A multi-omics approach identifies a blood-based miRNA signature of cognitive decline in two large observational trials

Identifying individuals before the onset of overt symptoms is a key prerequisite for the prevention of Alzheimers disease (AD). A wealth of data reports dysregulated microRNA (miRNA) expression in the blood of individuals with AD, but evidence in individuals at subclinical stages is sparse. In this study, a qPCR analysis of a prioritised set of 38 candidate miRNAs in the blood of 830 healthy individuals from the CHARIOT PRO cohort (West London, UK) was undertaken. Here, we identified six differentially expressed miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A pathway enrichment analysis for the six miRNAs indicated involvement of apoptosis and inflammation, relevant in early AD stages. Subsequently, we used whole genome sequencing (WGS) data from 750 individuals from the AD Neuroimaging Initiative (ADNI) to perform a genetic association analysis for polymorphisms within the significant miRNAs genes and CSF concentrations of phosphorylated-tau, total-tau, amyloid-{beta}42 and soluble-TREM2 and BACE1 activity. Our analysis revealed 24 SNPs within MIR29C to be associated with CSF levels of amyloid-{beta}42 and soluble-TREM2 and BACE1 activity. Our study shows the potential of a six-miRNA set as diagnostic blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within MIR29C suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.