Elevation in Plasma p-tau217 Concentrations Among Blood Donors: An Exploratory Cross-Sectional Study

Importance: Phosphorylated tau at threonine 217 (p-tau217) and brain-derived tau (BD-tau) are increasingly used as blood biomarkers of Alzheimer's disease (AD) and related neurological disorders. However, the distributions and biological correlates of elevated plasma p-tau217 and BD-tau in plasma from individuals eligible for blood donation remain unclear. Objective: To estimate the proportions of plasma p-tau217 and BD-tau exceeding exploratory study-specific thresholds, and examine associated inflammatory and transcriptomic features. Design: Cross-sectional study. Setting: Hospital blood bank. Participants: 257 de-identified donor samples were obtained between September 2025 and June 2026. Plasma samples from 30 population reference participants and 20 AD patients were used to derive study-specific thresholds. Complementary transcriptomic analyses were performed in 29 fresh whole blood samples. Main Outcomes and Measures: The primary outcome was the proportion of donor samples exceeding the study-specific ROC-derived Youden threshold. The proportion exceeding the prespecified published p-tau217 threshold was the secondary outcome. Other measures included plasma concentrations of BD-tau, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6); correlations among plasma p-tau217, BD-tau and inflammatory cytokines; and associated transcriptomic alterations. Results: Plasma p-tau217 concentrations exceeded the study-specific ROC-derived Youden threshold in 53 of 256 donor samples (21%; 95% CI, 16%-26%) and the published threshold, used for a secondary comparison, in 99 of 256 samples (39%; 95% CI, 33%-45%). Plasma BD-tau concentrations exceeded the study-specific threshold in 89 of 257 samples (35%; 95% CI, 29%-41%). Plasma p-tau217 concentrations were positively associated with plasma TNF-alpha (Kendall's tau = 0.339; P < .001) and IL-6 (Kendall's tau = 0.310; P < .001) concentrations. Exploratory transcriptomic analyses identified gene expression patterns associated with p-tau217 concentrations. Measurement using a second p-tau217 antibody showed the similar findings. Conclusions and Relevance: Plasma p-tau217 and BD-tau concentrations exceeded exploratory study-specific thresholds in a subset of blood-donor samples, and higher p-tau217 concentrations were associated with inflammatory biomarkers and exploratory transcriptomic differences. These findings raise the possibility of elevated circulating tau species in some blood donors, but their clinical significance requires confirmation. Whether elevated circulating p-tau217 in donated blood has biological consequences for transfusion recipients is unknown, but deserves investigation.