PROJECT SUMMARY – BIOMARKER CORE The overall goal of the Biomarker Core is to collect, bank, and distribute fluid biospecimens and to generate and share extensive biomarker datasets with the scientific community to address the heterogeneity and improve diagnosis for Alzheimer’s disease (AD) and AD-related dementias (ADRD). Indeed, the Mayo Clinic ADRC continues to lead efforts to define AD/ADRD across the clinical spectrum. Biofluid biomarkers are critical to these efforts, informing early changes in the development and progression of AD/ADRD, and supporting the etiologic diagnosis of cognitive impairment. Synergy among the Biomarker, Clinical, Neuroimaging, and Neuropathology Cores is also key to understanding multiple etiology dementias – the central theme of this renewal application. In support of this goal, the Biomarker Core, together with the newly formed Genomics Core, will systematically process, bank and distribute biospecimens from individuals with AD/ADRD, including Lewy Body spectrum disorders and frontotemporal lobar degeneration (FTLD), and will measure established and emerging AD/ADRD-related biofluid biomarkers in ADRC participants. The latter will include comparisons of various pTau217 assays for detecting AD neuropathologic change, and the development and validation of assays for the detection of pathological aggregates of α-synuclein associated with Lewy body disease. Furthermore, given our recent findings that functional loss of TDP-43 causes the retention of cryptic exons (CE) in hundreds of transcripts, some of which generate de novo CE-harboring proteins detectable in cerebrospinal fluid (CSF), we will evaluate the ability of CE-proteins to serve as surrogate biomarkers of TDP-43 pathology. Discovery of a biomarker of TDP-43 pathology would inform its contributions to the clinical variability in AD/ADRD, support accurate antemortem diagnoses of FTLD-TDP and FTLD-tau, and enable assignment of patients with FTLD to clinical trials of investigational agents targeting TDP-43 or tau. The resources created by the Clinical and Biomarker Cores, in concert with other Cores, will support biomarker evaluation in increasingly diverse cohorts and underrepresented groups. Already, we have examined plasma AD biomarker profiles (Aβ42/40, pTau181, GFAP, NfL) and their relationship to cognition and comorbidities in African American/Black and non-Hispanic White participants. Acknowledging that structural and social determinants of health (SSDoH) are fundamental drivers of AD/ADRD disparities, we will expand our studies and investigate the contribution of race, additional SSDoH, and other health factors on AD/ADRD biomarkers. To accomplish these goals, the Biomarker Core has assembled a team of investigators who have collectively undertaken comprehensive biomarker studies evaluating the susceptibility/risk, diagnostic, prognostic and pharmacodynamic utility of putative AD/ADRD biomarkers, and have devoted substantial effort towards biofluid ba...