TY - JOUR
T1 - Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease
AU - Pichet Binette, Alexa
AU - Franzmeier, Nicolai
AU - Spotorno, Nicola
AU - Ewers, Michael
AU - Brendel, Matthias
AU - Biel, Davina
AU - Strandberg, Olof
AU - Janelidze, Shorena
AU - Palmqvist, Sebastian
AU - Mattsson-Carlgren, Niklas
AU - Smith, Ruben
AU - Stomrud, Erik
AU - Alzheimer’s Disease Neuroimaging Initiative
AU - Ossenkoppele, Rik
AU - Hansson, Oskar
N1 - Publisher Copyright: © 2022. The Author(s).
PY - 2022/11/4
Y1 - 2022/11/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141890639&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-022-34129-4
DO - https://doi.org/10.1038/s41467-022-34129-4
M3 - Article
C2 - 36333294
SN - 2041-1723
VL - 13
SP - 6635
JO - Nature communications
JF - Nature communications
IS - 1
ER -