Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease
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 cont...
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BMC
2025-03-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | https://doi.org/10.1186/s13024-025-00822-3 |
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| author | Nicolai Franzmeier Sebastian Niclas Roemer-Cassiano Alexander Maximilian Bernhardt Amir Dehsarvi Anna Dewenter Anna Steward Davina Biel Lukas Frontzkowski Zeyu Zhu Johannes 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 |
| author_facet | Nicolai Franzmeier Sebastian Niclas Roemer-Cassiano Alexander Maximilian Bernhardt Amir Dehsarvi Anna Dewenter Anna Steward Davina Biel Lukas Frontzkowski Zeyu Zhu Johannes 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 |
| author_sort | Nicolai Franzmeier |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9db79ea53a6f48a98c72d027c4c0f9e9 |
| institution | OA Journals |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-9db79ea53a6f48a98c72d027c4c0f9e92025-08-20T02:06:36ZengBMCMolecular Neurodegeneration1750-13262025-03-0120111510.1186/s13024-025-00822-3Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s diseaseNicolai Franzmeier0Sebastian Niclas Roemer-Cassiano1Alexander Maximilian Bernhardt2Amir Dehsarvi3Anna Dewenter4Anna Steward5Davina Biel6Lukas Frontzkowski7Zeyu Zhu8Johannes Gnörich9Julia Pescoller10Fabian Wagner11Fabian Hirsch12Hannah de Bruin13Rik Ossenkoppele14Carla Palleis15Felix Strübing16Michael Schöll17Johannes Levin18Matthias Brendel19Günter U. Höglinger20Institute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichDepartment of Neurology, LMU University Hospital, University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichDepartment of Nuclear Medicine, University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), University Hospital, LMU MunichAlzheimer Center Amsterdam, Neurology, Vrije Universiteit AmsterdamDepartment of Neurology, LMU University Hospital, University Hospital, LMU MunichCenter for Neuropathology and Prion Research, University Hospital, LMU MunichThe Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, University of GothenburgMunich Cluster for Systems Neurology (SyNergy)Munich Cluster for Systems Neurology (SyNergy)Munich Cluster for Systems Neurology (SyNergy)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.https://doi.org/10.1186/s13024-025-00822-3 |
| spellingShingle | Nicolai Franzmeier Sebastian Niclas Roemer-Cassiano Alexander Maximilian Bernhardt Amir Dehsarvi Anna Dewenter Anna Steward Davina Biel Lukas Frontzkowski Zeyu Zhu Johannes 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 Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease Molecular Neurodegeneration |
| title | Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease |
| title_full | Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease |
| title_fullStr | Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease |
| title_full_unstemmed | Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease |
| title_short | Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease |
| title_sort | alpha synuclein co pathology is associated with accelerated amyloid driven tau accumulation in alzheimer s disease |
| url | https://doi.org/10.1186/s13024-025-00822-3 |
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