Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

Abstract

ABSTRACTFor optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand 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. In early stages of AD, increased concentration of soluble CSF p-tau was the main driver of accumulation of insoluble tau aggregates across the brain, and mediated the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations were 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 were associated with cognitive decline, which was mediated by faster increase of tau aggregates. In AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline was driven by 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.