MicroRNAs in Alzheimer’s Disease: From Molecular Pathogenesis to Biomarkers and Therapeutic Strategies

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline due to accumulation of amyloid-beta plaques outside neurons and neurofibrillary tangles inside neurons. The polygenic, multifactorial nature of the disease has limited the efficacy of single-target therapeutics and has shifted interest towards agents that act on several pathological pathways. MicroRNAs (miRNAs) are well suited to this purpose: they are small non-coding RNAs that regulate gene expression post-transcriptionally, and a single miRNA can regulate many transcripts within a common pathway. Since their first identification, appreciation of their regulatory capacity in the healthy and diseased brain has grown substantially and altered miRNA expression is now linked to a range of neurodegenerative diseases. In AD, selected miRNAs have been associated with amyloidogenic APP processing, BACE1 expression, tau phosphorylation, apolipoprotein E lipidation and neuroinflammation. Circulating miRNA signatures in blood and cerebrospinal fluid are being explored as minimally invasive diagnostic biomarkers alongside established plasma phosphorylated tau and Aβ42/40 measures. More recently, attention has turned to the therapeutic potential of these molecules, with crossing the blood–brain barrier remaining the major hurdle. This review summarizes the biogenesis and mechanism of action of miRNAs and critically assesses their emerging value as biomarkers and therapeutic candidates.