Investigation of Potential Brain Microbiome in Alzheimer’s Disease: Implications of Study Bias

Abstract

Background: Dysbiotic microbiota in the gastrointestinal tract promotes and aggravates neurodegenerative disorders. Alzheimer’s disease (AD) has been shown to correlate to dysbiotic bacteria and the immune, metabolic, and endocrine abnormalities associated with abnormal gut-brain-axis signaling. Recent reports also indicate that brain dysbacteriosis may play a role in AD pathogenesis. Objective: To evaluate the presence and differences of brain-region dependent microbiomes in control and AD subjects and the contribution of study bias. Methods: Two independent cohorts of postmortem AD brain samples were collected from separate locations, processed with different extraction protocols and investigated for the presence of bacterial DNA indicative of a brain microbiome with V4 16S next generation sequencing. Results: In both cohorts, few differences between the control and AD groups were observed in terms of alpha and beta diversities, phyla and genera proportions. Independent of study in both AD and control subjects the most abundant phyla were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Variations in beta diversity between hippocampal and cerebellum samples were observed indicating an impact of brain region on the presence of microbial DNA. Importantly, differences in alpha and beta diversities between the two independent cohorts were found indicating a significant cohort- and processing-dependent effect on the microbiome. Finally, there were cohort-specific correlations between the gut microbiome and subject demographics indicate that postmortem interval may have a significant impact on brain microbiome determination. Conclusion: Regardless of the study bias, this study concludes that bacterial DNA can be isolated from the human brain suggesting that a brain microbiome may exist; however, more studies are required to understand the variation in AD.