Beyond p-tau217: When Do Additional Blood Biomarkers Improve Alzheimer’s Disease Decisions?

Blood-based biomarkers are increasingly used to identify Alzheimer’s disease (AD)-related pathology, but detecting existing pathology, predicting future cognitive decline, staging disease biology, and improving clinical decisions are different objectives. This critical narrative review examines when adding biomarkers beyond plasma phosphorylated tau 217 (p-tau217) provides decision-relevant information. Targeted searches of indexed literature, publisher records, and clinical guidance were used to identify systematic reviews, longitudinal cohorts, direct model comparisons, and staged-testing studies. The search was not systematic, and a formal risk-of-bias assessment was not performed. A 2025 meta-analysis of 113 studies and 29,625 participants estimated p-tau217 sensitivity at 88.1%, specificity at 88.7%, and area under the receiver operating characteristic curve at 0.911 for biologically defined AD. Across studies, additional markers showed conditional rather than universal value: some improved long-term prediction modestly, selected second-stage strategies helped resolve indeterminate first-line results, and combinations of p-tau217 with eMTBR-tau243 showed promise for biological staging. These findings concern different populations and outcomes and should not be treated as interchangeable. Better discrimination or fewer modeled referrals does not by itself demonstrate better patient outcomes or cost-effectiveness. Additional biomarkers are most defensible when a prespecified comparison improves a meaningful decision beyond a strong baseline and is externally evaluated in the intended population.