Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease

Abstract

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e., abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status (AUC = 0.947; pdiff < 0.015) or progression to Alzheimer's dementia (AUC = 0.932; pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange, 0.835-0.872; pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji, and p-tau181Splex (AUCrange, 0.642-0.813; pdiff ≤0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; pdiff = 0.003 vs p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange, 0.320-0.669). In conclusion, the findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx, and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.

Is plasma amyloid-β 1–42/1–40 a better biomarker for Alzheimer’s disease than AβX–42/X–40?

“…The amyloid-β (Aβ)42/40 ratio in blood plasma has turned out to represent a highly attractive and robust peripheral biomarker of the cerebral amyloid pathology associated with Alzheimer’s disease (AD) [ 1 – 5 ]. Furthermore, a number of recent studies have shown that also the plasma concentrations of specific phosphorylated forms of tau protein, namely p-tau181, ptau217 and ptau231, can reliably detect an abnormal brain Aβ status as indicated by Aβ-positron emission tomography (Aβ-PET) or low CSF Aβ42/40 [ 6 – 11 ]. Recently, the first plasma Aβ42/40 assay gained approval by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Amendments (CLIA) protocol [ 12 ].…”

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

“…21 Similarly, previous comparisons between multiple species and assays of p-tau measures showed only a modest correlation, suggesting also significantly different diagnostic performance. 11,22 Considering the differences in clinical performance of different assays for the same biomarkers, importance the use of high-performing assays is of utmost when comparing different biomarkers to avoid reporting differences that are related to the method rather than the biomarkers themselves.…”

Plasma phosphorylated tau 181 predicts amyloid status and conversion to dementia stage dependent on renal function

“…This observation is very important, and we advocate minimizing the false detection of a pathological situation in patients by always combining plasma P-Tau181 with an assessment of renal function, e.g., through creatinine measurement and GFR estimation. This recommendation should be confirmed for other P-Tau isoforms (P-Tau217, P-Tau231) measured by immunoassay 25 or mass spectrometry 30 . The clearance of P-Tau by the kidney will have to be studied in more detail, taking into account our knowledge of the urinary excretion of protein in physiological and pathological conditions 31 and the very small amounts of this biomarker detected so far in the urine in free form 32 or associated with exosomes 33 .…”

“…We advocate minimizing the false detection of a pathological situation in patients by always combining plasma P-Tau181 with an assessment of renal function, e.g., through creatinine measurement and GFR estimation. This recommendation should be confirmed for other P-Tau isoforms (P-Tau217, P-Tau231) measured by immunoassay 25 or mass spectrometry 30 . We cannot exclude at this stage that altered renal function may also contribute in some way to the progression of AD.…”