Predictive Value of Plasma Biomarkers in Tau-PET Transitions.
OBJECTIVE: The objective of this study was to determine the predictive value of amyloid-positron emission tomography (PET) versus the plasma ratio of phosphorylated tau at threonine 217 (p-tau217) to non-phosphorylated tau217 (%p-tau217) for tau-PET transitions (T- to T+). The added value of combining plasma amyloid-β 42 and amyloid-β 40 (Aβ42/40) and %p-tau217 into an amyloid probability score (APS2) was also assessed. METHODS: Mayo Clinic Study of Aging (MCSA) participants had plasma markers measured at via mass spectrometry (MS), an amyloid-PET scan, and a tau-PET (meta-temporal region of interest [ROI]) negative scan (standardized uptake value ratio [SUVR] <1.29) at the index (baseline) date, along with one or more follow-up tau-PET scans. The BioFINDER-2 cohort was used for validation. Cox proportional hazards models adjusted for age, sex, and apolipoprotein (APOE) ε4 were used to assess predictors, with scaling to the interquartile range (IQR) for comparability of hazard ratios (HR). RESULTS: Among 255 tau-PET negative MCSA participants (median age: 71.9 years), 37 converted to tau-PET positive (median follow-up time: 3.81 years). Higher %p-tau217 (HR: 1.52 [95% CI: 1.28-1.80]), amyloid-PET centiloid (HR: 1.47 [95% CI: 1.20-1.79]), and APS2 (HR: 1.62 [95% CI: 1.22-2.16]) predicted tau-PET conversion. However, Aβ42/40 (HR: 0.94 [95% CI: 0.54-1.66]) was not associated with tau-PET conversion. In the BioFINDER-2 cohort (605 tau-negative, median age: 70.2), 33 converted to tau-positive (median follow-up time: 2 years), with higher %p-tau217 (HR: 1.80 [95% CI: 1.50-2.17]), amyloid-PET centiloid (HR: 2.29 [95% CI: 1.77-2.97]), and lower Aβ42/40 (HR: 2.38 [95% CI: 1.17-4.83]) predicting conversion. INTERPRETATION: In two cohorts, %p-tau217 was associated with tau-PET conversion, comparable to amyloid-PET. APS2 also predicted conversion in the MCSA cohort, whereas Aβ42/40 predicted conversion in the BioFINDER-2 cohort, which had more individuals with cognitive impairment. ANN NEUROL 2025;98:1249-1260.