Alzheimer’s disease (AD) is a progressive neurodegenerative disease with marked neuronal loss, memory impairment, and cognitive decline that devastates the affected individuals and their families. AD pathology is multifactorial, involving several risk factors: genetics, environmental factors, aging, impaired autophagy, and neuroinflammation. Most recently, the potential influence of probiotics on neuroinflammation in AD has garnered attention. We investigated the role of probiotics in reducing AD phenotype in AppNL-G-F mice, an animal model for AD. We hypothesized that probiotics would reduce AD phenotype in AppNL-G-F, which would be evident by the enrichment of pathways related to neuronal regulation and immune modulation. To investigate this, we treated 6-month-old female AppNL-G-F and C57BL6 (wild-type) mice with either vehicle or probiotics (VSL#3) ad libitum in drinking water for three months. AD mice were utilized because they exhibit heightened Aβ levels attributed to the influence of three Familial AD mutations: Swedish “NL”, Iberian “F”, and Arctic “G”. After treatment, total RNA was collected from the telencephalon, hippocampus, and colon and used to generate libraries for genome-wide RNA -Seq. Differential expression analysis using limma-voom was performed to identify differentially expressed genes (DEGs) in relevant comparisons. Study findings show a significant difference between wild-type and AppNL-G-F mice with probiotic treatment in the hippocampus and colon. These observed changes in gene expression point to a reduction in the AD phenotype, specifically pathways associated with inflammation. Future work will explore enriched pathways in comparison with publicly available human AD transcriptomic datasets to identify potential therapeutic gene candidates.