Core C: Fluid Biomarker Project Summary/Abstract Biomarker data have been critical for defining Alzheimer disease (AD) as a continuum, with pathology developing decades prior to the onset of cognitive symptoms that eventually progress to dementia. This concept has impacted disease nomenclature, diagnostic criteria, prognostic potential, and clinical trial design. Revisions in diagnostic criteria to incorporate biomarker results have been proposed in order to increase the confidence of AD as the underlying etiology of a clinical impairment and to permit a diagnosis of AD across the disease continuum, perhaps even in the asymptomatic period. Individuals in this preclinical stage (as in the ACS) are receiving intense focus as a targeted population for prevention trials aimed at identifying disease-modifying therapies that have the best chance of preserving normal cognitive function. Since study inception, the Fluid Biomarker Core (Core C) has developed and implemented standard operating procedures and efficient workflows for the standardized collection, storage, tracking and sharing of fasted CSF and plasma samples. The ACS has identified biomarker abnormalities that characterize preclinical AD, defined when these changes develop during the adult lifespan and how they progress. We are now poised to expand our analyses to characterize the progression of preclinical AD over its 20+ year course, investigate whether the biomarker changes observed during this preclinical period are predictive of transition to symptomatic AD, and assess factors that may accelerate or retard this transition. In the next funding cycle we will extend our proven track record for excellence by continuing to provide the infrastructure for the collection, storage, and distribution of samples to Project 2 (for the measurement and evaluation of established, emerging and novel biomarkers [e.g., inflammation] to predict clinical progression) and to outside AD investigators studying preclinical AD. Fluid biomarker data generated in Project 2 will also be used by other ACS Projects in their investigations of biomarker associations with imaging measures of neuroinflammation (via DBSI) and tangle load (via tau PET) (Project 1), the gut microbiome (Project 3) and physical activity and cardiovascular risk factors (Project 4). In keeping with our emphasis on biomarker assay rigor, reproducibility and standardization efforts, Core C will also perform annual assay validation and lot bridging experiments in support of sample analyses carried out in Project 2. We will also continue our interactions and collaborations with other domestic and international research groups (industrial, academic and clinical) to foster quality control (QC) efforts required for sample collection protocol harmonization and biomarker assay standardization. To this end, we propose the following three Specific Aims: 1) Continue to maintain and grow a biorepository of fasted CSF and plasma for present and futur...