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

项目摘要 阿尔茨海默氏病和阿尔茨海默氏病相关的痴呆症构成了巨大的公共卫生挑战。在 缺乏治愈、预防或延迟病理的方法，为控制疾病提供了最有希望的途径。 疾病尽管越来越多的人认识到心脏代谢危险因素是认知功能障碍的主要因素， 老年痴呆症和老年痴呆症相关的痴呆症，在我们的研究中仍然存在许多空白。 了解葡萄糖稳态和认知功能之间的机制和途径。而 2型糖尿病（T2 D）越来越被认为是阿尔茨海默病的主要可预防风险因素， 尽管T2 D与痴呆相关，但在试验中，T2 D的强化血糖控制并未显示出可预防认知能力下降。 这一发现以及血糖控制（HbA 1c）对认知能力下降影响的不一致结果， 问题：代谢障碍的哪些方面及其逆葡萄糖稳态增加了 阿尔茨海默病或相关痴呆症？这项研究的总体目标是调查精神障碍在 在血糖谱中对阿尔茨海默病和阿尔茨海默病的神经认知标志物的影响 多种族队列中的疾病相关痴呆：动脉粥样硬化的多种族研究（梅萨）。梅萨 从2000年开始招收了6 814名男女学生。梅萨参与者已经被广泛研究， 关于心血管风险因素和结果，MESA-MIND，一种认知辅助工具， 全面的认知测试和神经成像，包括大脑MRI和淀粉样蛋白β PET扫描。梅萨具有 2021年至2023年之间的第七次检查将与第二次MESA-MIND访问一致。而 在每次检查时获得空腹血糖，在某些检查时测量HbA 1C和HOMA-IR，连续 葡萄糖未被测量。将动态血糖监测可穿戴技术添加到梅萨Exam 7并在两年后重复提供了一个独特而及时的机会来回答有关 继续阻碍制定成功的预防战略， 阿尔茨海默病和阿尔茨海默病相关痴呆。这项研究还将增加新的测量 胰岛素抵抗（HOMA-IR）。这对梅萨的辅助将1）调查 葡萄糖稳态（来自检查7（n=2000）时的连续葡萄糖监测仪）和两年的变化 （n=1000），2.确定血糖稳态、代谢紊乱和 随着时间的变化与阿尔茨海默病或阿尔茨海默病的神经认知指标有关 疾病相关性痴呆（n=2000），和3.研究精神障碍对阿尔茨海默氏症的影响 按性别和种族/民族列出的疾病和相关痴呆病理（n=2000）。这项研究的结果将 确定阿尔茨海默病和阿尔茨海默病相关疾病发展的新机制 痴呆症，发现新的一级和二级预防目标，并有可能改变临床 在乎

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.