Introduction 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).
Methods 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).
Results 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).
Discussion CSF β-syn increases in the whole AD continuum since the preclinical stage and represents a promising biomarker of synaptic damage in AD.
- alzheimer's disease
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LP and MO are joint senior authors.
Contributors All authors made substantial contributions to conception and design, and/or acquisition of data and/or analysis and interpretation of data. All authors gave final approval of the version to be submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Conception and design of the study: LB, LP and MO. Sample collection and data management: LB, SAR, GB, FPP and SH. Study management and coordination: LB, LP, MO. Statistical methods and analysis: LB, SAR, FM, GB, PS. Interpretation of results: LB, SAR, FM, GB, FPP, LG, PO, SH, PS, LP and MO. Manuscript writing (first draft): LB. Critical revision of the manuscript: LB, SAR, GB, FPP, FM, LG, PO, SH, PS, LP and MO.
Funding This study was supported by the EU Joint Programme-Neurodegenerative Diseases networks Genfi-Prox (01ED2008A), the German Federal Ministry of Education and Research (FTLDc 01GI1007A), the EU Moodmarker programme (01EW2008), the German Research Foundation/DFG (SFB1279), the foundation of the state Baden-Wuerttemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009), the Thierry Latran Foundation (D.2468) and the Roux programme of the Martin Luther University Halle-Wittenberg.
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).
Provenance and peer review Not commissioned; externally peer reviewed.
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