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

项目总结/摘要 阿尔茨海默病（AD）是一种慢性和致残性疾病，是美国第六大死亡原因， 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 老年痴呆症和认知障碍的基础仍然不完整，这种知识的差距阻碍了 科学进步和改善临床护理和预防。糖尿病等血管疾病 糖尿病（DM）是常见的，特别是在少数民族群体中，并被认为是增加痴呆症 风险由于这些因素可以通过治疗和生活方式来改变， 阿尔茨海默病/阿尔茨海默病相关痴呆（AD/ADRD）的因素比 史以来新出现的数据表明，表观基因组可能在这一联系中发挥作用， 表观基因组现在是可用的。5-羟甲基胞嘧啶（5 hmC）是胞嘧啶的表观遗传修饰 我们现在可以测量血液中循环无细胞DNA（cfDNA）的全基因组变化， 基因组DNA（gDNA）。我们的团队开发了一种高度敏感和选择性的分析方法 捕获并测序含5 hmC的DNA片段，以绘制全基因组分布图，以及 已经成功地使用这种方法来开发5 hmC评分，该评分可以区分患有和 在没有不同条件的情况下，包括最近的AD和DM研究。为了满足迫切需要， 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 总体目标是阐明将血管危险因素与AD/ADRD临床和临床表现联系起来的表观遗传机制， 病理表型，在老年白人和黑人。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，包括采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，冷冻脑组织样品）。在白色和黑色的人，我们将收集新的 全基因组5 hmC数据，以生成血清特异性（目的1和4）和脑特异性5 hmC评分（目的2 和4），使用不同人群的发现和验证实验，区分 患有和不患有痴呆症的人。然后，我们将血液和脑5 hmC数据与AD/ADRD临床和 病理表型，包括偶发性痴呆和认知下降（目的1和4），脑血管和 AD病理学（目的2）。我们将进一步检查是否有血管危险因素（糖尿病，血液）的差异 血压[BP]和体重指数[BMI]）和其他因素（例如，性别;目标1 -4），如果可推广到 黑人（目标4）。由于血管危险因素是常见的和可改变的，这项研究将 阐明白色和黑人老年人中AD/ADRD和血管疾病的5 hmC机制，将 填补了关于痴呆症的科学知识的重大空白，并为未来的研究提供了重要数据。 并最终改善痴呆症的临床护理和预防。

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.