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Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease

Pereira, Joana B. LU ; Janelidze, Shorena LU ; Ossenkoppele, Rik LU ; Kvartsberg, Hlin ; Brinkmalm, Ann ; Mattsson-Carlgren, Niklas LU orcid ; Stomrud, Erik LU orcid ; Smith, Ruben LU ; Zetterberg, Henrik LU and Blennow, Kaj LU , et al. (2021) In Brain : a journal of neurology 144(1). p.310-324
Abstract

It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor... (More)

It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
amyloid-β, MRI, neurofilament, neurogranin, PET, tau PET
in
Brain : a journal of neurology
volume
144
issue
1
pages
15 pages
publisher
Oxford University Press
external identifiers
  • scopus:85102153601
  • pmid:33279949
ISSN
1460-2156
DOI
10.1093/brain/awaa395
language
English
LU publication?
yes
id
4a2e0e0a-2e46-4b91-996c-f3f50242e74b
date added to LUP
2021-03-17 10:55:15
date last changed
2024-04-18 04:37:33
@article{4a2e0e0a-2e46-4b91-996c-f3f50242e74b,
  abstract     = {{<p>It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.</p>}},
  author       = {{Pereira, Joana B. and Janelidze, Shorena and Ossenkoppele, Rik and Kvartsberg, Hlin and Brinkmalm, Ann and Mattsson-Carlgren, Niklas and Stomrud, Erik and Smith, Ruben and Zetterberg, Henrik and Blennow, Kaj and Hansson, Oskar}},
  issn         = {{1460-2156}},
  keywords     = {{amyloid-β; MRI; neurofilament; neurogranin; PET; tau PET}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{310--324}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1093/brain/awaa395}},
  doi          = {{10.1093/brain/awaa395}},
  volume       = {{144}},
  year         = {{2021}},
}