Microorganisms of the gastrointestinal (GI) tract include bacteria, fungi, viruses and parasites that are collectively referred to as the “microbiota” or “microbiome.” While the bacteria or bacteriome remains the most explored area, the ecological niche occupied by other groups, especially the fungi or mycobiome, cannot be ignored. More than a century ago, Nobel laureate Elie Metchnikoff proposed and postulated that the good bacteria of the gut, famously referred to as probiotics, benefit the host in many ways, including mitigation of stress-related anxiety and delaying senility in humans. This is the basis of fecal transplantation that involves administration of the microbiome from healthy subjects to diseased individuals. Based on our previous findings, there appears to be a synergistic association between the bacteriome and mycobiome, the dynamics of which is dependent on numerous factors such as antibiotic usage, stress, infection, and other metabolic and environmental factors. In this study we propose aims to address this area, with emphasis on how some of the above factors induce changes in microbiome profile and how that impacts the brain in Alzheimer’s disease (AD), using mouse models. The research strategies were designed based on recent accumulating evidence that demonstrate a link between central nervous system (CNS) disorders and the gut microbiome. In this study we will continue working on our previous aims, include additional ones based on our earlier findings, and use AD mouse models to investigate the impact of gut microbes on the brain during early and late stages of AD. Identifying specific genus and species of fungi and bacteria that emerge post treatment, and whether their presence mitigates or accelerates CNS insult, will be the main focus of our proposed goals. Findings are likely to provide better understanding toward designing novel strategies for early treatment of AD.