Blood-Based Circular RNA Biomarkers Outperform Gold-Standard Tests, Enable Preclinical Risk Stratification Years Before Symptom Onset, and Open New Era in Precision Neurology

• Highlights of Circular Genomics' Alzheimer's assays: 
• • validated across nearly 2,400 individuals in three independent cohorts
  • Achieved AUC 0.945 for detecting AD in patients with clinical symptoms
  • Achieved AUC 0.870 for predicting the development of AD in patients without clinical symptoms
  • 61% stronger predictive power for progression to symptomatic AD than pTau217 only, enabling true preclinical risk stratification.
  • Capture multi‑pathway AD biology—including amyloid, tau, synaptic dysfunction, neuroinflammation, and APP modulation—through a single blood‑based circRNA signature.

SAN DIEGO, July 2, 2026 /PRNewswire/ -- Circular Genomics today announced the launch of CircPATH™, the company's proprietary circular RNA discovery and validation engine, following the publication of landmark findings in Nature Medicine demonstrating that blood-based circular RNA (circRNA) biomarkers can predict Alzheimer's disease (AD) progression with unprecedented accuracy. The study, led by Dr. Carlos Cruchaga at Washington University in St. Louis, represents the first demonstration that circRNAs can predict progression to symptomatic AD and outperform existing gold-standard biomarkers. CircPATH™ serves as the technological backbone powering all of Circular Genomics' future diagnostic product offerings, translating novel RNA biology into clinically actionable tools that promise to transform how neurodegenerative diseases are detected, monitored, and treated.

The results published in Nature Medicine represent a paradigm shift in how we evaluate neurodegenerative disease. For the first time, researchers have identified a class of biomarkers that not only detect disease with outstanding accuracy but also capture the full spectrum of AD biology—including amyloid and tau pathology—enabling true precision medicine approaches for patients, clinicians, and drug developers.  These circRNAs are brain-enriched and brain-derived, crossing the blood-brain barrier to reflect central nervous system disease biology directly in a simple blood draw.

The CircPATH™-identified circRNA biomarker signatures achieved an area under the curve (AUC) of 0.945 for detecting biomarker-confirmed Alzheimer's disease in the large well-characterized ADRC clinical cohort, significantly outperforming plasma pTau217 (AUC 0.877), the current clinical gold standard. When integrated with pTau217, the combined model reached an AUC of 0.967—approaching near-perfect diagnostic accuracy and rivaling the performance of invasive cerebrospinal fluid tests and expensive PET imaging.  The breakthrough extends far beyond diagnosis. For predicting which cognitively normal individuals at baseline will progress to symptomatic MCI/AD, circRNAs demonstrated a hazard ratio of 2.92 compared to pTau217's hazard ratio of 1.81—a 61% improvement in predictive power. The integrated circRNA-pTau217 model achieved a hazard ratio of 4.83, representing landmark performance for progression prediction. For identifying individuals who will develop symptoms within five years, the circRNA model achieved an AUC of 0.870 versus pTau217 alone at 0.676—a dramatic 29% improvement that translates directly into better patient stratification and clinical trial design.

The 34-circRNA biomarker signature was discovered and rigorously validated across three independent cohorts: two Knight Alzheimer's Disease Research Center cohorts (Knight-ADRC, n=1,221, and n=551) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study cohort (n=676), ensuring robust, generalizable performance across diverse patient populations.

"This study represents the first time we've demonstrated that blood-based circular RNAs can predict progression to symptomatic Alzheimer's disease, and they do so with performance that exceeds our current gold-standard biomarkers," said Dr. Carlos Cruchaga, Professor of Psychiatry and Director of the Neurogenomics and Informatics Center at Washington University School of Medicine in St. Louis, and lead author of the Nature Medicine study. "What makes this particularly exciting is that these biomarkers begin changing years before symptoms appear and they capture disease biology that goes beyond amyloid and tau. We're opening a new chapter in precision neurology—one where we can identify at-risk individuals earlier, monitor disease more comprehensively, and ultimately intervene more effectively. The potential to transform both clinical care and drug development is immense."

