Blood circRNAs may predict Alzheimer’s before symptoms emerge

 With this your doctor could then implement THOSE EXACT DEMENTIA PROVENTION PROTOCOLS! They incompetently don't exist, do they?

Blood circRNAs may predict Alzheimer’s before symptoms emerge

A blood-based circRNA signature could help identify early Alzheimer’s biology and progression risk, offering a promising new layer beyond amyloid and tau testing.

Study: Blood-based circular RNAs for early diagnosis of Alzheimer’s disease. Image Credit: Andrii Vodolazhskyi / Shutterstock

In a recent study published in the journal Nature Medicine, researchers identified circular ribonucleic acids (circRNAs) in blood with high predictive value for biomarker-confirmed early Alzheimer’s disease (AD) diagnosis. Combining these circRNAs with established markers, such as phosphorylated tau-217 (pTau217), yielded the highest predictive ability. These findings suggest that circRNA investigations could eventually complement blood-based AD biomarker panels to identify people with early AD biology or elevated progression risk. However, the findings need to be validated in larger, diverse prospective clinical cohorts.

AD is the leading cause of dementia. Since pathological alterations in this condition appear before cognitive decline, scientists are developing new strategies to detect AD early and support timely intervention aimed at slowing disease progression. Early identification of the disease before clinical symptoms appear could enable prompt treatment and better clinical planning, and may improve outcomes when paired with effective interventions, while potentially reducing mortality associated with severe disease.

About the study

In the present study, researchers analyzed blood samples of 1,221 participants, including 405 AD patients and 816 cognitively unimpaired adults, using RNA sequencing (RNA-seq). They aimed to identify and validate blood-based circRNAs that could help diagnose AD and monitor disease progression. They used the CircAtlas 3.0 database to examine circRNA expression across 33 tissues and quantitative polymerase chain reaction (qPCR) to assess selected circRNA expression in these tissues.

The team calculated area under the curve (AUC) values to determine the diagnostic utility of a model based on the blood-based circRNAs. They compared the results with blood pTau217 levels to classify biomarker-confirmed AD status. The researchers also replicated the results among 551 participants in the Knight Alzheimer's Disease Research Center (Knight ADRC), including 76 with AD and 475 cognitively unimpaired individuals. They additionally tested the model in the preclinical Anti-Amyloid Treatment in Asymptomatic AD cohort (A4, 1,767 participants), in which almost all participants were cognitively unimpaired at baseline. They used logistic regression models, including the top differentially expressed circRNAs, for statistical analysis.

Among the Knight ADRC participants, the team evaluated the ability of circRNAs and pTau217 biomarkers in blood, and of amyloid-PET status, to predict symptomatic progression. They used Cox regression models to estimate the hazard ratios (HRs) for this analysis.

The team assessed the specificity of blood-based circRNAs for disease detection by comparing findings across other neurodegenerative conditions, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). They also evaluated whether the overall 34-circRNA model could predict progression of dementia severity using Clinical Dementia Rating (CDR) scores. They also conducted sensitivity analyses stratified by sex, ancestry, and apolipoprotein E4 (APOE4) status. They performed principal component analysis (PCA) to generate covariates for genetic ancestry.

Results

The team identified 34 circRNAs linked to clinical AD status. The overall 34-circRNA prediction signal linearly and consistently increased from the presymptomatic stage around two to four years before symptom onset until symptomatic AD. Most of the identified AD-related circRNAs were highly expressed and showed preferential expression in the brain, although the study could not prove that the blood circRNAs were brain-derived, and their links with clinical AD were observed regardless of their cognate linear messenger RNA counterparts. The overall circRNA model scores were associated with dementia severity and could capture dynamic signals of AD progression that other pathology-focused biomarkers might miss.

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The results were comparable to blood pTau217 levels and also replicated in the A4 and Knight ADRC study groups. The circRNA-based model outperformed blood pTau217 alone for biomarker-confirmed A−T− cognitively unimpaired versus A+T+ AD classification, achieving an AUC of 0.95 compared with 0.88 for blood pTau217 alone. The team achieved the highest AUC by integrating both biomarkers (0.97-0.98). The combined circRNA and pTau217 model helped differentiate non-progressors from high-risk progressors. This could be potentially useful for monitoring AD progression in the era of new AD treatments, especially those targeting amyloid plaques, as circRNAs may indicate broader biological changes and symptom progression beyond amyloid pathology.

The blood-based circRNA model also specifically detected AD-related changes and showed low predictive performance for conditions such as PD, DLB, and FTD. These markers may therefore potentially help stratify progression risk and be explored for monitoring disease biology beyond amyloid pathology. Among Knight ADRC participants, circRNAs (HR, 2.9) outperformed pTau217 (HR, 1.8) and amyloid-PET in predicting progression to the symptomatic stage of AD. The sensitivity analysis yielded similar results, highlighting the robustness of the primary findings. The findings were largely similar for European, African, and mixed populations, supporting potential robustness across ancestries, although some ancestry subgroups were small.

