Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

Abstract

The links between β-amyloid (Aβ) and tau in Alzheimer’s disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

Soluble P-tau217 reflects both amyloid and tau pathology in the human brain and mediates the association of amyloid with neocortical tau

“…3). These results are congruent with recent studies showing that both blood and CSF P-tau217 is associated with Aβ PET also in tau PET negative cases 7,12 . Together, these results imply that plasma P-tau217 is not associated with tau tangle pathology independent from Aβ pathology, including primary age-related tauopathy (PART, see Fig.…”

“…Plasma P-tau217 levels have particularly high accuracy for AD, and are correlated with tangle densities in post-mortem data 6 . However, recent studies have suggested that CSF P-tau217 (and other P-tau variants) can be increased as a function of Aβ accumulation, in individuals who are tau negative as determined by positron emission tomography (PET) 7,8 (but note that tau PET has limited sensitivity to detect very sparse tau aggregation 9 ). It is unclear to what degree plasma P-tau217 levels depend on Aβ versus tau load in the brain.…”

Connectome-mediated prediction of future tau-PET burden in Alzheimer’s disease

“…Our findings, showing a strong predictive association between total baseline amyloid and future tau PET accumulation support the scenario where amyloid is causally associated with the deposition of tau PET (Mattsson-Carlgren et al 2020).…”

“…The mounting evidence associating tau accumulation and progression of Alzheimer's disease (Giannakopoulos et al 2003;La Joie et al 2020;Mattsson-Carlgren et al 2020) combined with the failure of anti-amyloid therapies to slow down cognitive decline in AD patients has made tau the new target for many therapies (Lo et al 2014). For drug developers, the ability to predict the longitudinal progression of tau can enormously impact the design of and patient selection for clinical trials.…”

“…Forecasting the pattern and magnitude of tau accumulation, however, remain a challenge. While some studies (Jack et al 2018;Pontecorvo et al 2019) have shown a significant association between magnitude of SUVr increase and the pattern of baseline tau burden, others (Harrison et al 2019;Sintini et al 2019) have shown FTP increasing in frontal areas that do not coincide with regions with major FTP binding at baseline in AD patients or even that only CSF tau (but not tau PET) predicts tau PET accumulation in cognitively impaired individuals (Mattsson-Carlgren et al 2020). Variety of these results illustrates a knowledge gap around the factors leading to tau accumulation in particular regions of the brain.…”