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 ri...