Examining The Potential Of P-tau217 To Provide Earlier Diagnosis Of Alzheimer's
A conversation between Lilly SVP of Clinical Biomarkers and Diagnostics Nino Sireci, MD, MSc, and Clinical Leader Executive Editor Abby Proch
Blood-based biomarkers — particularly P-tau217 — just might reshape Alzheimer’s diagnosis by moving testing from specialized, costly procedures toward a faster, more accessible blood draw.
In this Q&A, Lilly’s Nino Sireci, MD, MSc, discusses the current state of early Alzheimer’s diagnosis and the work Lilly’s doing in collaboration with Roche Diagnostics to develop a blood-based biomarker test to help rule in and rule out Alzheimer’s pathology. Sireci also outlines the goals of the ANCHOR-AD and TEACH-AD trials, two real-world evidence studies designed to better understand what elevated P-tau means over time and how guidelines advise clinicians about how they may act on blood test results in primary and secondary care settings.
Clinical Leader: What is the current diagnostic landscape for Alzheimer's disease?
Nino Sireci: The diagnostic landscape for Alzheimer's has developed so quickly. When I was in medical school, you diagnosed Alzheimer's based on symptoms. And then the true diagnosis happened at autopsy. In the early 2000s, we started developing PET tracers, and that's currently what's available right now to detect amyloid and tau deposits in the brain. For the first time, we could actually see the pathology in vivo. That allowed us to move away from a nebulous diagnosis based on symptomatology and clinical features to an imaging approach, which is great, but it’s expensive, time-consuming, and potentially invasive because of the tracers.
Now, 10 or 15 years later, we’re looking at protein biomarkers in the blood. We started looking specifically at amyloid and different versions of amyloid, then moved pretty quickly to phosphorylated tau. And now the field is moving toward phosphorylated-tau217, or P-tau217. Once we start incorporating these blood-based biomarkers for appropriate patients, they will have easier access to diagnosis and potential downstream treatments or therapies. In fact, the FDA has now cleared two P-tau217 blood tests for use in helping to identify AD pathology.
What is the competitive landscape for P-tau217 blood testing?
Lilly was involved in the early development of antibodies against these proteins, but we're not the only ones. What Lilly contributed here was part of the ecosystem. And I should also say that we're developing a diagnostic with Roche Diagnostics.
Right now, there's two FDA-cleared tests for P-tau217, and those are from Fujirebio and Roche Diagnostics. We also know that other vendors are moving in the space to develop FDA-authorized assays for P-tau217 in early symptomatic and, hopefully, down the line, cognitively unimpaired patient populations. I'll also add that there are other FDA-authorized assays out there for different types of P-tau.
What sets P-tau217 apart?
Its performance characteristics in the plasma. We talk about two use cases for a biomarker: the rule in and rule out. If you're positive for a biomarker, can we say you have the disease? That's the rule in. If you're negative for that biomarker, can we say you don't have the disease and with confidence? That’s rule out. And that confidence is generally measured in the positive and negative predictive value of that biomarker for identifying AD pathology. P-tau217 is able to do both, however, these are not standalone test. The physician still needs to use it alongside other clinical assessments.
And generally, the advantage of a blood biomarker is you can have it drawn during your physical. You're 65, you have early cognitive symptoms, and maybe it’s not normal aging. That blood test expedites the diagnostic process.
Theoretically, once these biomarkers are in wide-scale use, they should cut down the time it takes to make a diagnosis and identify patients earlier in their disease process.
Focusing on your ANCHOR-AD real-world evidence study for the P-tau217 diagnostic, what kind of patient profiles best fit your enrollment strategy?
The ANCHOR-AD study intends to fill the evidence gap related to the natural history of patients who start out as cognitively unimpaired but have elevated P-tau levels. We’re asking, “What happens to them over time?” The value of the trial, in addition to longitudinal follow-up, is that it's being run across a multitude of patient types and ethnicities. It's designed to answer a lot of very basic questions about what it means to have elevated P-tau and what different values across different tests mean.
What’s most exciting or intriguing about P-tau217 testing?
What's not surprising, actually, is the science in drug development is moving way faster than the diagnostics. We're playing catch-up. And then on top of that, clinical practice is nowhere near catching up to where the diagnostics and the drug development are. We have amyloid-targeting therapies, we have anti-inflammatory therapies, we have vascular therapies, we have all sorts of approaches that we take. We have antibody shuttles that all aim to target this pathology, but the diagnostics has dragged a little bit. And so, we're at a point now where the diagnosis is catching up, and it’s happening really fast.
I am really close to Lilly’s TEACH-AD study, which is looking at the use of this P-tau biomarker in patients both in primary and secondary care who present with subjective complaints of cognitive decline. Patients are just starting to notice something's a little off and that it may not be normal aging. Their doctor orders the test and receives the results, and we’re looking at what they do next. That's the key.
Maybe just having the blood test around reminds doctors to do a cognitive assessment. If we give doctors the test, and they give it to their patient, what do they do with the answer?
We also have a pretty cool control arm that doesn't know they're a control arm. They're in silico from medical records. So, when a physician uses this test, what do they do differently for a patient with a subjective cognitive complaint versus someone who doesn't have the test? That’ll go a long way in answering the question: Is there a value in using this test in such early settings?
What are the risks of introducing blood-based biomarker testing before clinicians and health systems are fully prepared to act on the results?
The biggest risk is that a test result could be interpreted in isolation, without the clinical context, counseling and follow-up needed to help a patient understand what it does and does not mean. Blood-based biomarkers should be incorporated into a thoughtful care pathway that includes appropriate confirmatory testing when needed, referral options and support for patients and care partners.
If TEACH-AD shows that P-tau217 testing can change provider behavior, what would that look like?
Provider behavior change would look like clinicians using P-tau217 blood testing as a practical, noninvasive tool to start conversations with symptomatic patients and referrals sooner, helping to identify disease earlier in its progression when intervention, planning, and care coordination can have the greatest impact.
Then, if provider behavior improved in that way, how would you ensure that using the test would become standard of care for these types of patients? How do you work to engrain it into provider decision-making?
As P-tau217 blood testing gains broader clinical acceptance and adoption, translating these advances into everyday clinical practice is crucial for identifying early symptomatic Alzheimer’s disease. Greater education, earlier screenings, and increased collaboration within the healthcare system will be needed to improve outcomes in these patients.
About The Expert:
Anthony “Nino” Sireci, MD, is senior vice president of clinical biomarkers and diagnostics development at Eli Lilly and Company. He is a board-certified clinical pathologist and practicing molecular pathologist. Before joining Loxo@Lilly, he was an assistant professor of pathology and cell biology at Columbia University and medical director of Columbia Medical Center’s Personalized Genomic Medicine Laboratory.
He serves on the Association for Molecular Pathology (AMP)’s Strategy Committee and formerly vice chair for new codes and pricing on the Economic Affairs Committee, the College of American Pathologists (CAP)’s Pathology Coding Caucus and the American Medical Association (AMA)’s Molecular Pathology Advisory Group.
Dr. Sireci received his bachelor’s degree in chemistry from New York University, medical degree from Johns Hopkins University School of Medicine, and master’s degree in biostatistics from Columbia University’s Mailman School of Public Health. He completed his clinical pathology residency at New York Presbyterian Hospital-Columbia, serving as chief resident.