microRNA-150-5p: A Novel Blood-Based Biomarker for Alzheimer’s Dementia with Good Correlation to Cognition, Cerebrospinal Fluid Amyloid-β, and Cerebral Atrophy

Background: There is an urgent need for non-invasive, cost-effective biomarkers for Alzheimer’s disease (AD), such as blood-based biomarkers. It is not only to support clinical diagnosis of dementia, but also to allow for timely pharmacological and non-pharmacological interventions evaluation. The aim of this study is to identify and validate a novel blood-based microRNA (miRNA) biomarker for dementia of Alzheimer’s disease type (DAT). The miRNA correlations with AD pathology and AD clinical-radiological imaging were conducted.Methods: We conducted miRNA-sequencing (miRNA-Seq) using peripheral blood mononuclear cells (PBMCs) isolated from a discovery cohort comprising DAT, mild cognitive impairment (MCI), and healthy subject (HS). Identified miRNA was validated in an independent cohort. Correlation analysis evaluated the relationships between miRNA expression and DAT clinical measures, including Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, CSF Aβ1-42 and tau levels, and AD pattern cerebral atrophy. Furthermore, we conducted bioinformatics analysis and cell-based assay to identify miRNA target genes. Results: MiRNA-seq identified a distinct miRNA (miR-328-3p, miR-7706, and miR-150-5p) expression signature differentiating DAT from MCI and HS. qPCR analysis reveals that miR-150-5p was consistent with the miRNA-seq data and was further validated. Specifically, we found that miR-150-5p expression was significantly upregulated in DAT compared to MCI and HS, and discriminated DAT from MCI and HS with a high accuracy with AUC of 0.86 and 0.86, respectively. We further found that higher miR-150-5p levels correlated with clinical measures of DAT, including lower global cognitive scores of MMSE and MoCA, lower CSF Aβ1-42, and higher CSF tau. Interestingly, we observed that higher miR-150-5p levels is associated with the lower grey matter volumes in the medial temporal lobe, posterior cingulate cortex and precuneus. These regions implicated default mood network and executive control network regions that are important for AD brain atrophy. Furthermore, pathway analysis identified the targets of miR-150-5p to be enriched in the Wnt signalling pathway, including programmed cell death 4 (PDCD4). We further found that PDCD4 was downregulated in DAT blood and was downregulated by miR-150-5p at both transcriptional and protein levels.Conclusions: Our findings demonstrated that miR-150-5p is a reliable clinical blood-based biomarker for DAT.