Pyroglutamate-modified amyloid β (AβpE3) could be a biomarker for Aβ plaque pathology in the brain. An ultra-high-sensitive assay is needed for detecting AβpE3-40.Immunomagnetic reduction was used for quantification of AβpE3-40 in plasma from 46 participants. The concentrations of AβpE3-40 of these subjects were compared with 18F-florbetapir positron emission tomography (PET) images.AβpE3-40 concentration was 44.1 ± 28.2 fg/mL in PET- (n = 28) and 91.6 ± 54.6 fg/mL in PET+ (n = 18; P < .05). The cutoff value of AβpE3-40 for discriminating PET- from PET+ was 55.5 fg/mL, resulting in a sensitivity of 83.3%, a specificity of 71.4%. The concentration of AβpE3-40 showed a moderate correlation (r = 0.437) with PET standardized uptake value ratio.We did not enroll pre-clinical AD subject with normal cognition but Aβ PET+. It would be an important issue to explore the feasibility of using AβpE3-40 for screening pre-clinical subjects.These results reveal the feasibility of detecting Aβ pathology using quantification of a plaque-derived Aβ molecule in plasma.