Clinical utility of plasma Aβ42/40 ratio by LC-MS/MS in Alzheimer’s disease assessment

Abstract

ABSTRACTINTRODUCTIONPlasma Aβ42/40 ratio can be used to help predict amyloid PET status, but its clinical utility in Alzheimer’s disease (AD) assessment is unclear.METHODSAβ42/40 ratio was measured by LC-MS/MS in 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and 6,192 consecutive clinical specimens submitted for Aβ42/40 testing.RESULTSHigh diagnostic sensitivity and negative predictive value (NPV) for Aβ-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients’ cognitive impairment and help reduce PET evaluation by about 40%.DISCUSSIONUsing high-throughput plasma Aβ42/40 LC-MS/MS assays can help reduce PET evaluations in patients with low likelihood of AD pathology, allowing for cost savings.HighlightsA new plasma LC-MS/MS assay for the Aβ42/Aβ40 ratio has clinical utility in AD assessment.Performance was assessed using specimens with a moderate prevalence of Aβ-PET positivity.Analysis was extrapolated to 6,192 consecutive clinical specimens submitted for ratio testing.Assay cutpoints were proposed to help suggest clinical management decisions.Based on the assay’s high NPV, costly PET evaluations may be avoided for many individuals.Research in ContextSystematic ReviewAβ42/Aβ40 ratio data were analyzed from 250 ADRC cohort participants and 6,192 plasma specimens submitted for Aβ42/40 ratio testing by LC-MS/MS at Quest Diagnostics.InterpretationBased on its high NPV, the assay identifies individuals likely to have negative amyloid PET results. Higher discriminatory power and larger fold-changes between PET-positive and negative individuals were observed compared with previous studies. Our “real-world” data set, combined with known performance characteristics, allows us to suggest cutpoints and clinical decisions based on plasma Aβ42/40 ratios.Future DirectionsLongitudinal plasma specimens from individuals who convert from PET-negative to positive, or that transition from cognitively normal to MCI and AD, will improve understanding of the prognostic utility of the Aβ42/40 ratio. Using Aβ42/40 ratio alone or combined with other biomarkers, to follow patients with cognitive impairment may yield insights regarding their disease conditions and progression and who may benefit from disease-modifying therapeutics.