Alzheimer's disease biological PET staging using plasma p217+tau.

Background: Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer's disease (AD) neuropathology. However, their ability to substitute for tau PET to identify AD biological stage is unclear.

Methods: Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay, ¹⁸F-NAV4694 Aβ-PET (A) and ¹⁸F-MK6240 tau-PET (T) data. Biological PET stages were defined according to the Revised Criteria for Diagnosis and Staging of Alzheimer's Disease (2024): Initial (A + T-), Early (A + T_MTL + ), Intermediate (A + T_MOD + ), and Advanced (A + T_HIGH + ). The threshold for A+ was 25 Centiloid and for T_HIGH + , the 75th percentile SUVR_{temporo-parietal} in A + CI. Sixty percent were A + , 36% Intermediate/Advanced, and 9% Advanced. The performance of p217+tau in discriminating AD stages was assessed using Receiver Operating Characteristic (ROC) analysis and logistic regression.

Results: Plasma p217+tau concentrations increase across the AD biological PET stages, except between Initial and Early stages. Screening for all AD stages (vs. A-T-), combined Intermediate/Advanced stages, or Advanced stage yields AUC of 0.92, 0.92, and 0.91, respectively (CI only: AUC 0.93, 0.89, 0.83). Plasma p217+tau Youden threshold provides sensitivity of 0.77 [0.73-0.90], specificity 0.91 [0.80-0.95], PPV 0.84 [0.71-0.89], and NPV 0.88 [0.85-0.93] for combined Intermediate/Advanced stages. For the Advanced stage alone, sensitivity is 0.89 [0.79-0.97], specificity 0.82 [0.75-0.9], NPV 0.99 [0.98-1.0], but PPV is only 0.33 [0.25-0.47].

Conclusions: In addition to accurately screening for A+ individuals, plasma p217+tau is useful for identifying a combined Intermediate/Advanced stage AD cohort or pre-screening to reduce the tau-PET required to identify Advanced stage AD individuals.