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

Abstract

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 (<i>n</i> = 64, <i>p</i> < 0.01) and confirmed this finding in two validation cohorts (AD: <i>n</i> = 40 and <i>n</i> = 49, controls: <i>n</i> = 44 and <i>n</i> = 25). βSyn was already increased in patients with mild cognitive impairment (<i>p</i> < 0.01) and was also markedly increased in Creutzfeldt-Jakob disease (CJD; <i>n</i> = 25, <i>p</i> < 0.001) but not behavioral variant frontotemporal dementia (<i>n</i> = 16), dementia with Lewy bodies/Parkinson's disease dementia (<i>n</i> = 13), Parkinson's disease (<i>n</i> = 25), or amyotrophic lateral sclerosis (<i>n</i> = 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.