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

β-synuclein (β-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 β-syn in subjects at different AD stages, including preclinical AD (pre-AD), and to compare its behaviour with another synaptic biomarker, α-synuclein (α-syn), and two biomarkers of neuro-axonal damage, namely neurofilament light chain protein (NfL) and total tau protein (t-tau). We measured β-syn, α-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). CSF β-syn, α-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 β-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). CSF β-syn increases in the whole AD continuum since the preclinical stage and represents a promising biomarker of synaptic damage in AD.

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Déclaration de conflit d'intérêts

Competing interests: MO gave scientific advice for Fujirebio, Roche, Biogen and Axon. The foundation of the state Baden-Wuerttemberg handed in a patent for the measurement of β-synuclein. Relevant authors are MO, SH, and PO. GB is currently supported by the JPND bPRIDE (blood Proteins for early Discrimination of dEmentias) project. The Project leading this result has received funding under the call “JPco-fuND-2: Multinational research projects on Personalised Medicine for Neurodegenerative Diseases” (CUP number J99C18000210005).