Abstract
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.