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

Author

Listed:
  • Alexa Pichet Binette

    (Lund University)

  • Nicolai Franzmeier

    (University Hospital, LMU Munich)

  • Nicola Spotorno

    (Lund University)

  • Michael Ewers

    (University Hospital, LMU Munich
    German Center for Neurodegenerative Diseases (DZNE))

  • Matthias Brendel

    (University Hospital, LMU Munich
    Munich Cluster for Systems Neurology (SyNergy))

  • Davina Biel

    (University Hospital, LMU Munich)

  • Olof Strandberg

    (Lund University)

  • Shorena Janelidze

    (Lund University)

  • Sebastian Palmqvist

    (Lund University
    Skåne University Hospital)

  • Niklas Mattsson-Carlgren

    (Lund University
    Skåne University Hospital
    Lund University)

  • Ruben Smith

    (Lund University
    Skåne University Hospital)

  • Erik Stomrud

    (Lund University
    Skåne University Hospital)

  • Rik Ossenkoppele

    (Lund University
    Vrije Universiteit Amsterdam, Amsterdam UMC)

  • Oskar Hansson

    (Lund University
    Skåne University Hospital)

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 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.

Suggested Citation

  • Alexa Pichet Binette & Nicolai Franzmeier & Nicola Spotorno & Michael Ewers & Matthias Brendel & Davina Biel & Olof Strandberg & Shorena Janelidze & Sebastian Palmqvist & Niklas Mattsson-Carlgren & Ru, 2022. "Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34129-4
    DOI: 10.1038/s41467-022-34129-4
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    References listed on IDEAS

    as
    1. Zhuohao He & Jennifer D. McBride & Hong Xu & Lakshmi Changolkar & Soo-jung Kim & Bin Zhang & Sneha Narasimhan & Garrett S. Gibbons & Jing L. Guo & Michael Kozak & Gerard D. Schellenberg & John Q. Troj, 2020. "Transmission of tauopathy strains is independent of their isoform composition," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    2. Jacob W. Vogel & Yasser Iturria-Medina & Olof T. Strandberg & Ruben Smith & Elizabeth Levitis & Alan C. Evans & Oskar Hansson, 2020. "Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Nicolai Franzmeier & Julia Neitzel & Anna Rubinski & Ruben Smith & Olof Strandberg & Rik Ossenkoppele & Oskar Hansson & Michael Ewers, 2020. "Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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    Cited by:

    1. Linda Karlsson & Jacob Vogel & Ida Arvidsson & Kalle Åström & Shorena Janelidze & Kaj Blennow & Sebastian Palmqvist & Erik Stomrud & Niklas Mattsson-Carlgren & Oskar Hansson, 2024. "Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Nicolai Franzmeier & Amir Dehsarvi & Anna Steward & Davina Biel & Anna Dewenter & Sebastian Niclas Roemer & Fabian Wagner & Mattes Groß & Matthias Brendel & Alexis Moscoso & Prithvi Arunachalam & Kaj , 2024. "Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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