Blood-Based RNA Biomarker Improves Prediction of Alzheimer’s Onset

Timely identification of patients approaching symptomatic Alzheimer’s disease (AD) remains a major clinical challenge, even as blood-based biomarkers continue to advance. Current assays are highly effective at detecting amyloid biology long before cognitive decline, but they provide limited insight into when symptoms are likely to emerge. This uncertainty complicates both clinical trial enrollment and early therapeutic decision-making. New findings now demonstrate that blood-based circular RNAs (circRNAs) may predict near-term progression more accurately than established markers.

The National Institutes of Health (NIH; Bethesda, MD, USA) highlights a blood-based approach centered on circRNAs, small loops of genetic material detectable in circulation. Published in Nature Medicine on July 1, 2026, the work indicates that these molecules are more dynamic than amyloid plaques and may reflect more recent brain activity. Unlike existing tests that detect amyloid plaque markers, which can be positive years before impairment develops, circRNA levels were linked more closely to the timing of symptom onset.

Investigators analyzed blood data from more than 1,200 individuals across multiple independent cohorts and identified a panel of 34 circRNAs associated with AD. Predictive models built from these associations successfully identified individuals with AD pathology, performing on par with models trained on the protein pTau217, a leading clinical blood-based biomarker. Prior research at Washington University School of Medicine in St. Louis had connected brain circRNAs to dementia and neuropathological severity, prompting the new blood-based evaluation.

In longitudinal analyses, the circRNA model outperformed pTau217 for forecasting progression to symptomatic AD. Elevated levels of specific circRNAs nearly tripled the risk of developing symptoms, and their trajectories appeared to diverge from normal approximately two to four years before symptom onset. Similar results were observed in samples from two independent cohorts. According to the NIH summary, these findings may lay groundwork for tests that help clinicians identify candidates for novel treatments and monitor response, particularly for therapies targeting amyloid plaques.

“In a clinical setting, being able to identify patients on the verge of symptom onset would be invaluable. Having this information could help us select the right patients for clinical trials and better determine which treatments are effective at preventing cognitive decline,” said Richard Hodes, M.D., director of NIH’s National Institute on Aging (NIA).

“Patients being treated with novel Aβ-removal therapies can become pTau negative but still have Alzheimer’s disease. These circular RNAs may grant us a more complete perspective on someone’s overall disease biology,” said Carlos Cruchaga, Ph.D., the study’s corresponding author and the Barbara Burton and Reuben Morriss III Professor of Psychiatry with joint appointments in genetics and neurology at Washington University School of Medicine.

Related Links
NIH’s National Institute on Aging (NIA)
Washington University School of Medicine