AbstractBackgroundIn Alzheimer's disease (AD), plasma amyloid beta (Aβ)_1‐42 and phosphorylated tau (p‐tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown.MethodsPrototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.ResultsThe p‐tau181/Aβ_1‐42 ratio showed the best prediction of Aβ‐PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86–0.95) and in CN (AUC = 0.873; 0.80–0.94), and symptomatic (AUC = 0.908; 0.82–1.00) adults. Plasma p‐tau181/Aβ_1‐42 ratio correlated with cerebrospinal fluid (CSF) p‐tau181 (Elecsys, Spearman's ρ = 0.74, P < 0.0001) and predicted abnormal CSF Aβ (AUC = 0.816; 0.74–0.89). The p‐tau181/Aβ_1‐42 ratio also predicted future rates of cognitive decline assessed by AIBL Preclinical Alzheimer Cognitive Composite or Clinical Dementia Rating Sum of Boxes (P < 0.0001).DiscussionPlasma p‐tau181/Aβ_1‐42 ratio predicted both Aβ‐PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical AD trials.