Two-Year Prognostic Utility of Plasma P217+tau Across the Alzheimer’s Continuum

BackgroundPlasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-& beta; (A & beta;) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET A & beta; and tau in predicting cognitive decline are unknown.ObjectivesTo evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on A & beta; (F-18-NAV4694) and tau (F-18-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET A & beta; (A+) and tau (T+) with and without p217+tau pre-screening.DesignA prospective observational cohort study.SettingParticipants of the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT).Participants153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals.MeasurementsBaseline p217+tau Simoa & REG; assay F-18-MK6240 tau-PET and F-18-NAV4694 A & beta;-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 & PLUSMN; 0.8 years.ResultsIn CI, p217+tau was a significant predictor of change in MMSE (& beta; = -0.55, p < 0.001) and CDR-SB (& beta; =0.61, p < 0.001) with an effect size similar to A & beta; Centiloid (MMSE & beta; = -0.48, p = 0.002; CDR-SB & beta; = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: & beta; = -0.62, p < 0.001; CDR-SB: & beta; = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (& beta; = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU.ConclusionsSubstantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.