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(T2D)药物的相关性， 主要是二甲双胍，糖尿病预防中的认知损害及其潜在的神经病理 方案(DPP)结果研究(DPPOS)队列。重新调整T2D药物的用途，特别是胰岛素 致敏药物，已被提议用于治疗和预防阿尔茨海默病(AD)。 二甲双胍是一线治疗药物，也是应用最广泛的T2D药物，但关于这方面的数据相互矛盾。 二甲双胍对阿尔茨海默病和认知障碍的风险是有益的、有害的还是没有影响的。这个 DPP/DPPOS提供随机分配的二甲双胍，现在包括20多年的累积数据 二甲双胍暴露。这为研究二甲双胍与认知功能的关系提供了一个独特的机会。 损害和相关的神经病理学。GLP1a、DPP4i和SGLT2i最近使用较少 经常在DPPOS中与二甲双胍进行比较，并可在探索性基础上进行检查。我们现在提议 以确定所有DPPOS参与者的痴呆症和MCI。我们将检查淀粉样蛋白(A？42/40比率)、tau(ptau- 181)、神经变性(神经丝光[NFL])和神经炎症(胶质纤维酸性蛋白 [GFAP])在所有参与者的血浆中。在650名参与者中，我们将使用18F-Florbetaben来确定大脑淀粉样蛋白 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、白质微结构、 和静止的功能连接。我们将认知综合征分为AD连续体或非AD 遵循国家老龄研究所(NIA)/阿尔茨海默氏症协会(AA)研究框架的病理学使用 主要是Ptau-181在所有参与者中。我们将探讨tau、神经退行性变和血管的分类。 认知障碍和痴呆症(VCID)的贡献。我们将运用统计方法确保 研究结果不会因为使用T2D药物的倾向而感到困惑。我们将通过 目的如下：(1)研究二甲双胍累积暴露与健忘症和非遗忘症的关系。 遗忘性认知功能减退、MCI和痴呆；(2)检查累积二甲双胍的相关性 650名脑成像受试者暴露于脑淀粉样蛋白、神经退行性变和脑血管病； 检查累积二甲双胍暴露与淀粉样蛋白血浆生物标记物的轨迹之间的关系， 牛磺酸、神经退行性变和神经炎症。我们还将探索：其他T2D药物作为暴露； 二甲双胍相关的钴胺缺乏与认知障碍的关系；神经元胰岛素信号转导作为一种 结果；血糖，晚期糖基化终末产物，胰岛素血症，外周炎症，内皮功能， 血管危险因素和神经保护因素作为介体；T2D药物和 体力活动；目标1-3中调节关联性的基因组签名；性别影响修改， 民族/种族群体、认知储备和所有目标的载脂蛋白E-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.