HAI Book 2025 - Flipbook - Page 496
Franzmeier, Nicolai
Alpha Synuclein co-pathology accelerates amyloid associated tau
accumulation in Alzheimer9s disease
Nicolai Franzmeier1,2,3, Sebastian N Roemer1,4, Alexander Bernhardt4, Amir Amir Dehsarvi1,
Anna Dewenter1, Anna Steward1, Lukas Frontzkowski1,5, Zeyu Zhu1, Johannes Gnörich5, Julia
Pescoller1, Fabian Wagner1, Fabian Hirsch1,2,3, Hannah DeBruin6, Rik Ossenkoppele6,7, Carla
Palleis4, Michael Schöll3,8,9, Johannes Levin2,4,10, Matthias Brendel2,5,10, Guenter Hoeglinger2,4,10
1
Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Munich, DE
Munich Cluster for Systems Neurology (SyNergy), Munich, DE
3
University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of
Psychiatry and Neurochemistry, Gothenburg, SE
4
Department of Neurology, LMU University Hospital, Munich, DE
5
Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, DE
6
Alzheimer’s Center, VU University Medical Center Amsterdam, Amsterdam, NL
7
Clinical Memory Research Unit, Lund University, Lund, SE
8
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, SE
9
Dementia Research Centre, Queen Square Institute of Neurology, University College London, London, GB
10
German Center for Neurodegenerative Diseases (DZNE), Munich, DE
2
Objectives: Alpha-Synuclein (³-Syn) is a hallmark pathology in Parkinson9s disease but also the most common copathology in Alzheimer9s disease (AD). Preclinical studies suggest that ³-Syn can amplify amyloid-beta (A´)associated tau aggregation, implying that ³-Syn co-pathology may contribute to the A´-induced tau aggregation
observed in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine
³-Syn positivity with PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with
dementia, examining whether ³-Syn co-pathology accelerates A´-driven tau accumulation and cognitive decline.
Methods: In 284 A´-positive and 308 A´-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and
a CSF-based ³-Syn SAA assay to detect in vivo ³-Syn aggregation. CSF p-tau181 measures were available for 410
subjects to assess early tau abnormalities. A subset of 155 A´-positive and 135 A´-negative subjects underwent
longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether ³-Syn
positivity was linked to stronger A´-related increases in baseline fluid and PET tau biomarkers, faster A´-driven
tau-PET increase, and more rapid cognitive decline.
Results: ³-Syn positivity was more common in A´+ subjects (CN/MCI/Dementia: CN/MCI/Dementia: 20/23/45%,
Fig.1A) and increased with clinical severity compared to A´- subjects (14/12/22%; p
