A recent study published in Nature Medicine reports that a blood-based circular RNA (circRNA) signature could help identify early Alzheimer’s disease biology and progression risk, offering a new layer beyond amyloid and tau testing, according to findings released on July 2.
Researchers analyzed blood samples from 1,221 participants—405 with Alzheimer’s disease (AD) and 816 cognitively unimpaired adults—using RNA sequencing to identify circRNAs associated with AD. They found that combining these circRNAs with established markers like phosphorylated tau-217 (pTau217) produced the highest predictive ability for biomarker-confirmed early AD diagnosis. The team replicated their results among additional cohorts, including participants from the Knight Alzheimer's Disease Research Center and the Anti-Amyloid Treatment in Asymptomatic AD cohort.
The study identified 34 circRNAs linked to clinical AD status. Researchers reported that the overall prediction signal of these circRNAs increased consistently from two to four years before symptom onset until symptomatic AD developed. The model based on these biomarkers achieved an area under the curve (AUC) of up to 0.98 when combined with pTau217, compared to an AUC of 0.88 for pTau217 alone.
Researchers also assessed whether these blood-based circRNAs were specific for detecting Alzheimer’s compared with other neurodegenerative conditions such as Parkinson’s disease, dementia with Lewy bodies, and frontotemporal dementia. Results showed low predictive performance for those other conditions but high specificity for AD-related changes. Sensitivity analyses stratified by sex, ancestry, and apolipoprotein E4 status yielded similar results across most groups.
According to the study authors, “the findings highlight blood-based circRNAs as promising, non-invasive, scalable, and high-precision investigational biomarkers for predicting biomarker-confirmed AD status and symptomatic progression risk,” they said, adding that this approach could eventually complement existing diagnostic tools if validated in larger prospective studies.
