Objective: We examined whether plasma Aβ42/Aβ40, as measured by a high precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF pTau181/Aβ42 as reference standards. Methods: Using an immunoprecipitation and liquid chromatography-mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within eighteen months of an amyloid PET scan. Results: Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (ROC AUC 0.88, 95% confidence intervals [CI] 0.82-0.93) and CSF pTau181/Aβ42 (AUC 0.85, 95% CI 0.79-0.92). The combination of plasma Aβ42/Aβ40, age and APOE ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90-0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (p=0.01). Conclusions: Plasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia. Classification of Evidence: This study provides Class I evidence that plasma Aβ42/Aβ40, as measured by a liquid chromatography-mass spectrometry assay, accurately diagnoses brain amyloidosis in cognitively normal research participants.