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

INTRODUCTIONPlasma A{beta}42/40 ratio can be used to help predict amyloid PET status, but its clinical utility in Alzheimers disease (AD) assessment is unclear. METHODSA{beta}42/40 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 A{beta}42/40 testing. RESULTSHigh diagnostic sensitivity and negative predictive value (NPV) for A{beta}-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between A{beta}42/40 values for individuals with positive vs negative A{beta}-PET results. Assuming a moderate prevalence of A{beta}-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 A{beta}42/40 LC-MS/MS assays can help reduce PET evaluations in patients with low likelihood of AD pathology, allowing for cost savings. HighlightsO_LIA new plasma LC-MS/MS assay for the A{beta}42/A{beta}40 ratio has clinical utility in AD assessment. C_LIO_LIPerformance was assessed using specimens with a moderate prevalence of A{beta}-PET positivity. C_LIO_LIAnalysis was extrapolated to 6,192 consecutive clinical specimens submitted for ratio testing. C_LIO_LIAssay cutpoints were proposed to help suggest clinical management decisions. C_LIO_LIBased on the assays high NPV, costly PET evaluations may be avoided for many individuals. C_LI Research in ContextO_ST_ABSSystematic ReviewC_ST_ABSA{beta}42/A{beta}40 ratio data were analyzed from 250 ADRC cohort participants and 6,192 plasma specimens submitted for A{beta}42/40 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 A{beta}42/40 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 A{beta}42/40 ratio. Using A{beta}42/40 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.