The field of Alzheimer's disease diagnostics is on the cusp of a significant transformation, with highly accurate plasma tests poised to receive FDA approval and become integrated into clinical practice. According to Suzanne Schindler of Washington University, St. Louis, these blood tests have reached a "tipping point" and are ready for widespread use.
Regulatory Submissions and Approvals
Fujirebio submitted its plasma p-tau217/Aβ1-42 test to the FDA in September, with plans to seek IVD approval in the EU and Japan. Roche Diagnostics International has also filed for FDA approval for its p-tau181 and p-tau217 assays, having received breakthrough device designation for its Elecsys Amyloid Plasma Panel. Beckman Coulter Diagnostics anticipates filing for IVD certification soon, leveraging ALZpath Inc.'s p-tau217 antibody. These regulatory advancements are expected to significantly alter the landscape of Alzheimer's diagnosis.
Potential Impact on Clinical Practice
Jonathan Schott from the Queen Square Institute of Neurology, London, highlighted the potential for blood tests to democratize molecular diagnosis, estimating that testing rates could rise from 2% to nearly 100% in the U.K. with the advent of blood-based diagnostics. Leaders in AD drug development are eagerly awaiting regulatory approval, particularly in Europe, where IVD status is often required for plasma tests in investigational drug trials.
Performance and Validation
Diagnostic criteria issued by a Global CEO Initiative panel, led by Schindler and Oskar Hansson, recommend blood biomarker tests have a sensitivity and specificity of at least 90% and 85%, respectively, for AD triage in primary care. Vendors are optimizing their tests to meet these criteria. Francesca De Simone from Fujirebio Diagnostics Inc. reported that the p-tau217/Aβ1-42 ratio outperformed p-tau217 alone, achieving PPVs and NPVs of 95% and 96%, respectively, with only 20% indeterminate results in a study of 208 volunteers. Similarly, Sharon Sha from Stanford University found that the p-tau217/Aβ1-42 ratio in samples from the Phase 3 trial of AriBio Inc.’s AR1001 yielded PPVs and NPVs of 91% and 97%, respectively, with 21% indeterminate.
Roche's Margherita Carboni reported that their p-tau217 assay performs well across the AD spectrum, with AUCs of 0.88 or higher in cohorts spanning from cognitively normal individuals to those with dementia. Eli Lilly's CertuitAD test, analyzing p-tau217 alone, identified amyloid positives with PPVs and NPVs of 95% and 84%, respectively, with only 18% indeterminate among 2,071 volunteers screened for the Trailblazer-Alz2 trial of donanemab.
Integration and Appropriate Use
Experts at CTAD emphasized the need for real-life studies to understand how these tests perform in diverse settings. San Won Seo and Jehyun Ahn at Samsung Medical Center in South Korea are investigating how different cutoffs for plasma p-tau217 at different stages of Alzheimer’s can improve test performance. Lilly’s clinical utility study for CertuitAD is assessing how plasma p-tau217 results affect diagnosis, treatment, and management, with results expected in early 2025. Michael Schöll at the University of Gothenburg is conducting a similar study in Sweden.
Marwan Sabbagh from Barrow Neurological Institute cautioned that physicians will need guidance, suggesting initial use for negative predictive value in patients with memory complaints. The Alzheimer’s Association is leading an effort to issue appropriate-use recommendations, starting with clinical practice guidelines for specialty care and eventually expanding to primary care.
Reimbursement Challenges
Jeff Dage raised concerns about the Centers for Medicare and Medicaid Services (CMS) proposing a reimbursement rate of $17.27 per test, arguing that this is insufficient given the complexity of the blood tests and the need for ultrasensitive detection. He suggested a minimum reimbursement rate of $130, comparable to CSF tests for similar analytes.
