Associations between misfolded alpha‐synuclein aggregates and Alzheimer's disease pathology in vivo

Author:

Pichet Binette Alexa1ORCID,Mammana Angela2,Wisse Laura3,Rossi Marcello2,Strandberg Olof1,Smith Ruben14,Mattsson‐Carlgren Niklas156,Janelidze Shorena1,Palmqvist Sebastian14, ,Ticca Alice7,Stomrud Erik14,Parchi Piero27,Hansson Oskar14

Affiliation:

1. Clinical Memory Research Unit Department of Clinical Sciences Malmö Lund University Lund Sweden

2. IRCCS Istituto delle Scienze Neurologiche di Bologna (ISNB) Bologna Italy

3. Diagnostic Radiology Unit Department of Clinical Sciences Lund Lund University Lund Sweden

4. Memory Clinic Skåne University Hospital Malmö Sweden

5. Department of Neurology Skåne University Hospital Malmö Sweden

6. Wallenberg Center for Molecular Medicine Lund University Lund Sweden

7. Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Abstract

AbstractINTRODUCTIONWe examined the relations of misfolded alpha synuclein (α‐synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts.METHODSWe included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER‐2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross‐sectional cerebrospinal fluid (CSF) α‐synuclein measurement from seed‐amplification assay as well as cross‐sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status.RESULTSAcross cohorts, the main biomarker associated with α‐synuclein positivity at baseline was higher levels of Aβ pathology (all p values ≤ 0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α‐synuclein –positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p = 0.02), compared to α‐synuclein –negative participants in BioFINDER‐2 but not in ADNI.DISCUSSIONWe showed associations between concurrent misfolded α‐synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans.Highlights: Amyloid beta (Aβ), but not tau, was associated with alpha‐synuclein (α‐synuclein) positivity. Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status. α‐synuclein–positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts.

Funder

National Institute on Aging

Alzheimer's Association

Hjärnfonden

Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse

Alzheimer's Disease Neuroimaging Initiative

National Institutes of Health

National Institute of Biomedical Imaging and Bioengineering

Alzheimer's Drug Discovery Foundation

BioClinica

Fujirebio Europe

GE Healthcare

Merck

Novartis Pharmaceuticals Corporation

Pfizer

H2020 European Research Council

Publisher

Wiley

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