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

Pichet Binette, Alexa LU ; Mammana, Angela ; Wisse, Laura LU orcid ; Rossi, Marcello ; Strandberg, Olof LU ; Smith, Ruben LU ; Mattsson-Carlgren, Niklas LU orcid ; Janelidze, Shorena LU ; Palmqvist, Sebastian LU orcid and Ticca, Alice , et al. (2024) In Alzheimer's and Dementia 20(11). p.7624-7634
Abstract

INTRODUCTION: We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We 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. RESULTS: Across cohorts, the... (More)

INTRODUCTION: We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We 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. RESULTS: Across 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. DISCUSSION: We 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
amyloid beta, co-pathology, Lewy body, neurodegenerative diseases, seed-amplification assay, tau
in
Alzheimer's and Dementia
volume
20
issue
11
pages
11 pages
publisher
Wiley
external identifiers
  • pmid:39258841
  • scopus:85203674904
ISSN
1552-5260
DOI
10.1002/alz.14225
language
English
LU publication?
yes
id
07f8048b-a531-440b-a2d4-14d1467bd541
date added to LUP
2024-12-13 12:55:09
date last changed
2025-07-12 19:10:04
@article{07f8048b-a531-440b-a2d4-14d1467bd541,
  abstract     = {{<p>INTRODUCTION: We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. METHODS: We 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. RESULTS: Across 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. DISCUSSION: We 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.</p>}},
  author       = {{Pichet Binette, Alexa and Mammana, Angela and Wisse, Laura and Rossi, Marcello and Strandberg, Olof and Smith, Ruben and Mattsson-Carlgren, Niklas and Janelidze, Shorena and Palmqvist, Sebastian and Ticca, Alice and Stomrud, Erik and Parchi, Piero and Hansson, Oskar}},
  issn         = {{1552-5260}},
  keywords     = {{amyloid beta; co-pathology; Lewy body; neurodegenerative diseases; seed-amplification assay; tau}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{7624--7634}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's and Dementia}},
  title        = {{Associations between misfolded alpha-synuclein aggregates and Alzheimer's disease pathology in vivo}},
  url          = {{http://dx.doi.org/10.1002/alz.14225}},
  doi          = {{10.1002/alz.14225}},
  volume       = {{20}},
  year         = {{2024}},
}