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

Franzmeier, Nicolai ; Roemer-Cassiano, Sebastian Niclas; Bernhardt, Alexander Maximilian ; Dehsarvi, Amir ; Dewenter, Anna ; Steward, Anna ; Biel, Davina ; Frontzkowski, Lukas; Zhu, Zeyu ; Gnörich, Johannes ; Pescoller, Julia; Wagner, Fabian ; Hirsch, Fabian; Bruin, Hannah de ; Ossenkoppele, Rik; Palleis, Carla ; Strübing, Felix; Schöll, Michael ; Levin, Johannes ; Brendel, Matthias und Höglinger, Günter U. (2025): Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease. In: Molecular Neurodegeneration, Bd. 20, 31

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-tau181 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 importantly, αSyn positivity was also associated with greater amyloid-associated CSF p-tau181 increases (p = 0.005) and higher tau-PET levels in AD-typical brain regions (p = 0.006). Longitudinal analyses confirmed further that αSyn positivity was associated with faster amyloid-related tau accumulation (p = 0.029) and accelerated amyloid-related cognitive decline, potentially driven driven by stronger tau pathology.

Conclusions: Our findings suggest that αSyn co-pathology, detectable via CSF-based SAAs, is more prevalent in advanced AD and contributes to the development of aggregated tau pathology thereby driving faster cognitive decline. This highlights that a-Syn co-pathology may specifically accelerate amyloid-driven tau pathophysiology in AD, underscoring the need to consider αSyn in AD research and treatment strategies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Institut für Neuropathologie ; Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Institut für Schlaganfall- und Demenzforschung (ISD) ; Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut ; Medizin > Klinikum der LMU München > Klinik und Poliklinik für Nuklearmedizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1750-1326
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198