Three microRNAs could serve as a potential biomarker for cognitive decline

The presence of three microRNAs measured in blood could represent a novel, minimally invasive, approach to the identification of cognitive decline in patients according to research by a team from DZNE and the University Medical Center Göttingen (UMG), Germany.

Cognitive decline is a key feature of neurodegenerative diseases and is often the first symptom experienced by patients and which develops slowly over time. However, the use of biomarkers that are elevated at the “pre-cognitive” decline stage could theoretically serve as a means of identifying those at risk of future and further decline.

The use of biomarkers for the early detection of diseases has advanced in recent years for example in Alzheimer’s disease,¹ and one area of research has focused on microRNAs, which are small (19–22 nucleotide), non-coding RNA molecules which regulate gene expression and protein homeostasis through binding with a target mRNA.² A further advantage of microRNAs is their stability in cell-free environments and that these have been implicated in the cause of Alzheimer’s disease³ and cognitive disturbances.⁴ 

For the present study,⁵ the German team used a maze test as a mouse model for age-associated memory decline with both young and older animals. The results showed that the older mice displayed behaviour that was indicative of cognitive decline. When analysing blood samples, it became clear that there were elevated levels of three microRNAs that were only present in the older mice. But whether these markers were also present in humans was unclear but using blood samples from adults with mild cognitive impairment, the researchers also found a significant elevation of the same three-microRNA signature which were absent in matched healthy controls. 

In an attempt to strengthen the association between the three-microRNA signature and cognitive decline, the German team used blood samples from patients in a study examining subjective cognitive decline. Interestingly, they found that patients with initial mild cognitive impairment who later developed Alzheimer’s disease, had a significantly higher expression of the three-microRNA signature. Further confirmation of the importance of the microRNA signature came from an analysis of cerebral spinal fluid (CSF) of those with cognitive impairment which also demonstrated significantly higher levels, confirming that the biomarker was present in both blood and in CSF. 

Because there was elevation of the three-microRNA signature, the team wondered if inhibition of the three-microRNA might reduce the degree of cognitive decline. Returning to the mice, the team injected an inhibitory mix into both older and younger mice and found that the older mice displayed an improved ability to escape the maze that was comparable to the younger animals. Finally, using a mouse disease model of Alzheimer’s disease, the team also demonstrated that the inhibitory mix appeared to ameliorate memory impairment in those with the Alzheimer’s disease model.

Although these were preliminary findings, the authors concluded that the screening approach ‘could improve the early detection of individuals at risk for pathological cognitive decline and increase the chance for efficient therapeutic intervention’.

References

1. Li D, Mieile MM. An Update on Blood-Based Markers of Alzheimer’s Disease Using the SiMoA Platform. Neurol Ther 2019;8(S2):73–82.
2. Gurtan AM, Sharp PA. The role of miRNAs in regulating gene expression networks. J Mol Biol 2013; 425(19):3582–600.
3. Hebert SS et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Nati Acad Sci USA. 2008;105(17):6415-20.
4. Zovoilis A et al. microRNA-34c is a novel target to treat dementias. EMBO J 2011;30(20):4299–308.
5. Islam MR et al. A microRNA signature that correlates with cognition and is a target against cognitive decline. EMBO Mol Med 2021;13(8):e13659.