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. 2024 May;20(5):3179-3192.
doi: 10.1002/alz.13764. Epub 2024 Mar 16.

Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aβ42/40 ratio to identify presence of brain amyloid

Matthew R Meyer  1 , Kristopher M Kirmess  1 , Stephanie Eastwood  1 , Traci L Wente-Roth  1 , Faith Irvin  1 , Mary S Holubasch  1 , Venky Venkatesh  1 , Ilana Fogelman  1 , Mark Monane  1 , Lucy Hanna  2 , Gil D Rabinovici  3 , Barry A Siegel  4 , Rachel A Whitmer  5 , Charles Apgar  6 , Randall J Bateman  4 , David M Holtzman  4 , Michael Irizarry  7 , David Verbel  7 , Pallavi Sachdev  7 , Satoshi Ito  8 , John Contois  1 , Kevin E Yarasheski  1 , Joel B Braunstein  1 , Philip B Verghese  1 , Tim West  1
Affiliations

Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aβ42/40 ratio to identify presence of brain amyloid

Matthew R Meyer et al. Alzheimers Dement. 2024 May.

Abstract

Background: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment.

Methods: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET.

Results: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status.

Discussion: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

Keywords: Alzheimer's; amyloid beta; blood biomarker; clinical validity; diagnostic; p‐tau217.

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Conflict of interest statement

All C2N co‐authors are salaried employees or consultants with equity interests in C2N Diagnostics. S.I., M.I., D.V., and P.S. are employees of Eisai Co., Ltd. D.M.H. co‐founded, has equity in, and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid. R.J.B. co‐founded, has equity in, and is on the scientific advisory board of C2N Diagnostics. R.J.B. has consulting relationships (12 months) with Roche (unpaid). B.A.S. reported grants and personal fees from the American College of Radiology during the conduct of the study; grants from Blue Earth Diagnostics, Curium Pharma, and Progenics Pharmaceuticals; and personal fees from Curium Pharma, Progenics Pharmaceuticals, Avid Radiopharmaceuticals, Capella Imaging, GE Healthcare, Lantheus Medical Imaging, and Siemens Healthineers outside the submitted work. G.D.R. receives research support from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, and Genentech. He has received consulting fees from Alector, Eli Lilly, Johnson & Johnson, and Merck. He is Associate Editor for JAMA Neurology. Ms. Hanna reported receiving grants from ACR during the conduct of the IDEAS study. All other authors declared no competing interests. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Differences in Aβ42/40 ratio and %p‐tau217 by CL status. Aβ42/40 ratio was significantly lower (p < 0.001) in CL > 25 participants (A). Blue line shows cut point of 0.089, which was defined for Aβ42/40 ratio in previous studies. Conversely, %p‐tau217 was statistically significantly higher (p < 0.001) in CL > 25 participants (B). Blue line shows optimal cut point (by Youden) of 4.2%. Aβ, amyloid beta; CL, Centiloid.
FIGURE 2
FIGURE 2
Diagnostic performance of APS2. APS2 was statistically significantly higher (p < 0.001) in CL > 25 participants (A). Blue line shows optimal cut point (by Youden) of 47.5. AUC‐ROC for individual analytes as well as APS2 result (B). The AUC‐ROC for p‐tau217 concentration (0.91, 95% CI: 0.89 to 0.94) was significantly lower than the AUC‐ROC for %p‐tau217 (0.94, 95% CI: 0.92 to 0.96, p < 0.0001, DeLong comparison). The AUC‐ROC for APS2 (0.94, 95% CI: 0.92 to 0.96) was not significantly different from the AUC‐ROC for %p‐tau217 (p = 0.27, DeLong comparison). APS2, Amyloid Probability Score 2; AUC‐ROC, area under receiver operating characteristic curve; CI, confidence interval; CL, Centiloid.
FIGURE 3
FIGURE 3
Concordance and discordance of Aβ42/40 ratio and %p‐tau217. APS2 heatmap and distribution of Aβ42/40 ratio and %p‐tau217 in combined cohort (A). APS2 values were calculated for all combinations of Aβ42/40 ratio and %p‐tau217 and color coded starting at green for 0 and ending in red for 100, with yellow anchored at optimal APS2 cut point of 47.5. Thus, the yellow diagonal line demonstrates where the Aβ42/40 ratio and %p‐tau217 merge to create a cut point that incorporates both amyloid (A) and tau (%pT217) biomarkers. The shape of the points represents the CL status for each of the study participants, with a circle (o) representing CL < 25 and a cross (x) representing CL > 25. Partitioning study participants into Aβ42/40 ratio positive/negative (A+/−) and %p‐tau217 positive/negative (%pT217+/−) shows significantly higher CL values in %pT217+ versus %pT217− participants (B). In the %pT217− participants, being A+ was associated with higher CL values, though the interquartile range of these CL values did not exceed the CL cut point of 25. Aβ, amyloid beta; APS2, Amyloid Probability Score 2; CL, Centiloid.
FIGURE 4
FIGURE 4
Accuracy of APS2 in subgroups. APS2 accuracy and the associated 95% confidence intervals were measured in the full data set as well as in subgroups based on race, ethnicity, sex, age, and apoE4 carrier status. Blue line shows the accuracy measured in the full dataset. Numbers in parentheses are the number of study participants enrolled in each of the subgroups. APS2, Amyloid Probability Score 2.
See this image and copyright information in PMC

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