The Study Design Behind P-tau217 Rule-In Performance

As blood-based biomarkers move closer to routine clinical use, demonstrating agreement with established diagnostic standards remains essential. For Alzheimer disease (AD), amyloid PET imaging has long served as a key reference for identifying underlying pathology, making comparisons between blood-based assays and PET a critical step toward broader adoption.

At the 2026 Alzheimer's Association International Conference (AAIC), investigators presented findings from the analysis, "Blood Biomarker Assays Demonstrate Strong Rule-In Performance for Identifying Cognitively Unimpaired AD." The study included 789 cognitively unimpaired participants from the Bio-Hermes study and pooled Lilly cohorts and evaluated P-tau217 assay performance against amyloid PET imaging. Across both cohorts, P-tau217 demonstrated strong rule-in performance, with positive predictive values exceeding 83%, supporting its ability to identify individuals with underlying AD pathology before objective cognitive impairment develops.

In this episode of the NeurologyLive^® Special Report, Yogesh Shah, MD, MPH, FAAFP, medical director of the Broadlawns Memory Clinic, site principal investigator for the University of Iowa Geriatric Workforce Empowerment Program, and board member of the Iowa Chapter of the Alzheimer's Association, discusses how studies validating P-tau217 against amyloid PET and cerebrospinal fluid biomarkers have been conducted. He also outlines practical considerations for clinicians adopting blood-based biomarker testing, including patient selection, cognitive assessment, interpretation of results, and the role of P-tau217 within a comprehensive diagnostic evaluation.

Transcript edited for clarity.

Yogesh Shah, MD, MPH, FAAFP: The study you're referring to, and many others like it, compared P-tau217 results against established diagnostic standards, including amyloid PET imaging and lumbar puncture biomarkers. I work closely with the Alzheimer's Association, and one of the goals has been to understand how closely these blood-based biomarkers correlate with the tests we've traditionally relied upon.

In these studies, patients undergo amyloid PET imaging and blood testing, and in some cases cerebrospinal fluid analysis as well. Researchers then compare the results to determine how closely the blood-based biomarkers match the findings from PET imaging and lumbar puncture.

Multiple studies have now shown that P-tau217 correlates very well with both amyloid PET and cerebrospinal fluid biomarkers. In fact, a large study published in JAMA in 2025 reviewed data from multiple international cohorts and demonstrated very consistent findings. The overall message is that P-tau217 performs remarkably well when compared with these more established diagnostic approaches.

The evidence has become strong enough that some centers are already using P-tau217 results to help guide decisions around anti-amyloid therapies without always requiring an amyloid PET scan.

NeurologyLive: Let's get into the findings. The P-tau217 blood tests demonstrated positive predictive values above 83% in both cohorts, meaning that when the test is positive, it's highly likely to reflect true amyloid positivity. What does that mean from a practical standpoint?

Yogesh Shah, MD, MPH, FAAFP: For clinicians who haven't yet incorporated P-tau217 into practice, my recommendation is to first follow a structured evaluation process whenever a patient presents with memory concerns.

The first step is not to dismiss those concerns, regardless of the patient's age. Perform some form of cognitive assessment in the office. There are several options available. The Alzheimer's Association recommends tools such as the AD8, and many clinicians also use the SLUMS examination or Mini-Cog. The specific test matters less than making sure some objective assessment is performed.

Next, obtain a thorough history. Does the patient have depression? Are sleep disorders contributing to the symptoms? Are they using their CPAP machine if they have sleep apnea? Review medications carefully. Many commonly used medications, including over-the-counter agents such as diphenhydramine, have anticholinergic properties that can negatively affect cognition.

Laboratory testing is also important to rule out other causes of cognitive decline. Once those steps have been completed, clinicians may consider ordering P-tau217 testing. Multiple laboratories now offer the assay, but it's important to understand the reference ranges and reporting structure used by the specific laboratory. Ideally, clinicians should use assays that provide positive, negative, and intermediate categories rather than relying on a single cutoff value.

Before ordering the test, clinicians should also discuss its purpose with patients and families. P-tau217 should never be used as a standalone test. It should be ordered when the results are expected to influence clinical decision-making. For example, a positive result may help identify a patient who could be a candidate for disease-modifying therapy or provide prognostic information about the likely trajectory of disease.

Not every patient with memory complaints needs P-tau217 testing, and not every patient with a positive result needs referral to a specialist. Referral is generally most valuable when disease-modifying therapy is being considered or when the clinical picture suggests a more complex or mixed pathology.

This conference coverage information is produced independently by Neurology Live and supported by Eli Lilly and Company who has no direct influence on the content itself.