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

项目摘要/摘要 阿尔茨海默病(AD)是一种慢性致残疾病，是美国第六大致死原因，也是一种 造成个人、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 潜在的老年痴呆症和认知障碍仍然不完全，这种知识差距阻碍了 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)很常见，特别是在少数族裔群体中，并被认为是日益严重的痴呆症 风险。因为这些因素可以通过治疗和生活方式来改变，所以研究将血管 阿尔茨海默病/阿尔茨海默病相关痴呆的因素(AD/ADRD)比 永远不会。新出现的数据表明，表观基因组可能在这种联系中发挥了作用，并提出了新的研究方法 表观基因组现已问世。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和血液中循环中无细胞DNA(CfDNA)的全基因组变化 组织中的基因组DNA(GDNA)。我们小组开发了一种高度敏感和选择性的分析方法 捕获含有5hmC的DNA片段并对其进行测序，以绘制全基因组分布图，以及 已经成功地使用这种方法开发了5hmC评分，以区分患有和 没有不同的条件，包括最近对AD和DM的研究。为了应对……的迫切需要 为了更好地了解AD/ADRD的病理生物学基础，我们提议与 阐明血管危险因素与AD/ADRD临床和临床相关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 生物标本(例如，冰冻的脑组织样本)。在白人和黑人中，我们将收集新的 全基因组5hmC数据以生成特定于血清的5hmC评分(目标1和4)和特定于大脑的5hmC得分(目标2 以及4)在不同人群中使用发现和验证实验，这区分了 痴呆症患者和非痴呆症患者。然后我们将把血液和脑5HmC数据与AD/ADRD临床和 病理表型，包括偶发痴呆症和认知能力下降(目标1和4)，脑血管和 AD病理学(目标2)。我们将进一步检查血管危险因素(DM、血液)是否区分关系 压力[BP]和身体质量指数[BMI])和其他因素(例如，性别；目标1-4)，如果可以概括为 黑人(目标4)。由于血管风险因素是常见的和可改变的，这项研究将 阐明5HmC在AD/ADRD和白人和黑人老年人血管疾病中的作用机制 填补痴呆症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的护理和预防。

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.