The host genes encoding these circRNAs span multiple critical AD pathways: GWAS-identified risk genes like PICALM, synaptic function regulators like DNAJC6, and amyloid precursor protein (APP) modulators. This multi-pathway mapping means circRNA biomarkers capture the full complexity of AD biology—neuroinflammation, synaptic dysfunction, protein aggregation, and neurodegeneration—in a single, integrated readout.

 "Circular Genomics is advancing the kind of bold innovation the Diagnostics Accelerator was created to support, technologies that can fundamentally transform how we detect, monitor, and understand Alzheimer's," said Laura Nisenbaum, PhD, Executive Director of Drug Development at the Alzheimer's Drug Discovery Foundation (ADDF). "Alzheimer's is an extraordinarily complex disease, and advancing precision medicine will require biomarkers that capture the full breadth of underlying biology. These findings suggest circRNA biomarkers may provide a more comprehensive window into disease processes through a simple blood test, with the potential to improve early detection, identify individuals at risk before symptoms emerge, and better track disease progression over time." 

CircPATH™-derived biomarkers enable enrichment of trial populations with individuals most likely to progress, reducing sample sizes and trial duration. They provide objective endpoints for monitoring treatment response across multiple biological pathways simultaneously. And they enable stratification strategies that can identify which patients are most likely to benefit from specific therapeutic mechanisms—accelerating the path from drug candidate to approved therapy.

"Our CircPATH™ engine harnesses the discovery Dr. Cruchaga and his team have pioneered and translates it into the next generation of diagnostic tools for neurodegenerative disease," said Dr. Nikolaos Mellios, co-founder and Chief Scientific Officer of Circular Genomics. "What sets circular RNAs apart is their ability to map multiple disease pathways simultaneously while remaining highly specific to Alzheimer's disease. This isn't just incremental improvement—it's a fundamentally different approach to biomarker development. CircPATH™ systematically identifies, validates, and translates these brain-enriched circRNA signals into clinically actionable molecular signatures that address real-world needs: earlier detection, better patient stratification, and more precise monitoring of treatment response."

Circular Genomics is advancing a robust pipeline of circRNA-based diagnostic products targeting Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. The company is actively pursuing partnerships with biopharma companies, clinical research organizations, and academic medical centers to integrate CircPATH™-derived biomarkers into drug development programs and clinical care pathways. With the validation of circRNA biomarkers in nearly 2,400 individuals across independent cohorts, Circular Genomics is positioned to deliver the precision diagnostic tools the field urgently needs—tools that enable earlier detection, smarter trial design, and better patient outcomes.  CircPATH™ represents a differentiated platform technology with applications across multiple high-value indications, validated performance in large clinical cohorts, and clear paths to both diagnostic products and strategic partnerships with major pharmaceutical companies and academic centers. It offers a solution to critical bottlenecks in neurodegenerative drug development.

About Circular Genomics

Circular Genomics is a precision medicine company developing circular RNA-based diagnostics and therapeutics to transform the understanding and treatment of neuropsychiatric and neurodegenerative conditions. By leveraging novel RNA biology through its proprietary CircPATH™ platform, the company aims to enable earlier detection, more precise patient stratification, and more targeted interventions across brain health. Circular Genomics is headquartered in San Diego, CA. For more information, visit www.circulargenomics.com.

About CircPATH^™

CircPATH™ is Circular Genomics' proprietary end-to-end circular RNA discovery and validation engine, serving as the technological backbone for all of the company's diagnostic product offerings. The platform systematically identifies disease-relevant circRNAs from complex biological samples, validates their performance across independent cohorts, and translates them into clinically actionable biomarker panels. By leveraging the unique biology of circular RNAs—their stability, tissue specificity, and functional independence from linear transcripts—CircPATH™ unlocks biomarker signals that have remained invisible to conventional approaches. The platform's ability to discover brain-enriched circRNAs detectable in blood creates a non-invasive window into central nervous system biology, enabling applications across the full spectrum of neurodegenerative and neuropsychiatric conditions.

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