S5‐01‐01: Novel CSF biomarkers of synaptic dysfunction

Neuropathological studies have shown that synapse loss occurs early in Alzheimer's disease (AD) and is more strongly correlated with cognitive decline than are plaques or tangles. Therefore, quantifiable biomarker measures of synaptic dysfunction and/or loss may be particularly useful for identifying neuronal pathology during early stages of the disease and for predicting future cognitive decline. Novel biomarker assays have recently been developed that measure the synapse-related proteins, Neurogranin (NGRN, post-synaptic) and synaptosomal-associated protein 25 (SNAP-25, pre-synaptic), in human CSF. Recent studies have demonstrated that levels of both of these proteins are elevated in individuals with AD dementia compared to cognitively normal controls, likely reflecting AD-associated synaptic degeneration. Levels of synaptic markers are also higher in amyloid-positive individuals diagnosed with mild cognitive impairment (MCI) and are associated with a faster rate of cognitive decline and predict progression to dementia. Although levels of NGRN and SNAP-25 are highly correlated with levels of CSF tau and ptau181 (markers of tangles and/or neuronal cell death), longitudinal, within-person comparisons of changes among these biomarkers are needed to determine their more precise temporal ordering with disease progression. Biomarkers of synaptic dysfunction may ultimately be useful for early disease diagnosis, predicting and monitoring cognitive decline during disease progression and for identifying drug effects on synaptic dysfunction and degeneration in clinical trials.