标 2 4），在不同的人群中进行发现和验证实验，区分患有或未患有痴呆症的人。然后，我们将血液和大脑 5hmC 数据与 AD/ADRD 临床和病理表型，包括痴呆和认知能力下降（目标 1 和 4）、脑血管和 AD 病理学（目标 2）。我们将进一步检查关系是否因血管危险因素（DM、血液压力 [BP] 和体重指数 [BMI]）以及其他因素（例如性别；目标 1-4），并且如果可以概括为黑人（目标 4）。由于血管危险因素很常见且可以改变，因此本研究将阐明白人和黑人老年人 AD/ADRD 和血管疾病中的 5hmC 机制，将填补有关痴呆症的科学知识的重大空白，并为未来的研究提供重要数据并最终改善临床痴呆症护理和预防。