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

这份U19提案关注阿尔茨海默病(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：认知的决定因素和性质是什么 糖尿病前期(PRED)和2型糖尿病(T2D)患者的损害，他们是糖尿病的高危人群 认知障碍并占美国人口的很大一部分？尽管知道 患有PRED和T2D的人是认知能力下降、轻度认知障碍(MCI)的高危人群，以及 痴呆、认知功能障碍的危险因素、机制和神经病理学 T2D仍不清楚。PRED和T2D对认知障碍的认识差距包括：(A)AD的作用 和/或血管以外的非阿尔茨海默病神经病理对认知障碍和痴呆(VCID)的贡献；(B) 血糖、相关代谢因素，如高胰岛素血症，以及传统微血管和大血管的作用 PRED/T2D的并发症；(C)降糖药物，主要是二甲双胍的作用；和(D) 身体活动、身体机能和身体虚弱是PRED和T2D的关键。我们提出了4个相互关联的项目，将 利用糖尿病预防计划(DPP)结果研究(DPPOS)队列和 其详细的PRED/T2D表型，增加了最先进的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，这群人处于寿命的一段时间 认知功能减退、MCI和痴呆症的发展速度加快。这一广泛的表型队列 代表了大约5000万美国人。为了解决这项提案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证候判定以及血浆和脑成像 AD/ADRD的生物标志物。我们将通过以下几点来解决我们项目的复杂的首要问题 目标：(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、认知评估和裁决核心、神经成像和血浆 生物标记物核心，以及生物统计和数据基础设施核心：(2)开展4个重点综合项目 关于这项提案的核心问题的关键方面：项目1将审查认知衰退的关联， 在DPPOS队列中，MCI和痴呆症与神经病理学和脑胰岛素信号转导的生物标记物以及与 社会人口学和行为因素；项目2将检查累积血糖、相关 代谢因素，微血管和大血管并发症，认知综合征和 神经病理的生物标记物；项目3将检查累积接触二甲双胍和 其他具有认知综合征和神经病理生物标记物的T2D药物；项目4将评估 体力活动、身体机能和虚弱的运动轨迹与认知综合征的关系 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.