PROJECT 1: SUMMARY/ABSTRACT The goal of Project 1, entitled ‘Synaptic and Inflammatory Markers for Preclinical AD’ is to examine several new measures related to synaptic function and systemic inflammation to determine their value as biomarkers for preclinical AD. These analyses will use longitudinally collected CSF and blood specimens from BIOCARD participants to evaluate these measures. For the synaptic markers, there are two primary aims: (1) to measure NPTX2, a synaptic protein, and related markers NPTX1 and NPTXR in CSF, and examine their relationship with the clinical, cognitive and biomarker data previously collected in the BIOCARD participants; and (2) to examine a blood-based assay that measures NPTX2 and related proteins in neural exosomes isolated from blood and determine if it has a similar association with comparable measures obtained from CSF. For the inflammatory markers, there are two primary aims: (1) to measure 3 key inflammatory biomarkers in blood (IL-6, TNFR1, and CRP) and examine their relationship with the clinical, cognitive and biomarker data previously collected in the BIOCARD participants; and (2) to conduct targeted exploratory metabolomic analyses in both blood and CSF samples, in order to identify inflammatory pathways that may be involved in preclinical AD. Overall, these studies will determine if the changes in these synaptic and inflammatory markers during preclinical AD can provide insights into measures that might be useful for a clinical trial in preclinical AD (i.e., for either selecting subjects to include in a clinical trial or for tracking response to treatment in a clinical trial), and/or provide insights into the underlying neurobiological processes that are evolving during the preclinical phase of AD.