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

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.

APOEε4 potentiates Aβ effects on longitudinal tangle accumulation via tau phosphorylation

“…Our statical models suggested that the APOEε4-dependent Aβ effects on longitudinal tau deposition were mediated by the concentrations of p-tau217 + . Although this suggest potential causal relationships that are accordance with previously proposed biological models of disease progression 27,38,39 , mechanistic studies are needed to examine this further. Finally, future multicenter studies with longer follow-up intervals and multiple time points are needed to better characterize the temporal relationships between APOEε4, Aβ, and tau across the AD spectrum.…”

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

“…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 Aβ accumulation, where neurodegeneration is typically not yet apparent. In late Aβ accumulators, a TREM2‐related microglial response parallels p‐tau 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 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 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 tau‐related changes in AD that is closely associated with Aβ, 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.…”

“…Previously it was shown that Aβ‐related increases in soluble hyperphosphorylated tau (i.e., p‐tau), detectable in plasma (Janelidze et al , 2021 ; Moscoso et al , 2021 ) and cerebrospinal fluid (CSF) (Mattsson‐Carlgren et al , 2020 ), precede tau aggregation. We have shown recently that soluble p‐tau increases may in fact drive tau aggregation and spread across interconnected brain regions (Pichet Binette et al , 2022 ) 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.…”

Construction of a DNA Nanoassembly Based on Spatially Ordered Recognition Elements for Inhibiting β-Amyloid Aggregation

“…Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, which is considered to be a kind of terrifying disease threatening human health and social well-being. , The symptoms of AD are characterized by gradual amnestic cognitive impairment accompanied by loss in speech express, visuospatial processing, and execution . The occurrence of cognitive symptoms often lags behind the progression of AD due to the slow and insidious onset of the disease. , However, current treatments cannot reverse the progress of the disease after the onset of cognitive symptoms. , Genetic evidence and biochemical and histopathological observations indicate that various neurotoxic aggregates formed during the aggregation of β-amyloid peptide (Aβ) and amyloid plaques formed by fibril deposition are the main factors for predisposing AD. , Aβ has been broadly regarded as an important biomarker and therapeutic target for AD. , Hence, developing therapeutic strategies by targeting Aβ is an effective pathway for AD treatment.…”