Cognition and MicroRNAs

In a previous blog (Calculating Dementia), I wrote about an online health and lifestyle questionnaire that could predict your risk of dementia over the coming 5 year period. The algorithm behind the questionnaire was based on data from about 50,000 men and women in Canada. However, the algorithm didn’t take into account family history or genetic factors so its predictive power was just in general terms and could have significant limitations for any specific person. What would be much more useful clinically is a test that actually measured an individual’s biomarkers so that a physician could used that information to make a personalized risk assessment. Various attempts have been made to find such predictive biomarkers for specific dementias, such as Alzheimer’s disease, with limited success. A newly published paper in EMBO Molecular Medicine takes a more general approach and described a set of microRNAs (miRNAs) whose increased expression correlates with cognitive decline.

miRNA are just one type of a variety of RNAs that are generated in our cells, each type with a specific function. In addition to miRNAs, this cadre of cellular RNAs includes messenger RNAs (mRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), small interfering RNAs, (siRNAs), and long noncoding RNAs (lncRNAs). Perhaps the most familiar type is mRNA that is copied from the DNA sequences in our genome. After it is produced, mRNA is transported to ribosomes where the information in the RNA is converted into a protein. mRNAs are highly variable in length though are usually hundreds to thousands of nucleotides long depending on the size of the protein they encode. In contrast, miRNAs are only 19-22 nucleotides in length yet they are highly important regulators of protein production. Each miRNA binds to a complementary mRNA sequence and represses protein production from that mRNA, so the miRNAs are critical factors that help regulate the amount of certain proteins produced in a cell. Humans have more than 2000 miRNAs and it is estimated that they help control protein production for about 60% of our genes.

In the EMBO paper, the authors looked at circulating miRNA profiles in the blood of healthy adults compared to those with mild cognitive impairment (MCI). They discovered a signature of 3 miRNAs (called miR-181a-5p, miR-148-3p, and miR-146a-5p) that were collectively increased in patients with MCI. Additionally, MCI patients with the highest levels were more likely to develop Alzheimer’s disease within 2 years. While they did not determine the specific functional role of these 3 miRNAs in cognition, these markers may be suitable for a simple blood test that could predict an upcoming cognitive deterioration. This could become a simple screening as part of a routine physical that would identify at-risk patients who needed more intensive testing such as brain imaging. Even more importantly, when the authors inhibited these miRNAs in mice with cognitive decline, the mice’s memory improved. These results provide hope that a therapeutic intervention targeting these specific miRNA could have beneficial effects in preventing or reversing cognitive impairment in humans. This work is still a long way from any direct clinical application, but is perhaps another small step towards understanding and ameliorating the scourge of age-associated declines in intellectual function.

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