High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis

Objective We examined whether plasma beta-amyloid (A beta)42/A beta 40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/A beta 42 as reference standards. Methods Using an immunoprecipitation and liquid chromatography-mass spectrometry assay, we measured A beta 42/A beta 40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan. Results Plasma A beta 42/A beta 40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88, 95% confidence interval [CI] 0.82-0.93) and CSF p-tau181/A beta 42 (AUC 0.85, 95% CI 0.79-0.92). The combination of plasma A beta 42/A beta 40, age, and APOE epsilon 4 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 A beta 42/A beta 40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma A beta 42/A beta 40 (p = 0.01). Conclusions Plasma A beta 42/A beta 40, especially when combined with age and APOE epsilon 4 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 A beta 42/A beta 40 are at increased risk for converting to amyloid PET-positive. Plasma A beta 42/A beta 40 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 II evidence that plasma A beta 42/A beta 40 levels accurately determine amyloid PET status in cognitively normal research participants.