PROJECT SUMMARY (APOE U19 Core D: Biomarker Core) The overall goal of the Biomarker Core (Core D) is to conduct and support the biomarker assessments for Alzheimer’s disease (AD) and age-related cognitive decline in fluid biospecimens including plasma and cerebrospinal fluid (CSF) among Projects and Cores in the U19 program with a specific focus on APOE. Given that APOE genotype (ε2, ε3 and ε4) has been shown to impact cognitive performances in the elderly, we hypothesize that apolipoprotein E (apoE) biochemical property (amount, lipidation, aggregation and post-translational modification) as well as its genotypes influence established and emerging biofluid-marker levels for AD. We will perform longitudinal biomarker studies based on APOE genotype over a time span of 2-3 years in elderly (≥65 years old) individuals by focusing on the change of Clinical Dementia Rating (CDR) between two visits in established cohorts from Mayo Clinic and Washington University School of Medicine in St. Louis. We will take advantage of the large sample numbers of biospecimens banked in the NIH-supported programs including Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Research Centers (ADRC) at both institutions. In Aim 1, we will organize the available dataset and fluid biospecimens from the cohorts. If available, we will also integrate the biospecimens with postmortem brain samples/neuropathological information through the Neuropathological Core (Core C) and peripheral blood mononuclear cells to generate induce pluripotent stem cells through Project 5 and the Human iPSC Models Core (Core E). In Aim 2, we plan to establish apoE-related fluid biomarkers for clinical dementia progression. We aim to develop apoE-targeted biomarkers for age-related cognitive decline and AD by assessing amounts and potential post-translational modification of apoE through LC-MS/MS approaches in plasma and CSF samples. Lipidation status and structural properties of apoE particles will also be explored through Project 1 and the Biochemistry and Structural Modeling Core (Core B). In Aim 3, we aim to uncover potential fluid biomarkers for clinical dementia progression using an ‘Omics approach through the Multi-Omics Core (Core F). In Aim 4, we will generate a fluid biomarker dataset to elucidate the effects of APOE on clinical dementia progression by measuring emerging AD-related biomarkers for synaptic damage and glial activation, as well as inflammation/vascular biomarkers. In Aim 5, we will support fluid biomarker measurements including apoE measurements and AD-related fluid biomarker assessments in mouse models from Projects 2-4 and iPSC models from Project 5 upon requests. Together, this comprehensive and innovative Biomarker Core will allow for integrated, systems-based, multidisciplinary studies by focusing on apoE isoforms in the disease cascade for AD and age-related cognitive decline. Monitoring how biomarkers change over time in asymptomatic and early symptomatic st...