Synaptic loss measured by various methods such as electron microscopy, neurochemical measurements of synaptic protein concentrations, and PET, has been reported to better correlate with cognitive decline in AD in multiple studies, rendering synaptic proteins a promising target for biomarker development. While established cerebrospinal fluid (CSF) AD biomarkers such as amyloid-ß42 (Aß42) and phospho-tau (pTau181) have proven to be of diagnostic value in AD, they are less predictive of cognitive decline, and it is unclear how well their levels reflect clinically relevant changes during disease progression or treatment trials. Synaptic dysfunction and loss occur early in Alzheimer’s disease (AD) and may be present before a reduction in neuronal density is apparent. Together, these synaptic markers hold promise to identify early AD pathology, to correlate with cognitive decline, and to monitor responses to disease-modifying drugs reducing synaptic degeneration. The data establishes PSD-95 as a promising CSF marker for neurodegenerative disease synaptic pathology, while SNAP-25 and Ng appear to be somewhat more specific for AD. High CSF levels of PSD-95 were also observed in a few subjects with other neurodegenerative disorders. Increased CSF levels of PSD-95, SNAP-25, and Ng were, however, not specific for AD and were present in sporadic cases with inflammatory or vascular disorders as well. AD subjects had on average higher concentrations of all three synaptic markers compared to those with non-AD neurodegenerative diseases, other neurological disorders, and HCs. CSF levels of PSD-95, SNAP-25, and Ng were all correlated, with the strongest correlation between the presynaptic SNAP-25 and the postsynaptic neurogranin. ResultsĪll subjects had detectable CSF levels of PSD-95, SNAP-25, and Ng. CSF samples from two well-characterized cohorts ( n=178 and n=156) were selected from banked samples obtained from diagnostic lumbar punctures containing subjects with amyloid-ß (Aß) positive AD, subjects with non-AD neurodegenerative diseases, subjects with other neurological conditions, and healthy controls (HC). We used novel Simoa assays to measure cerebrospinal fluid (CSF) levels of two synaptic biomarker candidates, postsynaptic density protein 95 (PSD-95/DLG4), and the presynaptically localized synaptosomal-associated protein 25 (SNAP-25), as well as neurogranin (Ng), an established postsynaptic biomarker. Synaptic dysfunction and loss occur early in AD and synaptic loss measured in the brain tissue and by PET are closely linked to cognitive decline, rendering synaptic proteins a promising target for biomarker development. There is currently a lack of reliable and easily accessible biomarkers predicting cognitive decline in Alzheimer’s disease (AD).

Protein scaffold roc curves manual