High concordance between plasma amyloid β biomarkers by IP‐MALDI‐MS and visual assessment of amyloid PET

Abstract

AbstractBackgroundAbnormal amyloid‐β (Aβ) deposition in the brain has been defined as the earliest pathological change of Alzheimer disease (AD). We combined immunoprecipitation (IP) with MALDI‐TOF MS to develop IP‐MALDI‐MS, which is an analytical technique for plasma Aβ. This technique has previously revealed that APP669‐711/Aβ1‐42 ratio, Aβ1‐40/Aβ1‐42 ratio, and a combination of these two biomarkers (a composite biomarker) in human plasma correlates highly with SUVR obtained from amyloid PET (Nakamura et al., Nature, 2018). In this work, we validated a concordance between plasma Aβ biomarkers by IP‐MALDI‐MS and visual amyloid PET status with an independent dataset from the previous report.MethodPlasma samples were obtained from 41 Aβ+ and 55 Aβ‐ subjects classified using PET with PIB tracer in National Center for Geriatrics and Gerontology. Aβ‐related peptides were immunoprecipitated from the sample spiked by stable isotope‐labeled (SIL) Aβ1‐38 using beads coupled with anti‐Aβ antibody. After the IP was performed two times consecutively, Aβ‐related peptides eluted from the antibody beads were applied to MALDI‐TOF MS. SIL‐Aβ1‐38 was used as an internal standard for normalizing an intensity of each Aβ‐related peptide. APP669‐711/Aβ1‐42 ratio and Aβ1‐40/Aβ1‐42 ratio were calculated from those intensities and then the composite biomarker was generated as previous reported.ResultAPP669‐711/Aβ1‐42 ratio, Aβ1‐40/Aβ1‐42 ratio and the composite biomarker were significantly higher in the Aβ+ group than the Aβ‐ group (p < 0.001). IP‐MALDI‐MS discriminated Aβ‐PET positivity with high AUC in APP669‐711/Aβ1‐42 ratio (92.8%), Aβ1‐40/Aβ1‐42 ratio (95.7%) and the composite biomarker (95.8%). Furthermore, an accuracy of the three biomarkers was 89.6‐92.7% in the Aβ+/‐ classification.ConclusionOur results demonstrated high concordance of plasma Aβ biomarkers with visual amyloid PET status. The measurement by IP‐MALDI‐MS can provide the biomarker values highly associated with Aβ‐PET positivity.