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Background and purpose Methods Results Conclusions This study was undertaken to compare the performance of plasma p‐tau181 with that of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the identification of early biological Alzheimer disease (AD).We included 533 cognitively impaired participants from the Alzheimer's Disease Neuroimaging Initiative. Participants underwent PET scans, biofluid collection, and cognitive tests. Receiver operating characteristic analyses were used to determine the diagnostic accuracy of plasma p‐tau181 and [18F]FDG‐PET using clinical diagnosis and core AD biomarkers ([18F]florbetapir‐PET and cerebrospinal fluid [CSF] p‐tau181) as reference standards. Differences in the diagnostic accuracy between plasma p‐tau181 and [18F]FDG‐PET were determined by bootstrap‐based tests. Correlations of [18F]FDG‐PET and plasma p‐tau181 with CSF p‐tau181, amyloid β (Aβ) PET, and cognitive performance were evaluated to compare associations between measurements.We observed that both plasma p‐tau181 and [18F]FDG‐PET identified individuals with positive AD biomarkers in CSF or on Aβ‐PET. In the MCI group, plasma p‐tau181 outperformed [18F]FDG‐PET in identifying AD measured by CSF (p = 0.0007) and by Aβ‐PET (p = 0.001). We also observed that both plasma p‐tau181 and [18F]FDG‐PET metabolism were associated with core AD biomarkers. However, [18F]FDG‐PET uptake was more closely associated with cognitive outcomes (Montreal Cognitive Assessment, Mini‐Mental State Examination, Clinical Dementia Rating Sum of Boxes, and logical memory delayed recall, p < 0.001) than plasma p‐tau181.Overall, although both plasma p‐tau181 and [18F]FDG‐PET were associated with core AD biomarkers, plasma p‐tau181 outperformed [18F]FDG‐PET in identifying individuals with early AD pathophysiology. Taken together, our study suggests that plasma p‐tau181 may aid in detecting individuals with underlying early AD. [ABSTRACT FROM AUTHOR]