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Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease

Pichet Binette, Alexa LU ; Franzmeier, Nicolai ; Spotorno, Nicola LU ; Ewers, Michael ; Brendel, Matthias ; Biel, Davina ; Strandberg, Olof LU ; Janelidze, Shorena LU ; Palmqvist, Sebastian LU orcid and Mattsson-Carlgren, Niklas LU orcid , et al. (2022) In Nature Communications 13(1). p.6635-6635
Abstract

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau... (More)

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
13
issue
1
pages
1 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85141890639
  • pmid:36333294
ISSN
2041-1723
DOI
10.1038/s41467-022-34129-4
language
English
LU publication?
yes
id
07bf1e35-fc85-4a61-be65-730d03b1afeb
date added to LUP
2022-12-28 15:04:03
date last changed
2024-06-14 00:40:19
@article{07bf1e35-fc85-4a61-be65-730d03b1afeb,
  abstract     = {{<p>For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.</p>}},
  author       = {{Pichet Binette, Alexa and Franzmeier, Nicolai and Spotorno, Nicola and Ewers, Michael and Brendel, Matthias and Biel, Davina and Strandberg, Olof and Janelidze, Shorena and Palmqvist, Sebastian and Mattsson-Carlgren, Niklas and Smith, Ruben and Stomrud, Erik and Ossenkoppele, Rik and Hansson, Oskar}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{1}},
  pages        = {{6635--6635}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1038/s41467-022-34129-4}},
  doi          = {{10.1038/s41467-022-34129-4}},
  volume       = {{13}},
  year         = {{2022}},
}