Simple SummaryAlzheimer’s disease (AD) is a progressive, age-related neurodegenerative disorder representing the most common cause of senile dementia and neurological dysfunction in our aging domestic population. MicroRNAs (miRNAs) are a small family of non-coding single-stranded RNAs (ssRNAs) that function in complex interactive networks to direct the post-transcriptional repression of messenger RNA (mRNA)-encoded genetic information. Current evidence suggests that these ssRNAs perform an important regulatory role in the expression of genes in the AD-affected brain and central nervous system (CNS). This review paper will focus on recent studies, developments and advancements in our appreciation and understanding of the complexity of miRNA signaling in AD-affected brain hippocampal CA1 compared to age- and gender-matched controls.AbstractAD is a complex, progressive, age-related neurodegenerative disorder representing the most common cause of senile dementia and neurological dysfunction in our elderly domestic population. The widely observed heterogeneity of AD is a reflection of the complexity of the AD process itself and the altered molecular-genetic mechanisms operating in the diseased human brain and CNS. One of the key players in this complex regulation of gene expression in human pathological neurobiology are microRNAs (miRNAs) that, through their actions, shape the transcriptome of brain cells that normally associate with very high rates of genetic activity, gene transcription and messenger RNA (mRNA) generation. The analysis of miRNA populations and the characterization of their abundance, speciation and complexity can further provide valuable clues to our molecular-genetic understanding of the AD process, especially in the sporadic forms of this common brain disorder. Current in-depth analyses of high-quality AD and age- and gender-matched control brain tissues are providing pathophysiological miRNA-based signatures of AD that can serve as a basis for expanding our mechanistic understanding of this disorder and the future design of miRNA- and related RNA-based therapeutics. This focused review will consolidate the findings from multiple laboratories as to which are the most abundant miRNA species, both free and exosome-bound in the human brain and CNS, which miRNA species appear to be the most prominently affected by the AD process and review recent developments and advancements in our understanding of the complexity of miRNA signaling in the hippocampal CA1 region of AD-affected brains.