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

Alexa Pichet Binette (), Nicolai Franzmeier, Nicola Spotorno, Michael Ewers, Matthias Brendel, Davina Biel, Olof Strandberg, Shorena Janelidze, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Ruben Smith, Erik Stomrud, Rik Ossenkoppele and Oskar Hansson ()
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Alexa Pichet Binette: Lund University
Nicolai Franzmeier: University Hospital, LMU Munich
Nicola Spotorno: Lund University
Michael Ewers: University Hospital, LMU Munich
Matthias Brendel: University Hospital, LMU Munich
Davina Biel: University Hospital, LMU Munich
Olof Strandberg: Lund University
Shorena Janelidze: Lund University
Sebastian Palmqvist: Lund University
Niklas Mattsson-Carlgren: Lund University
Ruben Smith: Lund University
Erik Stomrud: Lund University
Rik Ossenkoppele: Lund University
Oskar Hansson: Lund University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34129-4

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