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

Abstract

For 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.

sTREM2 is associated with amyloid‐related p‐tau increases and glucose hypermetabolism in Alzheimer's disease

“…Conflicting findings of microglial activation on the development of tau pathology may be explained by several factors, including the use of different animal models of AD, which recapitulate different aspects of AD pathophysiology, or using different markers of tau pathology including soluble and fibrillar forms of tau. CSF p-tau reflects hyperphosphorylated tau in its soluble form, one of the earliest taurelated changes in AD that is closely associated with Ab, preceding the formation of intracellular neurofibrillary tau aggregates (Hansson, 2021;Pichet Binette et al, 2022). Therefore, microglia may have different effects on p-tau hyperphosphorylation and aggregation, which will be important to study in greater detail in future studies by combining fluid and PET biomarkers of microglial activation and tau pathology.…”

“…Microglia consume large amounts of glucose (Xiang et al, 2021), hence a TREM2-related microglial response may result in FDG-PET hypermetabolism in the earliest stages of Ab accumulation, where neurodegeneration is typically not yet apparent. In late Ab accumulators, a TREM2-related microglial response parallels ptau 181 which has been associated with subsequent neurodegeneration (Ossenkoppele et al, 2021;Pichet Binette et al, 2022). Hence higher sTREM2 may be associated with FDG-PET hypometabolism in subjects with late-stage Ab accumulation.…”

Soluble TREM2 mediates earliest amyloid-associated p-tau increases and cerebral glucose hypermetabolism in Alzheimer’s disease

“…Microglia consume large amounts of glucose (16), hence sTREM2-related microglial activation may result in FDG-PET hypermetabolism in the earliest stages of Aβ accumulation, where neurodegeneration is typically not yet apparent. In late Aβ accumulators, sTREM2-related microglial activation parallels p-tau which has been associated with subsequent neurodegeneration (9, 41). Hence higher sTREM2 may be associated with FDG-PET hypometabolism in subjects with late-stage Aβ accumulation.…”

“…Conflicting findings of microglial activation on the development of tau pathology may be explained by several factors, including the use of different animal models of AD, which recapitulate different aspects of AD pathophysiology, or by the use of different markers of tau pathology including soluble and fibrillar forms of tau. CSF p-tau reflects hyperphosphorylated tau in its soluble form, one of the earliest tau-related changes in AD that is closely associated with Aβ, preceding the formation of intracellular neurofibrillary tau aggregates (9, 51). Therefore, microglia may have different effects on p-tau hyperphosphorylation and aggregation, which will be important to study in greater detail in future studies by combining fluid and PET biomarkers of microglial activation and tau pathology.…”

“…p-tau), detectable in plasma (6, 7) and cerebrospinal fluid (CSF) (8), precede tau aggregation. We have shown recently that soluble p-tau increases may in fact drive tau aggregation and spread across interconnected brain regions (9) therefore, soluble p-tau increases may be a key link between Aβ deposition and tau aggregation in AD. However, the underlying mechanisms that link Aβ and subsequent increases in soluble p-tau in CSF or plasma are not well understood.…”