ABSTRACT BIOMARKER CORE The Biomarker Core will oversee the assessment of multiple blood-based biomarkers and an MRI sub-study that will support and inform the EAS Program Project. Biomarkers were selected to index the most common mechanisms of non-normative cognitive decline in older adults, in particular, those related to Alzheimer’s disease and related dementias (ADRD) and those linked to vascular disease, as well as genomic markers and markers of processes that play a crucial role in aging such as autophagy. Blood-based biomarkers will include four categories: 1) Blood biomarkers of AD pathologic change and neurodegeneration: β-amyloid (Aβ40, Aβ42), tau (pTau181, pTau217, pTau231) and biomarkers of generalized neuronal damage, including glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) chain; 2) Genomics: single nucleotide polymorphisms (SNPs) including apolipoprotein E (ApoE) status, and genome-wide association study (GWAS) conducted through the Alzheimer’s Disease Genetics Consortium; 3) Blood chemistry: e.g., lipids, cholesterol, C-reactive protein (CRP), glucose, hemoglobin A1c (HbA1c), and insulin; 4) Autophagy biomarkers: macroautophagy and chaperone mediated autophagy activity (CMA). In addition, this Core will conduct a cross-sectional MRI sub-study in 250 individuals to quantify macrostructural, microstructural, and physiologic features that index neurodegenerative changes and vascular disease. The domains assessed include macrostructure, including indicators of AD, neurodegeneration and vascular disease, microstructural pathology with measures of anisotropy within tracts, and altered cerebrovascular physiology through assessment of global and regional resting cerebral blood flow (CBF). Other related biomarkers which complement the Core are assessed in Project 1 (Cerebral Blood Flow by Transcranial Doppler ultrasound), Project 2 (blood-based assessment of basal and stimulated inflammatory markers and markers of biological age [telomere length, DNA methylation]), and Project 4 (glucose regulation). The Biomarker Core will work with the Technology and Data Management Core to ensure that biomarker data are shared across all Projects and will assist in interpretation. Biomarkers will be used to improve diagnostic accuracy and inform the assessment of mechanistic associations between project-specific risk factors and short-term and long-term cognitive outcomes as assessed by conventional and ambulatory approaches in the Clinical Core.