A growing literature reports associations between the composition of the gut microbiome and mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The reigning hypothesis as to how particular bacterial combinations, frequencies, and concentrations in the gut could influence the risk of neurodegenerative diseases, including AD, is the induction of Pro-inflammatory mediatorspro-inflammatory mediators in the gut that enter the systemic circulation and cross the blood-brain barrier, thereby producing a chronic neuroinflammatory state. Several challenges have limited the ability to causally link the reported associations with the initiation or progression of AD. Most AD patients are on prescription medications that might impact the microbiota. The development of AD might be associated with self-selected changes in diet. Regional differences in gut microbiota might underlie some of the heterogeneous findings. Age-related changes in the gut microbiome in normal controls have not been sufficiently elucidated. The labor-intensive nature of this line of inquiry limits subject numbers, with the majority but not all the enrolled AD patients carrying the ϵ4 allele, thereby introducing genetic heterogeneity. Despite these challenges, several studies have reported that carriers of the ϵ4 allele have a microbiome composition that trends toward a more pro-inflammatory state than either ϵ3 or ϵ2 carriers. A limited number of prospective studies have reported that MCI patients also possess a more pro-inflammatory microbiome than cognitively normal subjects. Studies in transgenic mice expressing either ϵ4, ϵ3, or ϵ2 alleles have provided mechanistic support for the gut microbiome degenerative disease hypothesis. Future studies employing prospective designs and larger subject numbers are expected to clarify the possible relationship between gut microbiome bacterial products and effects on the brain. Furthermore, there is growing recognition that viruses, in addition to bacteria, might be playing a significant role in microbiome biochemical dynamics.