Use of High Density Lipoprotein Proteome in the Prediction of Cognitive Impairment and Alzheimer's Disease: (REGARDS)

项目摘要 阿尔茨海默病（AD）是一种进行性神经退行性疾病， 65岁或以上。慢性炎症是AD影响的大脑中存在的病理学的中心特征。 对神经变性的炎症反应增加了活性氧的产生， 细胞因子、粘附分子、补体蛋白和降解蛋白的细胞活化， 小胶质细胞和星形胶质细胞，以及β淀粉样蛋白的产生。补体C1 q是淀粉样蛋白B所必需的 小鼠模型中的突触毒性。在诊断为认知功能正常的个体的脑脊液中， APOE 4基因型与AD、轻度认知功能障碍、脑脊液 补体3、β淀粉样蛋白和过度磷酸化的tau（ptau）。C3和tau之间的关联是 仅在调整淀粉样蛋白后才显著。这些数据表明，补体级联和APOE 4 导致AD神经变性升高，淀粉样蛋白调节补体级联反应对AD神经变性的影响。 下游tau病理学。来自遗传、临床和实验研究的新证据支持 高密度脂蛋白（HDL）成分参与炎症、认知功能和进展 到AD。认知障碍（CI）与HDL蛋白apoA-I、apoA-II水平降低有关 以及apoH和更高水平的apoE和apoJ（clusterin）。20多个与HDL代谢相关的位点 导致AD的风险，包括clusterin的变体。这项研究旨在确定 （1）高密度脂蛋白（HDL）蛋白质组和（2）单核苷酸多态性（SNP）之间的关系 在非裔美国人和白色成年人中，与HDL和炎症蛋白相关的CI和AD。本研究 将从一项经验证的AD病例的全基因组关联研究中进行， 和中风的种族差异（REGARDS）研究参与者。

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that afflicts 5.1 million Americans aged 65 or older. Chronic inflammation is a central feature of the pathology present in AD-affected brains. Inflammatory responses to neurodegeneration increase production of reactive oxygen species, and expression of cytokines, adhesion molecules, complement proteins, and degradative proteins, cellular activation of microglia and astrocytes, and production of beta amyloid. Complement C1q is necessary for amyloid-B synaptoxicity in murine models. In the cerebrospinal fluid of individuals diagnosed with normal cognitive function, mild cognitive impairment and AD, APOE4 genotype was associated with cerebrospinal fluid complement 3, amyloid – beta and hyperphosphorylated tau (ptau). The association between C3 and tau was significant only after adjustment for amyloid. These data suggest that the complement cascade and APOE4 results in elevated AD neurodegeneration and that amyloid regulates the effect of the complement cascade on downstream tau pathology. Emerging evidence from genetic, clinical and experimental studies support the involvement of high-density lipoprotein (HDL) constituents in inflammation, cognitive function and progression to AD. Cognitive impairment (CI) has been associated with lower levels of the HDL proteins apoA-I, apoA-II and apoH and higher levels of apoE and apoJ (clusterin). More than 20 loci associated with HDL metabolism contribute to the risk of AD including variants in clusterin. This study is designed to determine the association between (1) the high-density lipoprotein (HDL) proteome and (2) single nucleotide polymorphisms (SNPs) related with HDL and inflammatory proteins with CI and AD in African-American and white adults. This study will be conducted from a genome wide association study of validated cases of AD in REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants.