Tailoring thresholds for interpreting plasma p-tau217 levels.

Background: Plasma phosphorylated tau (p-tau) 217 test has emerged as a minimally invasive and accessible alternative to positron emission tomography imaging and cerebrospinal fluid analysis for Alzheimer's disease (AD) diagnostics. However, the diagnostic performance of p-tau217 across diverse cognitive and demographic subgroups remains underexplored. This multicentre cross-sectional study aimed to assess the diagnostic utility of plasma p-tau217 using a double cut-off approach in a large, diverse cohort, focusing on subgroup analyses based on cognitive status, age, sex, body mass index and ε4 carrier status.

Methods: Plasma p-tau217 levels were analysed in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. Double cut-offs for p-tau217 levels were selected to classify participants into amyloid-negative, intermediate and amyloid-positive groups. Diagnostic performance metrics including sensitivity, specificity, positive predictive value and negative predictive value were evaluated across subgroups, and tailored cut-off strategies were explored for specific populations.

Results: The optimal cut-offs differed between CU and CI groups. In the CI group, diagnostic accuracy was consistently high across all subgroups, meeting confirmatory test standards with sensitivity and specificity ≥90%. In the CU group, the appropriate standards varied by subgroup. Participants aged <65 years required alternative cut-offs to improve sensitivity to 85.0% and maintain specificity at 95.7%.

Conclusion: Plasma p-tau217 demonstrated robust diagnostic accuracy across CI subgroups and highlighted the importance of tailored cut-off thresholds for CU populations. These findings support the integration of plasma p-tau217 into clinical workflows for AD diagnostics, emphasising its potential for early detection and risk stratification.