Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease

作者：Nicolai Franzmeier, Sebastian Niclas Roemer, Alexander Maximilian Bernhardt, Amir Dehsarvi, Anna Dewenter, Anna Steward, Davina Biel, Lukas K. Frontzkowski, Zeyu Zhu, Johannes S. Gnörich, Julia Pescoller, Fabian Wagner, Fabian Hirsch, Hannah de Bruin, Rik Ossenkoppele, Carla Palleis, Felix Strübing, Michael Schöll, Johannes Levin, Matthias Brendel, Günter U. Höglinger · 发表于：Molecular Neurodegeneration · 年份：2025 · DOI：10.1186/s13024-025-00822-3 · 被引用次数：60 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Dementia and Cognitive Impairment Research、Alzheimer's disease research and treatments

Abstract Background Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson’s disease but also one of the most common co-pathologies in Alzheimer’s disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine αSyn positivity with amyloid- and tau-PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with dementia, examining whether αSyn co-pathology accelerates Aβ-driven tau accumulation and cognitive decline. Methods In 284 Aβ-positive and 308 Aβ-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and a CSF-based αSyn seed-amplification assay (SAA) to detect in vivo αSyn aggregation. CSF p-tau 181 measures were available for 384 subjects to assess earliest tau abnormalities. A subset of 155 Aβ-positive and 135 Aβ-negative subjects underwent longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether αSyn SAA positivity was linked to stronger Aβ-related increases in baseline fluid and PET tau biomarkers, faster Aβ-driven tau-PET increase, and more rapid cognitive decline. Results αSyn SAA positivity was more common in Aβ + vs. Aβ- subjects and increased with clinical severity ( p < 0.001). Most importan...