Evaluation of Plasma pTau217 plus Abeta42/40, and pTau217/Abeta42 Ratio as Confirmatory Tests for Amyloid Pathology in Alzheimer’s Disease (AD)
John Winslow1, Ahmed Chenna1, Mintzu Lo1, Youssouf Badal1, Brandon Yee1, Robert Martone2, Christos Petropoulos1, Christopher Fowler3, Simon Laws4, Stephanie Rainey-Smith5, Ralph N Martins6, Christopher Rowe3, Colin Masters3, James D Doecke7
1Labcorp/Monogram Biosciences, 2Labcorp Drug Development, 3The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 4Centre for Precision Health, Edith Cowan University, 5Centre for Healthy Ageing, Murdoch University, 6School of Medical and Health Sciences, Edith Cowan University, 7The Australian e-Health Research Centre, CSIRO
Objective:
Multiple analytical approaches, based on plasma pTau217 and Aβ42/40 measurements, are evaluated using discriminatory performance for amyloid PET with the goal of developing a confirmatory test for Aβ pathology demonstrating >90% sensitivity and specificity.
Background:
Recent advances in automated immunoassays have enabled sensitive detection of AD neuropathological markers Aβ42/40 and pTau217 in blood plasma, however, most exhibit <90% sensitivity and specificity with the application of a single cutoff. Further characterization of increased diagnostic accuracy in pre- and symptomatic AD subjects is needed.
Design/Methods:
One hundred-ninety-seven participants from the AIBL cohort were selected representing a cross-sectional AD continuum population: cognitive unimpaired (CU) Aβ- (n=75), CU Aβ+ (n=48), mild cognitive impairment (MCI) Aβ+ (n=26), and AD Aβ+ (n=48) with amyloid PET positivity prevalence of 62.5%. EDTA-plasma samples were analyzed with Lumipulse pTau217 and Aβ42/40 assays. Multivariable models and ratios combining biomarkers, and +/- adjustment for demographic variables, were tested vs. single measurements for ROC-AUC concordance with amyloid PET, applying single vs. dual cutoff approaches.
Results:
Models containing pTau217 and Aβ42 or Aβ42/40 ratio, adjusted for demographic variables, provided improved concordance with amyloid PET over pTau217 alone in the entire group (AUC=0.965 vs 0.941). pTau217/Aβ42 ratio results in AUC=0.961 (unadjusted, p = 0.01 vs pTau217 alone) vs 0.97 (adjusted). Application of a single pTau217/Aβ42 cutoff results in 93% sensitivity, 92% specificity and 93% accuracy; an improvement over pTau217 alone (95% sensitivity, 83% specificity, 90% accuracy). Application of dual pTau217/Aβ42 cutoffs set to achieve 95% sensitivity and specificity results in 9% of participants in an intermediate category.
Conclusions:
The improved performance of the pTau217/Aβ42 ratio relative to pTau217 alone, comparable to more complex multivariable models, meets a recommended performance of a confirmatory AD blood biomarker test of >90% sensitivity and specificity. Further characterization will be performed in a cognitive impaired intent to treat population.
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