Conclusion

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. Based on these findings, circRNA detection in blood could one day be used as an adjunct to early AD detection, provided the findings are validated in larger, prospective clinical studies. In the future, researchers should also explore the influence of AD-related comorbidities on blood-based circRNA levels.

The findings are especially relevant since circRNAs are highly stable, tissue-specific, and can be measured in blood. This approach may be clinically useful because traditional AD biomarker assessment has often relied on cerebrospinal fluid (CSF) obtained through lumbar puncture or expensive amyloid PET scans.

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RNA Recycling Extends Lifespan

 How will your competent? doctor and hospital use this to recover your 5 lost years of brain cognition due to your stroke? Oh, your doctor doesn't consider that part of the job! Why hasn't that doctor been fired yet? Will your doctor and hospital ensure human testing occurs?

RNA Recycling Extends Lifespan

Summary: Researchers discovered a biological “trash disposal” mechanism that directly controls how fast we age. While circular RNA has long been known to accumulate in cells as we get older, this study proves for the first time that this buildup isn’t just a side effect of aging—it actually causes it. By identifying the enzyme RNASEK, which degrades this aging-linked RNA, scientists have found a way to potentially reset the cellular clock.

Key Facts

• The “Toxic” Buildup: Circular RNA is uniquely stable, meaning it doesn’t break down easily. As we age, it piles up inside cells, eventually clumping into harmful “stress granules” that impair cellular function.
• The Discovery of RNASEK: The team identified RNASEK as the specific enzyme responsible for degrading circular RNA. As organisms age, levels of this enzyme naturally drop, leading to RNA “traffic jams.”
• Lifespan Extension: In experiments with C. elegans (roundworms), artificially increasing RNASEK levels (overexpression) significantly extended healthy lifespan.
• The Chaperone Connection: RNASEK doesn’t work alone; it partners with a protein called HSP90 to prevent these RNA clumps from becoming toxic.
• Cross-Species Evidence: This mechanism was confirmed in both human cells and mouse models. When RNASEK was deficient in human cells, it led to signs of premature aging.
• Therapeutic Potential: Controlling RNASEK to clear out circular RNA could become a primary strategy for treating degenerative diseases and slowing human aging.

Source: KAIST

Cells in our bodies produce RNA based on genetic information stored in DNA, and RNA serves as a blueprint for making proteins. Researchers at our university have discovered a new phenomenon: removing ‘circular RNA’ that accumulates in cells as we age can slow down aging and extend lifespan. This study provides crucial clues for uncovering the principles of aging and developing treatment strategies for related diseases.

Professor Seung-Jae V. Lee’s research team (RNA-Mediated Healthspan and Longevity Research Center) from the Department of Biological Sciences, in collaboration with research teams led by Professors Yoon Ki Kim and Gwangrog Lee, announced on the 18th that they discovered the RNASEK protein—an enzyme that degrades circular RNA—plays a vital role in slowing aging and extending lifespan.

Until now, circular RNA has been regarded mainly as an aging marker because of its stability, which allows it to accumulate over time. However, the molecular mechanism for removing this RNA and its direct link to aging had not been clearly identified. The research team conducted this study to determine how the accumulation of circular RNA affects aging and whether an intracellular management system exists to regulate it.

Using Caenorhabditis elegans (C. elegans), a short-lived roundworm widely used in aging research, the team first confirmed that the circular RNA-degrading enzyme RNASEK is essential for longevity. They also discovered that as aging progresses, the amount of RNASEK decreases, resulting in an abnormal accumulation of circular RNA within cells.

Conversely, artificially increasing the levels of RNASEK (overexpression) extended the lifespan and allowed the organisms to survive longer in a healthy state. This implies that the process of appropriately removing cellular circular RNA is critical for maintaining health and longevity.

The research team also found that RNASEK prevents the toxic aggregation of circular RNAs in aged organisms. . When RNASEK is deficient and circular RNA accumulates, “stress granules”  form abnormally inside the cell, which can impair cellular functions and accelerate aging.

RNASEK works alongside the chaperone protein HSP90 (which helps proteins avoid misfolding or clumping) to inhibit the formation of these stress granules and help cells maintain a normal state. Notably, this phenomenon was observed not only in C. elegans but also in human cells. In mammals, RNASEK also functions to directly degrade circular RNA; a deficiency of RNASEK in human cells and mouse models led to premature aging.

The researchers explained that this study is significant as it identifies a mechanism for regulating aging at the RNA level. They suggested that research using RNASEK to control circular RNA could lead to the development of treatment strategies for human aging and degenerative diseases.

