Plasma Amyloid-Beta, Insulin, and Cognitive Decline

描述（由申请人提供）：大脑中β淀粉样蛋白（Abeta）的积累是阿尔茨海默病（AD）的病理标志，可能在其发病机制中起着重要作用。研究主要集中在Aa操纵作为一种减少或治疗AD的机制，但由于缺乏一种简单的方法来早期识别AD高危人群，研究结果的临床实用性受到限制；脑脊液中的β水平在某些情况下已经测量过，但对于广泛的临床应用来说是不切实际的。Abeta出现在循环血浆中，本研究的中心目的是通过探索其与认知能力下降（AD发展的早期阶段）的关系来研究血浆Abeta作为AD风险的早期指标的价值。这项提议的另一个目的是探索胰岛素在认知能力下降中的功能，以及它与β的相互作用；最近的研究已经证实胰岛素在体内和体外都能调节β的水平，然而，很少有研究检查胰岛素对认知的长期影响，或者在人群亚群中不同影响的可能性。这一建议代表了基础科学家和流行病学家之间的合作，以测试关于非糖尿病患者血浆β水平、胰岛素水平和胰岛素分泌（通过c肽测量）及其预测认知能力发展的新假设。

DESCRIPTION (provided by applicant): Cerebral accumulation of amyloid beta (Abeta) protein is a pathological hallmark of Alzheimer disease (AD), and likely plays a fundamental role in its pathogenesis. Research has focused on Aa manipulation as a mechanism for reducing or treating AD, but the clinical utility of findings is limited by lack of a simple way to identify early those at high risk of AD; Abeta levels in the CSF have been measured in some settings, but are impractical for widespread clinical applications. Abeta appears in circulating plasma, and a central aim of this proposal is to investigate the value of plasma Abeta as an early indication of AD risk by exploring its relation to cognitive decline, an early stage in the path of AD development. An additional aim of this proposal is to explore the function of insulin in cognitive decline, and its interaction with Abeta; irecent research has established that insulin modulates levels of Abeta in vitro and in vivo, however, little work has examined the long-term effects of insulin on cognition, or the possibility of different effects in subgroups of the population. This proposal represents a collaboration between basic scientists and epidemologists to test novel hypotheses in men and women regarding plasma Abeta levels, insulin levels, and insulin secretion (as measured by c-peptide) in non-diabetics and their ability to predict development of cognitive decline. The investigation will be conducted within the Nurses' Health Study, including women currently aged 70- 81 years and followed since 1976, and the Physician's Health Study II including men aged 65 years and older and followed since 1982. From each cohort, we will select 2,000 subjects with stored plasma samples collected at two points over 10 years, and with serial tests of cognitive function (3 repeated interviews by telephone, at 1.5-year intervals). The test battery measures general cognitive status, verbal memory, executive function, speed of processing, and working memory; we have conducted extensive demonstrations of the validity and reliability of the telephone method compared to in-person assessments, and have previously detected strong relations with numerous established risk factors for decline. Thus, these two established populations provide a highly cost-efficient setting in which to examine biomarkers of early cognitive decline, and gender and genetic interactions.