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

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.

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.

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].

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.