Study links Alzheimer's disease with circular RNA
Certain loops of ribonucleic acid — “circular RNAs” — in the brain are associated with the development of Alzheimer’s disease, according to a study reported recently in Nature Neuroscience. Because these circular RNAs can be detected not just in the brain but in cerebrospinal fluid and blood, they have the potential to be developed into lab tests to detect Alzheimer’s before symptoms appear.
RNAs are the molecules that carry instructions from genes to create proteins in the body. Most research has been done with the linear form, and scientists are just beginning to learn how the body uses circular RNA, especially in the brain. Using modern sequencing technologies, investigators at Washington University in St. Louis analyzed the complete RNA content in brain samples and compared circular RNAs in people with and without Alzheimer’s disease.
The investigators first compared the RNA sequences from brain tissue donated by 83 people who had Alzheimer’s with samples from 13 healthy people. Then they compared the RNA sequences from brain tissue samples from 89 people with Alzheimer’s, 66 probable or possible cases, and 40 controls obtained from the NIA-supported Accelerating Medicines Partnership Alzheimer’s Disease (AMP AD) Biomarkers Project.
In each of these two datasets, more than 3,500 circular RNAs were detected and analyzed. The researchers discovered that certain circular RNAs are strongly associated with the development of Alzheimer’s. In the first dataset, three circular RNAs, including one known as circHOMER1, were significantly associated with three Alzheimer’s traits: having a diagnosis of Alzheimer’s, a quantitative measure of dementia severity at the end of life, and the number and distribution of tau tangles throughout the brain.
The second dataset replicated those findings: 28 circular RNAs, including circHOMER1, were significantly associated with all three traits. Together, these findings suggest there is a significant association between the expression of certain circular RNAs like circHOMER1 in the brain and Alzheimer’s traits.
Next, the research team analyzed circular RNAs in samples from 21 brains donated by people with early-onset Alzheimer’s who were part of the NIA-supported Dominantly Inherited Alzheimer Network, which is a study to identify biomarkers to predict the development of Alzheimer’s. In these people with early-onset disease, the magnitude of changes in RNA expression was even greater than in the first two datasets. This finding suggests even more strongly that the correlation between certain circular RNAs and disease is meaningful and not merely a coincidence. However, it is not enough to suggest causation.
The investigators also analyzed circular RNAs in samples from people who had mild or no dementia but whose brains showed signs of Alzheimer’s. After comparing results to those from healthy controls and those with dementia from Alzheimer’s, the research team found evidence for early changes in circular RNA before the people had substantial symptoms of Alzheimer’s.
Taken together, these results suggest that specific circular RNAs might have the potential for use as biomarkers to detect Alzheimer’s disease before symptoms appear. Future studies are needed to better understand the functions of the circular RNAs identified in these analyses.
This research was supported in part by NIA grants R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG057777, K01AG046374, K23AG049087, P50AG05681, P01AG03991, P01AG026276 and UF1AG032438.
These activities relate to NIA’s AD+ADRD Research Implementation Milestones 2.A. “Create new research programs that use data-driven, systems-based approaches to integrate the study of fundamental biology of aging with neurobiology of aging and research on neurodegeneration, AD and AD-related dementias to better understand the mechanism(s) of vulnerability and resilience in AD across all levels of biologic complexity (from cellular to population level) and to gain a deeper understanding of the complex biology and integrative physiology of healthy and pathologic brain aging.” and Milestones 9.B. "Accelerate the development of the next generation CNS imaging ligands and biofluid molecular signatures targeting a variety of disease processes (neuroinflammation, bioenergetic/metabolic compromise, oxidative stress, synaptic pathology) that can be used as research tools or developed into diagnostic, prognostic, theragnostic or target engagement biomarkers." and 9.F. “Initiate studies to develop minimally invasive biomarkers for detection of cerebral amyloidosis, AD and AD-related dementias pathophysiology.”
Dube U, et al. An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. Nature Neuroscience. 2019; 22(11):1903-1912. doi: 10.1038/s41593-019-0501-5.