Background and objectives: Plasma phosphorylated tau 217 (p-tau217) levels have been shown to parallel neurofibrillary tangle and cognitive decline over time. Although recent clinical trials have demonstrated exploratory drug effects on plasma p-tau217, little is known about plasma p-tau217 effect size and performance as an endpoint in Alzheimer disease (AD) clinical trials. Therefore, the objective of this study was to assess the longitudinal performance and potential utility of plasma p-tau217 as a primary endpoint in early-stage AD clinical trials.

Method: This retrospective study included participants from 4 cohorts: ADNI (a multisite observational study), BICWALZS (a South Korean memory clinic-based cohort), MYHAT-NI (a Southwestern Pennsylvania population-based cohort), and WRAP (older adults at risk for AD). Eligible participants had plasma p-tau217 measurements at least at 2 timepoints, along with baseline Aβ PET imaging and clinical assessments. Linear mixed-effects models were used to assess associations between plasma p-tau217 trajectories and clinical or biomarker outcomes. Effect size was defined as the mean annual rate of change in p-tau217 divided by its standard deviation. We calculated the sample size required for a hypothetical clinical trial designed to detect a 25% drug effect with 80% power at a 0.05 test level.

Results: A total of 716 individuals were included in the analysis: 413 cognitively unimpaired (CU) participants (58.6% female; mean age = 70.6 years, SD = 7.9) and 303 cognitively impaired (CI) participants (54.7% female; mean age = 73.2 years, SD = 7.4). In Aβ-positive individuals, the annual rate of change in plasma p-tau217 was similar between CU (0.07 pg/mL/y, SD = 0.11) and CI (0.08 pg/mL/y, SD = 0.13) groups. Effect size was 0.64 and 0.62 in CU and CI Aβ-positive individuals, respectively. The minimum sample size required per study group to detect a 25% drug effect was 610 for the CU Aβ-positive and 664 for the CI Aβ-positive group. Notably, selecting individuals with intermediate Aβ levels (Centiloid 20-40) yielded higher effect sizes (CU: 0.85; CI: 0.72), which reduced the required sample sizes per study group to 342 for CU and 492 for CI.

Discussion: Our findings support that changes in plasma p-tau217 represent a robust endpoint for clinical trials targeting CU or CI individuals with Aβ pathology.