Association of cumulative exposure to metformin and other T2D medications with cognitive impairment and AD/ADRD biomarkers

项目3的目标是检查累积暴露于2型糖尿病（T2 D）药物的相关性， 主要是二甲双胍，伴有认知障碍及其在糖尿病预防中的潜在神经病理学 项目（DPP）结局研究（DPPOS）队列。2型糖尿病药物的再利用，尤其是胰岛素 增敏药物，已被提出用于治疗和预防阿尔茨海默病（AD）。 二甲双胍是一线治疗和最广泛使用的T2 D药物，但关于 二甲双胍对AD和认知障碍风险是否有益、有害或无效。的 DPP/DPPOS提供了随机分配的二甲双胍，现在包括超过20年的累积数据， 二甲双胍暴露。它提供了一个独特的机会，检查二甲双胍与认知功能障碍之间的关系。 损伤和相关神经病理学。GLP 1a、DPP 4 i和SGLT 2 i最近使用较多， 与二甲双胍相比，在DPPOS中经常发生，可以在探索性基础上进行检查。我们现建议 以确定所有DPPOS参与者中的痴呆和MCI。我们将检查淀粉样蛋白（A β 42/40比率）、tau（ptau-1）、 181）、神经变性（神经丝光[NfL]）和神经炎症（胶质纤维酸性蛋白 [GFAP]）。在650名参与者中，我们将用18F-Florbetaben确定脑淀粉样蛋白 正电子发射断层扫描（PET）;使用脑磁共振成像（MRI），我们将确定萎缩 （皮质厚度）和脑血管疾病（CVD），并探索微出血，白色物质显微结构， 和静息功能连接。我们将认知综合征分为AD连续体和非AD 根据国家老龄化研究所（NIA）/阿尔茨海默氏症协会（AA）的研究框架， 在所有参与者中主要是PTU-181。我们将探讨tau蛋白、神经变性和血管变性的分类。 认知障碍和痴呆（VCID）。我们将使用统计方法来确保 研究结果不受T2 D药物使用倾向的混淆。我们将通过以下方式实现我们的目标： 以下目的：（1）研究二甲双胍累积暴露与遗忘和非遗忘的关系， 遗忘性认知功能减退、MCI和痴呆;（2）检查二甲双胍累积与 在650名参与者中进行脑成像，以暴露于脑淀粉样蛋白、神经变性和CVD;（3） 检查二甲双胍累积暴露与淀粉样蛋白血浆生物标志物轨迹的相关性， tau、神经变性和神经炎症。我们还将探讨：其他T2 D药物暴露; 二甲双胍相关钴胺素缺乏症与认知功能障碍;神经元胰岛素信号传导作为认知功能障碍的一种 结果：糖尿病，晚期糖基化终产物，胰岛素血症，外周炎症，内皮功能， 血管风险因素和神经保护因素作为介质; T2 D药物的总暴露量， 身体活动;调节目标1-3中的关联的基因组特征;性别的影响修饰， 种族/人种、认知储备和APOE-ε4。

The goal of Project 3 is to examine the association of cumulative exposure to type 2 diabetes (T2D) medications, primarily metformin, with cognitive impairment and its underlying neuropathology in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS) cohort. Repurposing of T2D medications, particularly insulin sensitizing medications, has been proposed for the treatment and prevention of Alzheimer’s disease (AD). Metformin is the first line treatment and the most widely used T2D medication, but there are conflicting data on whether metformin is beneficial, harmful, or has no effects on AD and risk of cognitive impairment. The DPP/DPPOS provided randomly assigned metformin and now includes over 20 years of data on cumulative metformin exposure. It provides a unique opportunity to examine the association of metformin with cognitive impairment and related neuropathology. GLP1a, DPP4i, and SGLT2i have been used more recently and less frequently in DPPOS compared with metformin and can be examined on an exploratory basis. We now propose to ascertain dementia and MCI in all DPPOS participants. We will examine amyloid (Aß42/40 ratio), tau (ptau- 181), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (Glial Fibrillary Acidic Protein [GFAP]) in plasma in all participants. In 650 participants we will ascertain brain amyloid with 18F-Florbetaben Positron Emission Tomography (PET); using brain magnetic resonance imaging (MRI), we will ascertain atrophy (cortical thickness), and cerebrovascular disease (CVD), and explore microbleeds, white matter microstructure, and resting functional connectivity. We will classify the cognitive syndromes as AD continuum or non-AD pathology following the National Institute on Aging (NIA)/Alzheimer’s Association (AA) research framework using primarily ptau-181 in all participants. We will explore classification by tau, neurodegeneration, and vascular contributions to cognitive impairment and dementia (VCID). We will use statistical methods to ensure that findings are not confounded by propensity to use T2D medications. We will achieve our goal through the following aims: (1) To examine the association of cumulative metformin exposure with amnestic and non- amnestic cognitive decline, MCI, and dementia; (2) To examine the association of cumulative metformin exposure with brain amyloid, neurodegeneration and CVD in the 650 participants with brain imaging; (3) To examine the association of cumulative metformin exposure with trajectories of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation. We will also explore: other T2D medications as exposures; metformin associated cobalamin deficiency in relation to cognitive impairment; neuronal insulin signaling as an outcome; glycemia, advanced glycation end products, insulinemia, peripheral inflammation, endothelial function, vascular risk factors, and neuroprotective factors as mediators; the aggregate exposure to T2D medications and physical activity; the genomic signatures moderating the associations in aims 1-3; effect modification by sex, ethnic/racial group, cognitive reserve, and APOE-ε4 in all aims.