A new brain imaging test can detect a key hallmark of Alzheimer's disease before symptoms appear and earlier than the method currently used in clinical practice in the United States and Europe, report University of Pittsburgh School of Medicine researchers today in The Lancet .
The study team compared the ability of two 'tracers' – compounds that attach to proteins and light up in brain scans – to detect Alzheimer's-associated tangles of tau protein. Results suggest that the choice of tau tracers used for non-invasive PET scan brain imaging in Alzheimer's diagnostics can change who tests positive and influence disease detection and treatment eligibility.
"Tau is the biology most closely tied to symptoms and future decline," said corresponding author Tharick Pascoal, M.D., Ph.D., associate professor of psychiatry and neurology at Pitt and a behavioral neurologist at UPMC. "If we can detect tau earlier and stage it more precisely, we can make better decisions about who is truly on an Alzheimer's trajectory, which matters for clinical trials now and could shape clinical decision-making as new therapies emerge."
A growing body of evidence, including studies conducted at Pitt and UPMC, points to the importance of tau pathology in initiating the cascade of pathological brain changes associated with Alzheimer's disease. While many people who have the signs of another Alzheimer's precursor, amyloid pathology, in their brain do not develop Alzheimer's-associated dementia, the presence of tau clumps alongside amyloid plaques seems to create a permissive environment for downstream pathological changes to occur.
Because of that, early and accurate detection of tau can be essential for identifying people who are likely to benefit from an anti-amyloid treatment, or to avoid costly and burdensome procedures for people who are unlikely to develop behavioral symptoms of Alzheimer's disease.
To compare the effectiveness of tau tracers, the Pittsburgh-based research team coordinated a prospective multicenter study that enrolled 775 participants, of whom 682 completed all study procedures. In a head-to-head comparison, the participants underwent paired tau PET scans, one using the standard tau tracer Flortaucipir and the other with MK6240, a newer tracer primarily used in clinical trial settings. The participants also received an amyloid-β PET scan and detailed cognitive assessments within a 45-day window. Co-lead author Guilherme Povala, Ph.D., postdoctoral associate at Pitt, said the head-to-head design was essential for a fair comparison. "Because participants received both tracer scans within a short window, we're looking at the same moment in the disease course, so differences we see reflect the tracers, not changes over time," said Povala.
MK6240 detected tau positivity more often than Flortaucipir. In cognitively unimpaired, amyloid-β-positive participants, MK6240 identified more than twice as many tau-positive cases as Flortaucipir (15% vs. 6%), corresponding to 23 additional cases per 100. Among cognitively impaired participants, MK6240 also identified more tau involvement than Flortaucipir (28% vs. 16%), corresponding to 15 additional mild cognitive impairment cases and 21 additional dementia cases per 100 people scanned.
"People typically seek evaluation because they have memory concerns or other symptoms," emphasized co-lead author Bruna Bellaver, Ph.D., research assistant professor of psychiatry at Pitt. "Tau PET is one tool that can help clinicians stage disease biology and make more informed decisions."
This Lancet study builds on a research program launched in 2021, when Pitt scientists were awarded more than $40 million over five years from the National Institutes of Health to compare tau tracers head-to-head and improve how Alzheimer's biology is measured across research and clinical settings.
MK6240 is not yet approved by the U.S. Food and Drug Administration (FDA) for routine clinical use. Flortaucipir is FDA-approved for detecting advanced tau pathology.
Additional Resources:
- Project Summary and Abstract
- Longitudinal multicenter head-to-head harmonization of tau PET tracers
- Pascoal Lab
- Dementia and Cognitive Disorders | Neurology | UPMC
Additional University of Pittsburgh co-authors of this research are Firoza Z. Lussier, M.S., Livia Amaral, M.S., Guilherme Bauer-Negrini, Ph.D., Pamela C.L. Ferreira, Ph.D., Andreia Rocha, Ph.D., Emma Ruppert, M.D., Marina S. Medeiros, M.D., Cecile Tissot, Ph.D., and Dana L. Tudorascu, Ph.D. Additional co-authors are from Lawrence Berkeley National Laboratory, Houston Methodist Research Institute, Sant Pau Memory Unit, Barcelona Down Medical Center, CIBERNED, University of California San Francisco, Mayo Clinic, Brown University, Washington University in St. Louis, McGill University and University of Texas Southwestern Medical Center.
