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.
Highlights
The aberrant accumulation of aggregated amyloid-β (Aβ) peptides and abnormally phosphorylated tau protein as extracellular plaques and intraneuronal neurofibrillary tangles (NFTs), respectively, are the fundamental hallmarks of Alzheimer’s disease (AD) neuropathology and remain to be the conclusive confirmation of the disease— a definitive diagnosis cannot be attributed until post-mortem.1 3 Vol.:(0123456789)Acta Neuropathologica (2021) 141:709–724the characterization of AD in vivo has been greatly enhanced by the visualization of Aβ [52] and tau [35] aggregates by positron emission tomography (PET)
The findings show that plasma p-tau231, like plasma p-tau181, demonstrates high diagnostic accuracy in detecting AD in the dementia stage of the disease, which included neuropathologically
No report of plasma p-tau231 has been described in blood, despite it being a widely reported cerebrospinal fluid (CSF) biomarker [2, 11, 14, 15, 18, 20, 30, 33, 53, 58]
Summary
The aberrant accumulation of aggregated amyloid-β (Aβ) peptides and abnormally phosphorylated tau protein as extracellular plaques and intraneuronal neurofibrillary tangles (NFTs), respectively, are the fundamental hallmarks of Alzheimer’s disease (AD) neuropathology and remain to be the conclusive confirmation of the disease— a definitive diagnosis cannot be attributed until post-mortem.1 3 Vol.:(0123456789)Acta Neuropathologica (2021) 141:709–724the characterization of AD in vivo has been greatly enhanced by the visualization of Aβ [52] and tau [35] aggregates by positron emission tomography (PET). The reduction of Aβ42 or Aβ42/40 and the increase of totaltau (t-tau) and phosphorylated tau (p-tau) represent the core cerebrospinal fluid (CSF) biomarker changes [43] Both CSF and PET biomarkers have significant practical, logistic and economical drawbacks and are unlikely to be widely used in primary care for the assessment of AD or other neurodegenerative diseases. The emergence of blood biomarkers for the specific detection of AD pathophysiology offers the scalability required for patient or population triage. This would complement CSF and PET biomarkers in the initial assessment in memory clinics or therapeutic trial recruitment and monitoring. Plasma p-tau181 and p-tau217 are highly promising clinical biomarkers in the assessment of memory complaints and risk of disease progression
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