Soluble Phosphorylated Tau as a Target in Alzheimer's Disease and other Tauopathies

The primary thrust of Alzheimer's research and clinical development of therapies remains the targeting of amyloid-β and tau aggregates. The failure to produce meaningful benefits in patients, even given reductions in amyloid-β and tau, is not shifting the focus of most research groups to other entirely different approaches, but rather to question whether the complexity of amyloid-β and tau biochemistry means that the wrong locations or types of these molecules were targeted by the immunotherapies used to date in human trials.

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 positron emission tomography (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 cerebrospinal fluid (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 suggests that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.


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