Professor Seung-Jae V. Lee of KAIST, who led the study, explained, “Until now, circular RNA was merely regarded as a marker of aging that accumulates over time due to its stability. This study proves that circular RNA accumulated during aging actually induces aging, and that RNASEK, which removes it, is a key regulator that slows aging and induces healthy longevity.”

Drs. Sieun S. Kim, Seokjin Ham, Sung Ho Boo, and Donghun Lee from the KAIST Department of Biological Sciences participated as joint first authors.

The research results were published on February 24 in the world-renowned scientific journal Molecular Cell.

Funding: This research was conducted with support from the Leader Researcher Program of the National Research Foundation of Korea.

Key Questions Answered:

Q: If circular RNA is a “marker” of aging, why is it bad to have it?

A: Think of circular RNA like clutter in a house. A little bit is fine, but because it’s so stable, it never “goes out with the trash.” Over decades, this clutter turns into massive piles (stress granules) that block the hallways of the cell, stopping vital proteins and signals from getting where they need to go. This “cellular hoarding” eventually leads to cell death and aging.

Q: Can I just take a supplement to increase my RNASEK?

A: Not yet. While the study found that increasing RNASEK extends life in lab models, we are still in the early stages of translating this to humans. However, this discovery gives pharmaceutical researchers a specific target. Instead of just treating the symptoms of aging, we might one day have treatments that “re-activate” the RNASEK disposal system to keep cells clean.

Q: Why did they use roundworms for this research?

A: C. elegans are the “gold standard” for aging research because they live for only about 2–3 weeks, but share many of the same genetic pathways as humans. This allows scientists to see the entire aging process—and the effects of life-extending interventions—in a matter of days rather than years.

Editorial Notes:

• This article was edited by a Neuroscience News editor.
• Journal paper reviewed in full.
• Additional context added by our staff.

About this genetics and longevity research news

Author: JEEHYUN LEE
Source: KAIST
Contact: JEEHYUN LEE – KAIST
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Ribonuclease κ promotes longevity by preventing age-associated accumulation of circular RNA in stress granules” by Sieun S. Kim, Seokjin Ham, Sung Ho Boo, Donghun Lee, Hyemin Min, Eunseok Kang, Rosa Haque, Hanseul Lee, Yoonji Jung, Sujeong Kwon, Sangsoon Park, Hae-Eun H. Park, Eun Ji E. Kim, Wooseon Hwang, Eunah Kim, Gee-Yoon Lee, Kun-Young Park, Jae Myoung Suh, Gwangrog Lee, Yoon Ki Kim, and Seung-Jae V. Lee. Molecular Cell
DOI:10.1016/j.molcel.2026.01.031

Identification of Blood Circular RNAs as Potential Biomarkers for Acute Ischemic Stroke

Without saying how fast these tests can be done this is totally useless and will have to be redone. 

Identification of Blood Circular RNAs as Potential Biomarkers for Acute Ischemic Stroke

Dan Lu^1,2, Eric S. Ho^3,4, Hongcheng Mai^1,2†, Jiankun Zang^1,2, Yanfang Liu^1,2, Yufeng Li^1,2, Bing Yang¹, Yan Ding¹, Chi Kwan Tsang^2* and Anding Xu^1,2*

• ¹Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, Guangzhou, China
• ²Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China
• ³Department of Biology, Lafayette College, Easton, PA, United States
• ⁴Department of Computer Science, Lafayette College, Easton, PA, United States

Many hospitals lack facilities for accurate diagnosis of acute ischemic stroke (AIS). Circular RNA (circRNA) is highly expressed in the brain and is closely associated with stroke. In this study, we examined whether the blood-borne circRNAs could be promising candidates as adjunctive diagnostic biomarkers and their pathophysiological roles after stroke. We profiled the blood circRNA expression in mice subjected to experimental focal cerebral ischemia and validated the selected circRNAs in AIS patients. We demonstrated that 128, 198, and 789 circRNAs were significantly altered at 5 min, 3 h, and 24 h after ischemic stroke, respectively. Our bioinformatics analysis revealed that the circRNA-targeted genes were associated with the Hippo signaling pathway, extracellular matrix-receptor interaction, and fatty acid metabolism at 5 min, 3 h and 24 h after ischemic stroke, respectively. We verified that many of these circRNAs existed in the mouse brain. Furthermore, we found that most of the predicted circRNA-miRNA interactions apparently exhibited functional roles in terms of regulation of their target gene expression in the brain. We also verified that many of these mouse circRNAs were conserved in human. Finally, we found that circBBS2 and circPHKA2 were differentially expressed in the blood of AIS patients. These results demonstrate that blood circRNAs may serve as potential biomarkers for AIS diagnosis and reveal the pathophysiological responses in the brain after ischemic stroke.