Circulating small RNAs shed new light on dementia risk

Abstract

With populations aging worldwide, dementia has an enormous impact on individuals and societies. Alzheimer's disease (AD), the most common form of dementia, is currently estimated to afflict nearly seven million persons over age 65 in the United States, a number that could double in the coming decades.¹ Like every disease, the quest to prevent and treat dementia relies on the discovery of biomarkers,² quantifiable indicators that can aid the early risk prediction and disease diagnosis. Circulating (peripheral) molecular markers are particularly attractive candidates, given they can be easily accessed with minimally invasive procedures, allowing larger-scale applications to identify at-risk individuals. Yet a critical challenge is that circulating markers do not necessarily reflect pathological processes in the brain, the organ that plays a central role in dementia phenotypes.

Addressing this challenge, two complementary studies published in Alzheimer's & Dementia leveraged data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to suggest the promise of blood plasma microRNAs (miRNAs) as AD biomarkers. The first study assessed the diagnostic potential of a total of 300 miRNAs across 803 age- and gender-matched ADNI participants classified as controls or as having early mild cognitive impairment (MCI), late MCI, or AD.³ Findings showed that a composite signature consisting of three miRNAs could distinguish diagnoses at baseline and further predict the longitudinal (12-year) conversion of MCI to dementia with an accuracy comparable to or better than that of central biomarkers and clinical screening. The second study aimed to identify plasma miRNAs dysregulated in association with central AD biomarkers measured in ADNI participants’ cerebrospinal fluid (CSF).⁴ A total of 17 unique plasma miRNAs were found to be differentially expressed in association with established amyloid (Aβ1-42), tau (total-tau), and neurodegeneration (p-tau181) CSF markers. By performing pathway analyses of the miRNA-targeted genes, the two studies further showed that several molecular pathways were enriched in diagnostic groups and in association with central biomarkers. Key enriched pathways involved various dementia-related processes, including inflammatory signaling, cognitive processes, mitochondria function, cell migration, and neuronal projection. Together, these observations support circulating miRNAs as promising AD biomarkers and further suggest underlying biological processes through which the miRNA regulome may contribute to dementia risk.

Moreover, the foregoing observations have broader implications for research aiming to understand dementia risk and promote biomarker discovery. Most dementias are thought to result from a complex interplay between genetic and environmental factors,⁵ and epigenetic mechanisms are at the heart of this interplay.⁶ In particular, miRNAs provide a critical layer of dynamic epigenetic regulation by influencing the levels of their target gene transcripts without changing the underlying genetic code.⁷ Intriguingly, miRNAs are thought to disrupt and even cross the blood-brain barrier under certain conditions,⁸ indicating their potential to act as messengers of brain pathology detected in the periphery. Moreover, similar to other epigenetic modifications and in contrast to genetic mutations, dysregulated miRNAs are, in principle, preventable or reversible,⁹ which makes them a potentially modifiable molecular signature that could be targeted to improve dementia outcomes. This possibility has been supported by preclinical studies showing that interfering with select miRNAs modulates cognitive phenotypes.¹⁰

The prospects of this line of research are exciting, but future studies are required to determine the extent to which circulating miRNAs can serve as dementia biomarkers and treatment candidates. First, the findings in ADNI await replication and generalization in independent cohorts with available cognitive phenotypes and central biomarkers. Future work will also need to demonstrate the clinical utility of miRNA measurements by showing their ability to enhance or outperform the predictive and diagnostic accuracy of already established clinical screening and central biomarkers. Lastly, additional preclinical and, ultimately, early clinical studies will be needed to assess the feasibility, safety, and efficacy of modulating miRNA levels to ameliorate dementia outcomes.