Influence of co-pathology on CSF and plasma synaptic markers SNAP25 and VAMP2 in Alzheimer’s disease and Parkinson’s disease

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Abstract Background: Synaptic dysfunction is a relevant feature of Alzheimer's disease (AD) and Parkinson's disease (PD) and can be quantified through the measurement of cerebrospinal fluid (CSF) synaptic markers, such as the presynaptic proteins synaptosomal-associated protein 25 kDa (SNAP25) and vesicle-associated membrane protein 2 (VAMP2). Plasma-based assays for synaptic markers are also emerging. In neurodegenerative diseases, synaptic dysfunction can be directly driven by proteinopathies such as amyloidosis (A), tauopathy (T), and α-synucleinopathy (S), which in turn can be detected via CSF biomarkers. This observational study aimed to: (i) evaluate the concordance of SNAP25 and VAMP2 in CSF and plasma; (ii) compare SNAP25 and VAMP2 concentrations in CSF and plasma across AD, PD, and control groups; (iii) examine the impact on synaptic markers concentration of CSF α-synuclein seed amplification assay (αS-SAA) positivity (S+) in AD, and (iv) of CSF amyloid/tau (A+/T+) positivity in PD. Methods: We included 80 AD patients (preclinical, mild cognitive impairment [MCI], and dementia stages), 47 PD patients, and 41 controls with other neurological diseases (OND) and known CSF A/T/S profiles. All AD and 5/47 PD patients were CSF A+/T+, while 26/80 AD and all PD patients were CSF S+. All OND had a non-A+/T+ and a S− profile. SNAP25 and VAMP2 concentrations in CSF and plasma were measured using Simoa-based immunoassays. Results: CSF and plasma SNAP25 were positively correlated, but no correlation was observed for VAMP2 in these matrices. CSF and plasma SNAP25 and CSF VAMP2 were higher in AD compared to PD and OND. Synaptic markers were elevated in preclinical AD and remained stable across MCI-AD and AD dementia stages. AD patients with CSF αS-SAA positivity showed no significant difference in synaptic markers compared to those without CSF αS-SAA positivity, independent of clinical stage. In PD, A+/T+ patients had higher CSF and plasma SNAP25 (132.3±41.6; 1.9±0.5 pg/mL) compared to non-A+/T+ PD (105.4±34.2; 1.3±0.3 pg/mL) (pConclusions: SNAP25 reliably serves as a marker of synaptic injury when measured in both CSF and plasma, whereas VAMP2 demonstrates reliability exclusively in CSF. Both markers are primarily influenced by AD pathology and remain unaffected by α-synucleinopathy, suggesting their potential in detecting AD-related synaptic dysfunction.

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