Higher plasma β-synuclein indicates early synaptic degeneration in Alzheimer's disease

INTRODUCTION: β-Synuclein is an emerging synaptic blood biomarker for Alzheimer's disease (AD) but differences in β-synuclein levels in preclinical AD and its association with amyloid and tau pathology have not yet been studied. METHODS: We measured plasma β-synuclein levels in cognitively unimpaired individuals with positive Aβ-PET (i.e., preclinical AD, N = 48) or negative Aβ-PET (N = 61), Aβ-positive patients with mild cognitive impairment (MCI, N = 36), and Aβ-positive AD dementia (N = 85). Amyloid (A) and tau (T) pathology were assessed by [¹⁸F]flutemetamol and [¹⁸F]RO948 PET. RESULTS: Plasma β-synuclein levels were higher in preclinical AD and even higher in MCI and AD dementia. Stratification according to amyloid/tau pathology revealed higher β-synuclein in A⁺T⁻ and A⁺T⁺ subjects compared with A⁻T⁻. Plasma β-synuclein levels were related to tau and Aβ pathology and associated with temporal cortical thinning and cognitive impairment. DISCUSSION: Our data indicate that plasma β-synuclein might track synaptic dysfunction, even during the preclinical stages of AD. HIGHLIGHTS: Plasma β-synuclein is already higher in preclinical AD. Plasma β-synuclein is higher in MCI and AD dementia than in preclinical AD. Aβ- and tau-PET SUVRs are associated with plasma β-synuclein levels. Plasma β-synuclein is already higher in tau-PET negative subjects. Plasma β-synuclein is related to temporal cortical atrophy and cognitive impairment.