Associations between misfolded alpha-synuclein aggregates and Alzheimer's disease pathology in vivo

INTRODUCTION: We examined the relations of misfolded alpha synuclein (alpha synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER-2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross-sectional cerebrospinal fluid (CSF) alpha-synuclein measurement from seed-amplification assay as well as cross-sectional and longitudinal amyloid beta (Aj3) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. RESULTS: Across cohorts, the main biomarker associated with alpha-synuclein positivity at baseline was higher levels of Aj3 pathology (all p values <= 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, alpha-synuclein -positive participants had a statistically significant faster increase of Aj3 load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to alpha-synuclein -negative participants in BioFINDER-2 but not in ADNI. DISCUSSION: We showed associations between concurrent misfolded alpha-synuclein and A beta levels, providing in vivo evidence of links between these two molecular disease pathways in humans.