Glucose homeostasis and the risk of Alzheimer's disease and Alzheimer's disease related dementias in the Multi-Ethnic Study of Atherosclerosis

项目总结 阿尔茨海默病和阿尔茨海默病相关的痴呆症构成了巨大的公共卫生挑战。在……里面 缺乏治愈、预防或延迟病理提供了最有希望的途径来控制 疾病。尽管越来越多的人认识到心脏代谢风险因素是认知能力的主要贡献者 下降，阿尔茨海默氏症，以及阿尔茨海默病相关的痴呆，在我们的 了解葡萄糖稳态和认知功能之间的机制和途径。而当 2型糖尿病(T2D)越来越被认为是阿尔茨海默病的主要可预防危险因素， 与痴呆症相关，在试验中，T2D强化血糖控制并不能防止认知能力下降。 这一发现和关于血糖控制(HbA1c)对认知能力下降的影响的不一致结果表明 问：哪些方面的血糖紊乱及其反向的血糖稳态会增加患糖尿病的风险？ 阿尔茨海默病或相关痴呆症？这项研究的总体目标是调查血糖异常的作用 跨血糖谱对阿尔茨海默病和阿尔茨海默病相关神经认知标记物的影响 多民族队列中的疾病相关痴呆：动脉粥样硬化的多民族研究(MESA)。台地 从2000年开始招收6814名男性和女性。对MESA参与者进行了广泛的研究 考虑到心血管风险因素和结果，以及认知辅助因素MESA-Mind，补充道 全面的认知测试和神经成像，包括脑部核磁共振和淀粉样蛋白β正电子发射计算机断层扫描。梅萨有 第七次考试将在2021-2023年间举行，这将与第二次MESA-Mind访问相一致。而当 在每次检查中获得空腹血糖，并在某些检查中连续测量HbA1C和HOMA-IR 还没有测量到葡萄糖。MESA考试增加连续血糖监测可穿戴技术 7并在两年后重复提供了一个独特而及时的机会来回答关于以下问题的挑战性问题 继续阻碍制定成功的预防策略的血糖异常的作用 阿尔茨海默病和阿尔茨海默病相关的痴呆。这项研究还将增加新的测量方法 胰岛素抵抗(HOMA-IR)。MESA的这个辅助机构将1)调查以下因素的前置决定因素 血糖稳态(来自检查7(n=2000)的连续血糖监测仪)和两年内的变化 (n=1000)，2.确定糖稳态、血糖紊乱和 随时间的变化与阿尔茨海默病或阿尔茨海默病的意外神经认知指标相关 与疾病相关的痴呆(n=2000)，以及3.调查血糖异常对阿尔茨海默病的影响 按性别和种族/族裔分列的疾病和相关痴呆症病理学(n=2000)。这项研究的发现将 确定阿尔茨海默病和阿尔茨海默病相关发展的新机制 痴呆症，发现新的一级和二级预防目标，并有可能改变临床 关心。

PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease related dementias pose an enormous public health challenge. In the absence of a cure, prevention or delay of pathology offers the most promising avenue to control the disease. Despite growing recognition that cardiometabolic risk factors are major contributors to cognitive decline, Alzheimer’s disease, and Alzheimer’s disease related dementias, many gaps remain in our understanding of the mechanisms and pathways between glucose homeostasis and cognitive function. While type 2 diabetes (T2D) is increasingly recognized as a major preventable risk factor for Alzheimer’s disease and related dementias, intensive glucose control in T2D has not been shown to prevent cognitive decline in trials. This finding and inconsistent results for the influence of glucose control (HbA1c) on cognitive decline pose the question: What aspects of dysglycemia, and its inverse glucose homeostasis, increase the risk of Alzheimer’s disease or related dementias? This study’s overall goal is to investigate the role of dysglycemia across the glucose spectrum on incident neurocognitive markers of Alzheimer’s disease and Alzheimer’s disease related dementias in a multi-ethnic cohort: The Multi-Ethnic Study of Atherosclerosis (MESA). MESA enrolled 6814 men and women beginning in 2000. MESA participants have been extensively studied with respect to cardiovascular risk factors and outcomes and MESA-MIND, a cognitive ancillary, adds comprehensive cognitive testing and neuroimaging including brain MRI and amyloid β PET scans. MESA has a 7th exam occurring between 2021-2023 that will be concordant with the second MESA-MIND visit. While fasting glucose was obtained at every exam, and HbA1C and HOMA-IR measured at some exams, continuous glucose has not been measured. Adding continuous glucose monitoring wearable technology to MESA Exam 7 and repeated two years later provides a unique and timely opportunity to answer challenging questions about the role of dysglycemia that continue to impede the development of successful prevention strategies for Alzheimer’s disease and Alzheimer’s disease related dementias. This study will also add new measurements of insulin resistance (HOMA-IR). This ancillary to MESA will 1) Investigate the antecedent determinants of glucose homeostasis (from continuous glucose monitors at Exam 7 (n=2000) and change over two years (n=1000), 2. Determine whether continuous glucose markers of glucose homeostasis, dysglycemia, and change over time are associated with incident neurocognitive indicators of Alzheimer’s disease or Alzheimer’s disease related dementias (n=2000), and 3. Investigate the contributions of dysglycemia to Alzheimer’s disease and related dementia pathologies by sex and race/ethnicity (n=2000). Findings from this research will identify new mechanisms for the development of Alzheimer’s disease and Alzheimer’s disease related dementias, discover new primary and secondary prevention targets, and have the potential to change clinical care.