The goal of the Neuroimaging and Plasma Biomarkers Core (Biomarkers Core) of the Diabetes Prevention Program Outcomes Study (DPPOS) Alzheimer’s disease (AD) and AD related dementias (ADRD) project is to conduct all training, certification, quality assurance (QA) and quality control (QC) activities related to brain magnetic resonance imaging (MRI), brain amyloid positron emission tomography (PET) imaging, and plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation. In addition, the Biomarkers Core will support the Biostatistics and Data Infrastructure Core (Data Core) and the Cognitive Assessment and Adjudication Core (Cognition Core) to conduct analyses of neuroimaging and plasma biomarkers as independent outcomes and in combination with cognitive outcomes, following the 2018 National Institute on Aging (NIA)/Alzheimer’s Association (AA) research framework. The Biomarkers Core will harmonize methods for the study of the vascular contribution to cognitive impairment and dementia (VCID), with the MarkVCID consortium. Determination of biomarkers underlying AD/ADRD is critical to understanding disease mechanisms and potential therapeutic targets underlying cognitive impairment in persons with pre-diabetes (PreD) and type 2 diabetes (T2D), who represent over half of the US population aged 60 years and older at risk for cognitive impairment. We herein propose to perform multimodality MRI, including structural imaging, diffusion tensor imaging (DTI), cerebral blood flow, and functional MRI and amyloid PET in 650 participants representative of the DPPOS cohort in one wave that will span the two proposed waves of cognitive assessments. We also propose to conduct ascertainment of plasma biomarkers of amyloid (Aß42, Aß40), tau (ptau-181), neurodegeneration (neurofilament light [NfL]), neuroinflammation (glial fibrillary acidic protein [GFAP]), and peripheral neuropathy (peripherin) in all participants concurrent with the first wave of cognitive assessments, and two previous waves, 5 years apart, from stored samples. The Biomarkers Core is led by Ilya Nasrallah at the University of Pennsylvania, who will lead all brain imaging core activities, and Henrik Zetterberg at the University of Gothenburg, who will lead all plasma biomarker core activities. The Biomarkers Core will achieve its goals through the following specific aims: (1). To develop, maintain, update, and implement protocols and QA/QC procedures related to brain MRI and amyloid PET; (2) Develop an imaging pipeline for evaluation of AD and VCID biomarkers; (3) Conduct assays of Aß42, Aß40, ptau-181, NfL, GFAP, and peripherin, using Single Molecular Array (Simoaä) at the central plasma biomarkers laboratory located at the University of Gothenburg; (4) Conduct exploratory analyses relating brain imaging and plasma biomarkers data in collaboration with the Data and Clinical Cores; (5) In collaboration with the Data, Cognition, and Clinical Operations and Procedures Core (Clinical Co...