High ß‐synuclein plasma levels are coupled with amyloid PET positivity in memory clinic patients

Abstract Background Synaptic dysfunction plays a key role in cognitive decline during progression of Alzheimer’s disease (AD). Higher levels of several synaptic proteins including the presynaptic protein ß‐synuclein have been measured in cerebrospinal fluid (CSF) of individuals with AD. Recently a quantitative assay using mass spectrometry allowed detection of ß‐synuclein in plasma. The aim of this study was to investigate the relationship between plasma ß‐synuclein levels and brain amyloid‐β (Aβ) plaque load in a cohort of memory clinic patients who underwent [ 18 F]flutemetamol PET. Method A clinical cohort of 118 patients (age = 65.6±8.3, 65F/53M), who despite extensive clinical assessment (including neuropsychological testing, CT/MRI, CSF biomarker analysis) at the Karolinska University Hospital, Sweden had an uncertain diagnosis and were referred to [ 18 F]flutemetamol PET, was included in this work. The diagnostic groups were as follows: mild cognitive impairment (MCI, n = 16 Aβ+, and n = 24 Aβ‐), AD (n = 53), non‐AD dementia (n = 20),no dementia (n = 5). Plasma and CSF ß‐synuclein were measured using targeted mass spectrometry and ELISA. Result We found a significant correlation between β‐synuclein values in plasma and CSF (p<0.001), with higher plasma β‐synuclein levels in AD (11.53±3.25pg/mL,p<0.001) compared to MCI Aβ‐ (7.74±2.63pg/mL) and non‐AD (8.18±3.00 pg/mL), and also between MCI Aβ+ (10.85±2.75pg/mL,p<0.01) in comparison to MCI Aβ‐. No significant difference was observed in plasma/CSF β‐synuclein levels between AD and MCI Aβ+. 18 F‐Flutemetamol uptake positively correlated with plasma ß‐synuclein levels in the whole sample (R 2 = 0.29,p<0.001) and in the MCI group (R 2 = 0.26,p<0.01) (after controlling for sex and age). Individuals with comparable [ 18 F]flutemetamol uptake values showed great variability in plasma ß‐synuclein levels. No correlation was observed between plasma ß‐synuclein and MMSE, brain atrophy, or white matter changes. Conclusion In a clinical cohort of patients with [ 18 F]flutemetamol‐PET, significantly elevated ß‐synuclein in plasma mirrored the higher levels of ß‐synuclein in CSF of Aß+ individuals. In the AD continuum, plasma ß‐synuclein seemed to capture pathological processes which were more closely associated with amyloid‐pathology rather than neuronal loss or clinical stage of the disease. The variability in plasma ß‐synuclein levels of Aß+ subjects warrants further exploration of factors that might contribute to increased plasma ß‐synuclein.