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.

项目摘要/摘要阿尔茨海默氏病（AD）是一种慢性和残疾状况，美国第六个主要死亡原因，一个个人，社会和全球负担的主要原因。然而，我们对病原体机制的理解衰老中的潜在痴呆症和认知障碍仍然不完整，而知识的差距阻碍了科学进步，改善了临床护理和预防。糖尿病等血管状况 Mellitus（DM）很常见，尤其是在少数种族群体中，被认为痴呆症增加风险。由于这些因素可以通过治疗和生活方式方法进行修改，因此可以研究血管阿尔茨海默氏病/阿尔茨海默氏病有关的因素，与痴呆相关的痴呆症（AD/ ADRD）比曾经。新兴的数据表明，表观基因组可能在此链接中起作用，以及研究的新方法现在可以使用表观基因组。 5-羟基甲基胞嘧啶（5HMC）是胞嘧啶的表观遗传修饰现在，我们可以测量血液中无细胞DNA（CFDNA）的全基因组变化组织中的基因组DNA（GDNA）。我们的小组开发了一种高度敏感和选择性的分析方法捕获和序列5HMC的DNA片段以绘制全基因组分布，并且成功地使用了这种方法来开发5HMC分数，以区分患者和没有不同的条件，包括最近对AD和DM的研究。响应紧迫的需要更好地了解AD/ADRD的病理生物学基础，我们建议与阐明将血管危险因素与AD/ADRD临床和ADRD临床和拟议的研究将利用可用资源来自两项基于社区的队列研究，包括从中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亡后神经病理学数据，以及生物测量（例如，冷冻的脑组织样品）。在白人和黑人中，我们将收集新的全基因组5HMC数据生成血清特异性（目标1和4）和脑特异性5HMC分数（AIMS 2 4），使用在不同人组中的发现和验证实验，可以区分患有和没有痴呆症的人。然后，我们将将血液和脑5HMC数据与AD/ADRD临床联系起来病理表型，包括入射痴呆和认知能力下降（目标1和4），脑血管和 AD病理学（AIM 2）。我们将进一步检查是否因血管危险因素而差异（DM，血液）压力[BP]和体重指数[BMI]）和其他因素（例如性别； AIMS1-4），如果可以推广到黑人（目标4）。因为血管危险因素是常见和可修改的，所以这项研究将在白人和黑人老年人中阐明AD/ADRD和血管疾病中的5HMC机制，将填补有关痴呆的科学知识的主要空白，并提供重要数据以告知未来的研究并最终改善临床痴呆症护理和预防。