Synapses are the contacts between neurons in the brain, essential for information relay and for processes such as memory and learning. Dysfunction and loss of synapses is a central factor underlying cognitive impairment in Alzheimer's Disease (AD), and correlates strongly with the severity of dementia. It may result from toxic effects of amyloid beta protein (Aβ), a protein thought to initiate many of the adverse changes to the brain in AD, or from other mechanisms of neurodegeneration. The best established cerebrospinal fluid (CSF) biomarkers for AD are a pattern of proteins that are released into CSF in relation to plaque and tangle formation, namely Aβ42, tau and P-tau. This proposal aims to extend these by evaluating additional protein biomarkers in the cerebrospinal fluid that may reflect important pocesses dependent on synaptic integrity. When bursts of synaptic activity are related to information storage, they activate he expression of Immediate Early Genes (IEGs), which in turn increase the expression of specific proteins. We have found that proteins related to IEGs that help to control synaptic mechanisms of memory and learning can be measured in the cerebrospinal fluid. Two of these proteins, called Narp and NP1, have decreased levels in AD. These decrease appear to begin early in the course of AD and track with dementia severity.. They do not correlate with Aβ42, tau and P-tau in AD, and thus are measures of different brain processes. To develop these into readily useable biomarkers of synaptic integrity and AD progression, we propose to: 1) develop tools to set up more sensitive and specific assays to measure these proteins, 2) extend our preliminary findings, 3) measure how these proteins change over time in CSF in patients with mild cognitive impairment, AD and controls, 4) examine these proteins in postmortem brain in AD, MCI and control patients.