Elevated Plasma microRNA-206 Levels Predict Cognitive Decline and Progression to Dementia from Mild Cognitive Impairment

Background: With pre-symptomatic stages of Alzheimer's disease (AD) becoming the primary target for therapeutic intervention, there is an unmet need for practical biomarkers to facilitate the diagnosis of these early disease stages. MicroRNAs, small non-coding RNAs with a high stability in extracellular environments, are a promising source of accessible biomarkers. In this study we investigated the use of blood-based microRNAs as prognostic biomarkers for the development of dementia and diagnosis of AD. Methods: MicroRNAs were profiled via a genome-wide high-throughput platform in plasma from patients with mild cognitive impairment (MCI) and clinical AD. Identified candidate microRNAs were verified by individual RT-qPCR and a novel electrochemical detection system. Subjects were recruited as part of a longitudinal aging study and underwent annual clinical assessments and blood sampling. Findings: Let-7b and microRNA-206 were identified at elevated levels in MCI and dementia and AD, respectively. MicroRNA-206 displayed a strong correlation with cognitive decline and memory deficits. Longitudinal follow up over 5 years identified microRNA-206 increases preceding the onset of dementia. MiR-206 was also detected at increased concentrations in unprocessed plasma of AD and MCI subjects using a microfluidic device. Interpretation: While increased Let-7b levels in plasma may be used to identify patients with MCI, changes in plasma levels of microRNA-206 may be used to predict cognitive decline and progression towards dementia at an MCI stage. MicroRNA quantification via a microfluidic device could provide a practical cost-effective tool for stratification of patients with MCI according to risk of developing AD. Funding Statement: This work was supported by funding from the Health Research Board HRA-POR-2015-1243 to TE; Science Foundation Ireland (17/CDA/4708 to T.E, 18/FIP/3552 to ES and KA, and co-funded under the European Regional Development Fund and by FutureNeuro industry partners 16/RC/3948 to DCH) and funding from CIBERNED and the Spanish Ministry of Science (SAF2016-78603-R) to MM and MC. The Vallecas Project is supported by institutional grants from the Queen Sofia Foundation, CIEN Foundation and the Carlos III Institute of Health. Declaration of Interests: This work was supported by funding from the Health Research Board HRA-POR-2015-1243 to TE; Science Foundation Ireland (17/CDA/4708 to T.E, 18/FIP/3552 to ES and KA, and co395 funded under the European Regional Development Fund and by FutureNeuro industry partners 16/RC/3948 to DCH) and funding from CIBERNED and the Spanish Ministry of Science (SAF2016-78603-R) to MM and MC. The Vallecas Project is supported by institutional grants from the Queen Sofia Foundation, CIEN Foundation and the Carlos III Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The other authors have declared no conflict of interest. Ethics Approval Statement: The project was approved by the Ethics Committee of the Carlos III Institute of Health. All participants provided written informed consent.