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

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 18, 2025

Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson's disease but also one of the most common co-pathologies Alzheimer's (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying co-pathology may specifically contribute to Aβ-induced aggregation drives neurodegeneration and cognitive decline AD. To investigate this, we combined novel CSF-based seed-amplification assay (SAA) determine positivity with amyloid- tau-PET neuroimaging large cohort ranging from cognitively normal individuals those dementia, examining whether accelerates Aβ-driven accumulation decline. In 284 Aβ-positive 308 Aβ-negative subjects, employed amyloid-PET, Flortaucipir tau-PET, detect vivo aggregation. CSF p-tau181 measures were available for 384 subjects assess earliest abnormalities. A subset 155 135 underwent longitudinal over approximately 2.5 years. Using linear regression models, analyzed SAA was linked stronger Aβ-related increases baseline fluid PET biomarkers, faster increase, more rapid Aβ + vs. Aβ- increased clinical severity (p < 0.001). Most importantly, associated greater amyloid-associated = 0.005) higher levels AD-typical brain regions 0.006). Longitudinal analyses confirmed further amyloid-related 0.029) accelerated decline, potentially driven by pathology. Our findings co-pathology, detectable via SAAs, prevalent advanced AD contributes development aggregated thereby driving This highlights a-Syn accelerate amyloid-driven pathophysiology AD, underscoring need consider research treatment strategies.

Language: Английский

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Perspectives Toward the Development of Quantitative Seed Amplification Assays for α-Synuclein

Neurology, Journal Year: 2025, Volume and Issue: 104(5)

Published: Feb. 6, 2025

Language: Английский

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Evolving Perspectives on α-Synuclein Testing

JAMA Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

This Viewpoint discusses evolving perspectives on α-synuclein testing.

Language: Английский

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CSF α-synuclein aggregation is associated with APOE ε4 and progressive cognitive decline in Alzheimer's disease

Neurobiology of Aging, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Is Parkinson Disease Better Defined Solely by Biology or as a Clinical–Biological Entity? Lessons to be Learned from Alzheimer's Disease on Biological Definition and Staging

Movement Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

The development of Alzheimer's disease (AD) classification and staging systems between 2000 2010 marked significant progress in integrating the neurodegenerative process clinical syndrome. This was made possible by improved techniques for measuring amyloid tau deposition vivo. Two schemas emerged: National Institute on Aging Alzheimer Association (NIA-AA) framework International Working Group (IWG) approach.1 NIA-AA ultimately gained international recognition through its 2011 2018 publications,2 latter suggesting a biological definition AD. 2024 version this system, now without NIA involvement, has sparked controversy that single core AD biomarker is diagnostic can be applied to practice.3 In response, IWG re-emerged with critical evaluation value both cognitively normal impaired individuals.4 Their appraisal literature concluded evidence insufficient support definitive diagnosis based biomarker. Instead, they proposed labeling such cases as "at-risk" AD, reserving "premanifest AD" multiple indicators, positive PET scans neocortical regions.4 Dubois colleagues4 raised concerns about psychological societal impact diagnosing individuals criteria alone, particularly since these may never develop symptoms. They also highlighted potential issues testing accuracy practice direct-to-consumer settings.4 debate parallels similar discussions Parkinson's (PD) research centered fundamental distinction risk factors actual presence. Whether or deposits constitute indicate presence mirrors debates alpha-synuclein seeding amplification assay (SAA) interpretation PD.5 Diagnosing PD preserved motor function solely SAA positivity problematic, especially early non-motor symptoms like constipation, depression, anxiety are nonspecific. Furthermore, other neurological diseases,6, 7 questioning use criterion definition. contrast there still no pathological synuclein neuroimaging provide spatial temporal brain topographical correlate SAA. Moving towards exclusively SAA+ nonspecific unlikely facilitate trials would enroll very heterogeneous population. emphasizes importance longitudinal validation diverse cohort studies. It notes varies significantly across different healthcare settings. These points important steering research. While test might show high specialized care environments, performance decrease substantially primary self-referred populations. (1) Article Origination: A. Design, B. Analysis Literature, (2) Manuscript Preparation: Writing First Draft, Editing Final Version. T.A.M.: 1A, 1B, 2A. C.S.: 2B. Financial Disclosures All Authors (for Preceding 12 Months): T.A.M. received compensation consulting being an advisory board member following organizations: AbbVie, Parkinson Movement Disorder Society, CHDI Foundation/Management, Sunovion, Merz, Roche. He grants from EU Joint Program - Neurodegenerative Disease Research, uOBMRI, Ontario Research Fund, CIHR, Michael J. Fox Foundation (MJFF), Canada, Consortium Brain Canada. C.S. employee Management, Inc. (advisors Foundation) consultancy honorarium Pfizer, Kyowa Kirin, vTv Therapeutics, GW Pharmaceuticals, Neuraly, Neuroderm, Neuroxpharm, Inflictis, Biocodex, Thelonious Mind, Novartis, Biogen Green Valley Pinteeon Pharmaceuticals. Data sharing not applicable article datasets were generated analysed during current study.

Language: Английский

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Plasma proteome profiling identified biomarkers for the differential diagnosis and molecular staging of neurodegenerative dementias

Published: April 21, 2025

Plasma biomarkers are emerging as noninvasive tools to detect neurodegenerative diseases and monitor treatments in clinical trials. The bPRIDE study investigates blood-based improve the differential diagnosis molecular staging of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal (FTD). Using proximity extension assay proteomics, we analyzed n=1319 plasma samples from 6 well-characterized cohorts. More than 200 proteins were found dysregulated across different groups. Levels GFAP showed most substantial increase along AD continuum. Integrin ITGAV ITGAM strongest downregulated body disorders correlated α-synuclein pathology an independent autopsy-confirmed cohort (n=129). High NEFL low levels markers specifically associated FTD. Findings translated into a selection 21 enable classification models causes high diagnostic performances within one single assay.

Language: Английский

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