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Abstract
Alzheimer’s disease (AD) is a major health and socioeconomic problem. Despite increasing prevalence, its aetiology is still not completely understood. MicroRNAs (miRNA) are a class of non-coding RNA known to regulate protein expression post-transcriptionally. They have the potential to be novel and specific biomarkers for disease, because of their reported dysregulated expression in different biological and pathological states. This thesis aims to identify and elucidate the role of miRNAs as biomarkers for AD by examining differential blood miRNA expression in individuals with AD, mild cognitive impairment (MCI) and normal cognition, and to provide insight into the biological pathways involved and its relevance to AD pathology.
First, a pilot study (n=48) of differential miRNA microarray expression in blood between individuals with AD, MCI, and normal cognition was performed. There were 126 dysregulated miRNAs between AD and controls. Next, a larger cohort study (n=121) was conducted with participants recruited from the Australian Imaging Biomarkers Lifestyle Study of Ageing (AIBL) study with phenotype additionally defined by brain amyloid burden. MiRNA expression analysis was performed using small RNA sequencing and compared between groups of amyloid positive AD and MCI, and amyloid negative cognitively normal controls. There were 71 dysregulated miRNAs between AD and controls. The biological pathways of candidate miRNAs were then examined using the Ingenuity Pathway Analysis (IPA) and DAVID (the database for annotation, visualisation and integrated discovery). Of interest, miR-146b-5p and miR-15b-5p were found to be involved in the innate immune response pathway and cell cycle regulation/cancer pathways respectively, both of which are likely involved in AD pathogenesis. Finally, miRNA and messenger RNA (mRNA) expression were profiled in a small sample of monozygotic (MZ) twins discordant for brain amyloid burden (n=10) to obtain insight into the miRNA-mRNA relationship in vivo while controlling for genetic, maternal and early environment confounders.
This thesis provides several novel contributions to the literature by identifying candidate miRNA biomarkers for AD in well phenotyped study cohorts and investigating their role in biology and AD pathology. These miRNAs, in particular miR-146b-5p and miR-15b-5p, warrant further investigation in order to translate miRNA biomarkers into clinical practice.