Alzheimer's Disease and Alzheimer's Disease Related Dementias in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Outcomes Study AD/ADRD Project

这个U19提案关注的是阿尔茨海默病（AD）中最重要、最复杂的问题之一， 阿尔茨海默病相关痴呆（ADRD）研究：认知功能障碍的决定因素和性质是什么？ 糖尿病前期（PreD）和2型糖尿病（T2 D）患者是糖尿病的高危人群， 认知障碍，并代表美国（US）人口的很大一部分？尽管知道 PreD和T2 D患者是认知能力下降、轻度认知障碍（MCI）的高危人群， 痴呆，危险因素，机制和神经病理学的认知功能障碍的人与前D和 T2 D仍不清楚。关于PreD和T2 D认知障碍的知识差距包括：（a）AD的作用 和/或血管对认知障碍和痴呆（VCID）的贡献以外的非AD神经病理学;（B） 胰岛素、相关代谢因素如高胰岛素血症和传统的微血管和大血管 PreD/T2 D的并发症;（c）降糖药物的作用，主要是二甲双胍;和（d） 身体活动、身体功能和虚弱，是PreD和T2 D的关键。我们提出4个相互关联的项目， 利用糖尿病预防计划（DPP）结局研究（DPPOS）队列， 其详细的PreD/T2 D表型，添加最新的AD/ADRD表型。DPPOS队列目前 平均年龄为72岁，其中76%的人年龄在65岁以上。因此，该群体处于生命周期的一段时间， 认知能力下降、MCI和痴呆的发展加速。这个广泛表型化的队列 代表着大约五千万美国人为了解决这一提案中复杂的相互关联的问题，我们 将在拟议的5年资助期内进行两波最先进的AD/ADRD表型分析， 包括全面的认知评估和综合征裁定以及血浆和脑成像 AD/ADRD的生物标志物。我们将通过以下方式来解决我们项目的复杂的首要问题 目的：（1）建立5个核心，以支持4个综合科学项目：行政核心，临床核心， 操作和程序核心，认知评估和裁定核心，神经成像和血浆 生物标志物核心，以及生物统计学和数据基础设施核心：（2）进行4个综合项目，重点是 关于这个建议的中心问题的关键方面：项目1将研究认知能力下降， DPPOS队列中MCI和痴呆与神经病理学和脑胰岛素信号传导的生物标志物，以及 社会人口统计学和行为因素;项目2将研究累积性肥胖，相关 代谢因素，微血管和大血管并发症，认知综合征， 神经病理学生物标志物;项目3将检查二甲双胍累积暴露与 其他具有认知综合征和神经病理学生物标志物的T2 D药物;项目4将评估 身体活动轨迹、身体功能和虚弱与认知综合征的关联， 神经病理学的生物标志物。

This U19 proposal focuses on one of the most important, complex questions in Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (ADRD) research: What are the determinants and the nature of cognitive impairment among persons with pre-diabetes (PreD) and type 2 diabetes (T2D), who are a high-risk group for cognitive impairment and represent a large fraction of the United States (US) population? Despite knowledge that persons with PreD and T2D are a high-risk group for cognitive decline, mild cognitive impairment (MCI), and dementia, the risk factors, mechanisms, and neuropathology of cognitive impairment in persons with PreD and T2D remain unclear. Gaps in knowledge on cognitive impairment in PreD and T2D include: (a) the role of AD and/or non-AD neuropathology beyond vascular contributions to cognitive impairment and dementia (VCID); (b) the role of glycemia, related metabolic factors such as hyperinsulinemia, and traditional micro and macrovascular complications of PreD/T2D; (c) the role of glucose-lowering medications, primarily metformin; and (d) the role of physical activity, physical function, and frailty, key in PreD and T2D. We propose 4 interrelated projects that will address these gaps, leveraging the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS) cohort and its detailed PreD/T2D phenotyping, adding state of the art AD/ADRD phenotyping. The DPPOS cohort currently has a mean age of 72 years, with 76% over the age of 65. Thus, the cohort is in a period of the lifespan when the development of cognitive decline, MCI, and dementia accelerates. This extensively phenotyped cohort represents an estimated 50 million Americans. To address this proposal’s complex interrelated questions, we will perform two waves of state-of-the-art AD/ADRD phenotyping during the proposed 5-year funding period, including comprehensive cognitive assessments and syndrome adjudication and plasma and brain imaging biomarkers of AD/ADRD. We will address the complex overarching question of our project through the following aims: (1) To establish 5 cores to support the 4 integrated scientific projects: An Administrative Core, a Clinical Operations and Procedures Core, a Cognitive Assessment and Adjudication Core, a Neuroimaging and Plasma Biomarkers Core, and A Biostatistics and Data Infrastructure Core: (2) To conduct 4 integrated projects focused on key aspects of the central question of this proposal: Project 1 will examine the association of cognitive decline, MCI, and dementia in the DPPOS cohort with biomarkers of neuropathology and brain insulin signaling, and with sociodemographic and behavioral factors; Project 2 will examine the associations of cumulative glycemia, related metabolic factors, and microvascular and macrovascular complications, with cognitive syndromes and biomarkers of neuropathology; Project 3 will examine the association of cumulative exposure to metformin and other T2D medications with cognitive syndromes and biomarkers of neuropathology; Project 4 will evaluate the association of trajectories of physical activity, physical function and frailty with cognitive syndromes and biomarkers of neuropathology.