ABSTRACT/SUMMARY Aging population is increasing, and age-related cognitive, Alzheimer’s disease (AD) and its related dementias (ADRD) prevalence sharply rising, with no prognosis, prevention or treatment. This is because we do not fully understand the mechanisms responsible for cognitive decline and ADRD progression during aging. Studies have identified many genes associated with the risk of development of familial AD, however, few have examined how the underlying mechanisms involved with aging-related risk and progression of AD. Studies of microbiota showed strong evidence that gut bacteria and metabolites significantly contribute to the development of AD and AD-related dementias (ADRD). Interestingly, we and others found that the gut microbiome signature in older adults with mild cognitive impairment (MCI), an early stage of AD, and ADRD significantly differs from cognitively healthy age-matched individuals. However, the mechanisms by which the gut microbiome impacts brain health are not well understood. Emerging evidence from literature and our preliminary data suggests that miRNAs produced from gut cells in response to microbial changes can also play important role in AD. miRNAs are known to modulate AD pathogenesis through many pathways, including targeting proteins related to Aβ clearance, neurotoxicity, synaptic loss, and cellular senescence, but the role of gut-derived miRNAs in age- related cognitive decline and ADRD is obscure. Here we propose the hypothesis that novel miRNAs of the gut appear in the blood circulation of older adults with MCI and dementia compared to healthy controls. We also posit that these gut-associated exosomal miRNAs travel through blood to brain and impact gene expression program in specific cell types of brain. To address these translationally important studies, we will use the stools and plasma samples from our ongoing study called Microbiome in aging Gut and Brain (MiaGB) consortium to determine the unique signature of gut-originating miRNAs and their mechanism of action by focusing on the two specific aims. In aim 1, we will determine the miRNA signatures that uniquely originated from gut to blood in older adults with MCI and dementia compared to cognitively healthy. In aim 2, we will determine if the exosomal miRNAs travel from gut to brain, target cell types in brain and impact their gene expression. Our studies will define the unique miRNAs of MCI and dementia compared to healthy controls, as well as establish the mechanism by which these MCI/ADRD-specific miRNAs impact specific neuronal cell functions. Our studies are built as an ancillary of the ongoing large MiaGB study for completing cost-effective, high rigor and timely manner by utilizing expertise of interdisciplinary team.