Plasma Amyloid-Beta, Insulin, and Cognitive Decline

描述(由申请人提供)：大脑中淀粉样β蛋白(Abeta)的积聚是阿尔茨海默病(AD)的一个病理标志，可能在其发病机制中发挥重要作用。研究集中在AA操纵作为一种减少或治疗AD的机制上，但由于缺乏一种简单的方法来早期识别AD的高危人群，这些结果的临床应用受到限制；在某些情况下已经测量了脑脊液中的Abeta水平，但对于广泛的临床应用是不切实际的。Abeta存在于循环血浆中，这一建议的一个中心目的是通过探讨血浆Abeta与认知功能下降的关系来研究血浆Abeta作为AD风险的早期指标的价值。认知衰退是AD发展的早期阶段。这一建议的另一个目的是探索胰岛素在认知衰退中的作用，以及它与Abeta的相互作用；最近的研究证实，胰岛素在体外和体内调节Abeta的水平，然而，很少有人研究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。这项建议代表了基础科学家和流行病学家之间的合作，以在男性和女性中测试关于非糖尿病患者的血浆Abeta水平、胰岛素水平和胰岛素分泌(以c-肽衡量)以及他们预测认知能力下降的能力的新假设。 这项调查将在护士健康研究和医生健康研究II中进行，护士健康研究包括目前70-81岁的女性，自1976年以来一直跟踪；医生健康研究II包括65岁及以上的男性，自1982年以来一直跟踪。我们将从每个队列中选择2000名受试者，这些受试者在10年内的两个时间点收集了储存的血浆样本，并接受了一系列认知功能测试(3次电话重复采访，每隔1.5年进行一次)。测试电池测量一般认知状态、言语记忆、执行功能、处理速度和工作记忆；与面对面评估相比，我们对电话方法的有效性和可靠性进行了广泛的演示，并先前发现与许多既定的下降风险因素有很强的联系。因此，这两个已建立的群体提供了一个高成本效益的环境，在其中检查早期认知衰退的生物标记物，以及性别和遗传交互作用。

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.