Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Abstract

The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.

The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

“…To date, there have been five studies that have addressed the relationship between plasma p-tau measurements and post-mortem data. All studies confirmed that plasma p-tau could separate AD pathology from non-AD pathology with high accuracy [80][81][82][83]98]. It was reported that plasma p-tau217 had a high accuracy in predicting AD pathology from non-AD pathology and demonstrated a strong relationship between p-tau217 and NFT density score in ADwhich was not observed for non-AD [82].…”

“…It must be noted that the advantage of p-tau217 over p-tau181 has been demonstrated using mass spectrometry [99]. One recent report examines p-tau231 in blood [83] and suggests that while there is no diagnostic advantage over p-tau181, p-tau231 increases early in preclinical disease. Plasma Aβ42/Aβ40, which is superior to plasma Aβ42, only has achieved partial fulfilment for the same criteria fully achieved by p-tau.…”

“…MCI) stage where the interval between blood and post-mortem assessment would be considerable. We also recognize at the time of the review recent data on plasma p-tau231 could be included in the evaluation [83] despite being sporadically mentioned. A further limitation is that while we aimed to be as inclusive as possible when reviewing the literature, our search was not conducted as a formal systematic review.…”

“…A method to quantify plasma and serum p-tau181, more sensitive than the Simoa assay previously described, was then later developed [79]. These studies are the basis for the accumulating evidence for measuring p-tau181 by Simoa [79] and MSD [80,81] as well as p-tau217 [82] and more recently p-tau231 [83]. The phase 1 aim is fully achieved for p-tau.…”

“…In some p-tau studies, demographic factors were included in a linear regression model, suggesting an incidental effect on the biomarker performance, but were not individually reported. Karikari et al [79] and Ashton et al [83] presented data from young CU individuals (< 40 years) and demonstrated a significant reduction as compared to CU elderly adults without amyloid pathology (> 65 years) in p-tau181 and p-tau231, respectively. Further, Tatebe et al [76] demonstrated a positive correlation between age and p-tau181 in individuals with Down syndrome, with weak correlations reported by Lantero Rodriguez et al (r = 0.25-0.30) [98] and no relationship reported by Thijssen et al [81].…”