Cerebrospinal fluid β-synuclein as a synaptic biomarker for preclinical Alzheimer's disease

Introduction beta-synuclein (beta-syn) is a presynaptic protein, whose cerebrospinal fluid (CSF) levels are increased in patients with Alzheimer's diseases (AD) showing mild cognitive impairment (MCI) and dementia (dem). Here, we aimed to investigate CSF beta-syn in subjects at different AD stages, including preclinical AD (pre-AD), and to compare its behaviour with another synaptic biomarker, alpha-synuclein (alpha-syn), and two biomarkers of neuro-axonal damage, namely neurofilament light chain protein (NfL) and total tau protein (t-tau). Methods We measured beta-syn, alpha-syn, t-tau and NfL in CSF of 75 patients with AD (pre-AD n=17, MCI-AD n=28, dem-AD n=30) and 35 controls (subjective memory complaints, SMC-Ctrl n=13, non-degenerative neurological disorders, Dis-Ctrl n=22). Results CSF beta-syn, alpha-syn, t-tau were significantly elevated in pre-AD patients compared with controls (p<0.0001, p=0.02 and p=0.0001, respectively), while NfL only increased in dem-AD (p=0.001). Pre-AD cases showed lower t-tau concentrations than MCI-AD (p=0.04) and dem-AD (p=0.01). CSF beta-syn had the best diagnostic performance for the discrimination of pre-AD subjects from all controls (area under the curve, AUC=0.97) and from SMC-Ctrl subjects (AUC=0.99). Discussion CSF beta-syn increases in the whole AD continuum since the preclinical stage and represents a promising biomarker of synaptic damage in AD.

Automated summary

This study found that beta-syn levels in cerebrospinal fluid (CSF) increase in patients with Alzheimer's disease (AD) in the mild cognitive impairment (MCI) and dementia stages. In contrast, the behavior of other synaptic biomarkers, such as alpha-syn, and biomarkers of neuro-axonal damage, such as NfL and t-tau, is different. CSF beta-syn has the best diagnostic performance for distinguishing pre-AD patients from non-AD patients.