Association of glycemia and related factors and complications with cognitive impairment and AD/ADRD biomarkers

项目2的目标是研究2型糖尿病（T2 D）相关因素与认知功能障碍风险的相关性。 衰退、轻度认知障碍（MCI）、痴呆和相关神经病理学， 糖尿病预防计划结果研究（DPPOS）中的PreD和T2 D。T2d 相关因素包括血糖异常及其决定因素、胰岛素抵抗（IR）和胰腺β细胞功能障碍， 和下游病理生理学标志物，包括晚期糖基化终产物（AGE），以及 外周血管因素（内皮功能障碍、炎症、血压、血脂异常）、微血管 （视网膜病变、神经病变、肾病）和大血管（非致命性心肌梗死、冠状动脉 疾病）并发症，在DPPOS中纵向确定超过20年。大量证据表明 T2 D是认知障碍的一个重要的可改变的风险因素。然而，尚不清楚T2 D是否与 导致T2 D认知障碍的因素。很少有研究调查T2 D相关的时间变化， PreD和T2 D患者与认知综合征和神经病理学相关的因素。中所述 认知评估和裁定核心，认知障碍综合征将包括遗忘和非遗忘 遗忘性认知衰退MCI和痴呆。如生物标志物核心所述，我们将检查轨迹 神经病理学的血浆生物标志物，包括淀粉样蛋白（Aβ42/Aβ40比值）、tau蛋白（ptau-181）、神经丝光 (NfL)和胶质纤维酸性蛋白（GFAP）。与项目1合作，我们将 此外，研究脑胰岛素信号从血浆来源的神经细胞外囊泡作为一种新的 T2 D相关失调神经生理学的血浆生物标志物。在那些接受脑部成像的参与者中， 我们将使用神经病理学的成像生物标志物，包括通过PET的脑Aβ、皮质厚度和白色。 MRI上的高信号体积（WMHV）和梗死，以探讨脑病理学。最后，在那些 认知综合征，我们将探讨病理分类为AD连续或非AD病理 使用血浆生物标志物（见神经影像学和血浆生物标志物核心）和血管 通过临床中心裁定的卒中测量的损害或痴呆（VCID）。我们的目标 （1）检查代谢障碍、IR、β细胞功能障碍和AGE的轨迹与 认知综合征、神经病理学生物标志物和脑胰岛素信号传导;（2）检查 血管因素的轨迹以及微血管和大血管并发症的病史， 神经病理学的证候和生物标志物;（3）建立人群认知综合征的预测模型 使用T2 D相关因素（目的1和2），社会人口学因素（性别，种族/民族， 教育）和遗传风险因素（APOE-e4和糖尿病遗传风险评分）;探索性目的：目的1和 2将探讨性别、种族/民族和认知储备的测量（例如，教育水平和识字率）， 假设关联的调节者。

The goal of Project 2 is to study the associations of type 2 diabetes (T2D) related factors with risk for cognitive decline, mild cognitive impairment (MCI), dementia, and related neuropathologies, among persons with pre- diabetes (PreD) and type 2 diabetes (T2D) in the Diabetes Prevention Program Outcomes Study (DPPOS). T2D related factors include dysglycemia, its determinants, insulin resistance (IR) and pancreatic β-cell dysfunction, and downstream markers of pathophysiology including advanced glycation end products (AGE), as well as peripheral vascular factors (endothelial dysfunction, inflammation, blood pressure, dyslipidemia), microvascular (retinopathy, neuropathy, nephropathy) and macrovascular (non-fatal myocardial infarction, coronary artery disease) complications, ascertained longitudinally over 20 years in DPPOS. A vast body of evidence supports T2D as a significant modifiable risk factor for cognitive impairment. However, it is not clear that T2D related factors cause cognitive impairment in T2D. Few studies have investigated the temporal changes of T2D related factors in people with PreD and T2D in relation to cognitive syndromes and neuropathology. As described in the Cognitive Assessment and Adjudication Core, cognitive impairment syndromes will include amnestic and non- amnestic cognitive decline, MCI, and dementia. As described in the Biomarker Core we will examine trajectories of plasma biomarkers of neuropathology including amyloid (Aβ42/Aβ40 ratio), tau (ptau-181), neurofilament light (NfL), and Glial Fibrillary Acidic Protein (GFAP) in all participants. In collaboration with Project 1, we will additionally examine brain insulin signaling from plasma-derived neuronal extracellular vesicles as a novel plasma biomarker of T2D related dysregulated neurophysiology. Among those participants with brain imaging, we will use imaging biomarkers of neuropathology including brain Aβ via PET, cortical thickness, and white matter hyperintensity volume (WMHV) and infarcts on MRI to explore brain pathology. Finally, among those with a cognitive syndrome, we will explore pathologic classification as being AD continuum or non-AD pathologic change using the plasma biomarkers (see Neuroimaging and Plasma Biomarkers Core) and vascular contribution to impairment or dementia (VCID) measured via adjudicated stroke by the Clinical Core. Our aims are: (1) Examine the associations of trajectories of dysglycemia, IR, β-cell dysfunction, and AGE with risk of cognitive syndromes, biomarkers of neuropathology, and brain insulin signaling; (2) Examine the associations of trajectories of vascular factors and history of micro- and macrovascular complications with risk of cognitive syndromes and biomarkers of neuropathology; (3) Build prediction models of cognitive syndromes in persons with PreD or T2D using T2D related factors (Aims 1 and 2), sociodemographic factors (sex, race/ethnicity, education), and genetic risk factors (APOE-e4 and diabetes genetic risk scores); Exploratory aims: Aims 1 and 2 will explore sex, race/ethnicity, and measures of cognitive reserve (e.g., education level and literacy) as moderators of the hypothesized associations.