AbstractIntroductionSynaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed.MethodSolid‐phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross‐sectional studies including AD (n = 52) and controls (n = 37).ResultsIncreased concentrations of beta‐synuclein, gamma‐synuclein, neurogranin, phosphatidylethanolamine‐binding protein 1, and 14‐3‐3 proteins were observed in AD patients compared to controls, while neuronal pentraxin‐2 and neuronal pentraxin receptor were decreased.DiscussionWe have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.