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

Franzmeier, Nicolai LU ; Roemer-Cassiano, Sebastian Niclas ; Bernhardt, Alexander Maximilian ; Dehsarvi, Amir ; Dewenter, Anna ; Steward, Anna ; Biel, Davina ; Frontzkowski, Lukas ; Zhu, Zeyu and Gnörich, Johannes , et al. (2025) In Molecular Neurodegeneration 20(1).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Neurodegeneration
volume
20
issue
1
article number
31
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40098057
  • scopus:105000258224
ISSN
1750-1326
DOI
10.1186/s13024-025-00822-3
language
English
LU publication?
yes
id
b1d2283d-85c3-4f0f-9a6b-3b1f872243b9
date added to LUP
2026-01-12 15:00:14
date last changed
2026-01-13 03:00:06
@article{b1d2283d-85c3-4f0f-9a6b-3b1f872243b9,
  abstract     = {{<p>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<sub>181</sub> 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 &lt; 0.001). Most importantly, αSyn positivity was also associated with greater amyloid-associated CSF p-tau<sub>181</sub> 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.</p>}},
  author       = {{Franzmeier, Nicolai and Roemer-Cassiano, Sebastian Niclas and Bernhardt, Alexander Maximilian and Dehsarvi, Amir and Dewenter, Anna and Steward, Anna and Biel, Davina and Frontzkowski, Lukas and Zhu, Zeyu and Gnörich, Johannes and Pescoller, Julia and Wagner, Fabian and Hirsch, Fabian and de Bruin, Hannah and Ossenkoppele, Rik and Palleis, Carla and Strübing, Felix and Schöll, Michael and Levin, Johannes and Brendel, Matthias and Höglinger, Günter U.}},
  issn         = {{1750-1326}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Molecular Neurodegeneration}},
  title        = {{Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease}},
  url          = {{http://dx.doi.org/10.1186/s13024-025-00822-3}},
  doi          = {{10.1186/s13024-025-00822-3}},
  volume       = {{20}},
  year         = {{2025}},
}