Targeted Mass Spectrometry Suggests Beta-Synuclein as Synaptic Blood Marker in Alzheimer's Disease.

Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read-out for patient diagnosis and possible follow-up in clinical trials. Several synaptic markers for AD are described in cerebrospinal fluid (CSF), but studies in blood have failed so far. Using quantitative mass spectrometry (IP-MS, MRM) we observed increased concentrations of the presynaptic protein beta-synuclein (βSyn) in CSF and blood of AD patients ( = 64, < 0.01) and confirmed this finding in two validation cohorts (AD: = 40 and = 49, controls: = 44 and = 25). βSyn was already increased in patients with mild cognitive impairment ( < 0.01) and was also markedly increased in Creutzfeldt-Jakob disease (CJD; = 25, < 0.001) but not behavioral variant frontotemporal dementia ( = 16), dementia with Lewy bodies/Parkinson's disease dementia ( = 13), Parkinson's disease ( = 25), or amyotrophic lateral sclerosis ( = 30). The diagnostic sensitivity and specificity for CJD versus other neurodegenerative diseases was ≥96%. These findings suggest βSyn as a candidate blood marker for synaptic degeneration that might be used in clinical AD trials and patient follow-up as part of the recently suggested ATN biomarker panel. It can also serve in the differential diagnosis of CJD.