Researchers at the University of Kentucky Sanders-Brown Center on Aging are making strides in developing a pre-symptomatic diagnostic tool for Alzheimer’s disease using cutting-edge long-read sequencing technology.
The study, recently published in Nature Biotechnology, aims to identify and measure RNA isoforms, which are molecules that help translate genetic code from DNA into proteins, across the entire genome.
Dr. Mark T. W. Ebbert, a faculty member at Sanders-Brown and an associate professor in the Department of Internal Medicine and Department of Neuroscience at the UK College of Medicine, emphasizes the importance of early diagnosis in the fight against Alzheimer’s disease. “While the need for better treatments is clear, such treatments will not be very meaningful if they are administered after symptoms have onset. By then, Alzheimer’s disease has been ravaging the brain for decades to the point the brain can no longer compensate for the extreme cellular death,” Ebbert said.
Identifying RNA Isoforms in Alzheimer’s Disease
Ebbert’s team, which includes lead authors Bernardo Aguzzoli Heberle, a Ph.D. candidate at Sanders-Brown, and Dr. Jason A. Brandon, a scientist at Sanders-Brown and the Department of Internal Medicine, used long-read sequencing to analyze aged frontal cortex brain tissue from both healthy brains and those with Alzheimer’s disease. They identified 99 RNA isoforms that were either increased or decreased in Alzheimer’s brains, even when the overall gene activity remained unchanged.
“This shows the importance of understanding isoforms and their unique functions in a gene along with their roles in human health and disease. In fact, we found more than 1,900 genes expressing multiple RNA isoforms related to human disease,” Ebbert said. The team discovered that some of these genes are medically relevant in brain-related diseases, such as Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, and substance use disorder.
Discovering New RNA Variants and Future Implications
In addition to their findings related to Alzheimer’s disease, the Sanders-Brown researchers also discovered five new, complex RNA variants from mitochondrial DNA, which they believe is the first study to identify this genetic material in human tissue. Although their expression is low, Ebbert notes that these genes could serve as biomarkers for mitochondrial function, which plays a crucial role in many age-related diseases.
The team hopes that their findings can lead to new and more precise targets for disease treatment and diagnosis across a wide range of complex human diseases. “With this method, we’ve shown there’s potential to specifically target isoforms that are either promoting cellular health or dysfunction rather than treating a gene as a single entity,” Ebbert said. “The analysis can also help us reveal unique signatures in Alzheimer’s disease not detectable at the gene level.”
However, the researchers acknowledge that larger studies are needed to better understand the RNA patterns in complex diseases, and deep long-read RNA sequencing will be a necessary tool for that work. Ebbert also expresses gratitude to the patients who have donated to the UK Alzheimer’s Disease Center Tissue Bank, stating that without their participation, this level of scientific study would not be possible.
The study brought together a team of researchers from various departments within the UK College of Medicine, as well as collaborators from Emory University School of Medicine, University College of London, Cold Spring Harbor Laboratory, and the Mayo Clinic.
