Gut microbiome alterations in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood. Recent studies in rodents suggest that alterations in the gut microbiome may contribute to amyloid deposition, yet the microbial communities associated with AD have not been characterized in humans. Towards this end, we characterized the bacterial taxonomic composition of fecal samples from participants with and without a diagnosis of dementia due to AD. Our analyses revealed that the gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age- and sex-matched individuals. We identified phylum- through genus-wide differences in bacterial abundance including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of AD participants. Furthermore, we observed correlations between levels of differentially abundant genera and cerebrospinal fluid (CSF) biomarkers of AD. These findings add AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.

Figure 1

Alzheimer’s disease is associated with alterations in gut microbiome composition. (A) Faith’s Phylogenetic Diversity is decreased in the microbiome of AD participants. *p < 0.05. (B) Non-metric multidimensional scaling (NMDS) plot of weighted UniFrac analysis of relative sample OTU composition. NMDS analysis was limited to two dimensions, with a stress measurement of 0.17. Each dot represents a scaled measure of the composition of a given participant, color- and shape-coded by cohort. (C) Differential abundance analysis identified 14 OTUs that were increased and 68 OTUs that were decreased in AD relative to Control participants (p < 0.05, FDR-corrected). Each point represents an OTU. Data plotted as log₂ fold change; OTUs to the right of the zero line are more abundant and OTUs to the left of the zero line are less abundant in AD compared to Control groups. OTUs are organized on the y-axis according to the lowest taxonomic classification possible. (D) OTUs grouped at the phylum level and analyzed using Metastats show that AD participants have decreased abundance of Firmicutes and Actinobacteria, and increased abundance of Bacteroidetes compared to Control participants (p < 0.05, FDR-corrected). Tukey plots show median, IQR, and participant data points for phylum relative abundance.

Figure 2

Bacterial families and genera differentially represented in feces from AD participants compared to Control participants (p < 0.05, FDR-corrected). Tukey plots are colored by phylum and show median, IQR, and participant data points for genus or family relative abundance.

Figure 3

Bacterial taxa correlate with CSF biomarkers of AD pathology. 13 genera identified as differentially abundant in AD were correlated with CSF biomarkers of AD including the Aβ₄₂/Aβ₄₀ ratio (with lower CSF levels reflecting greater amyloid deposition in the brain), phosphorylated tau (p-tau), and the p-tau/Aβ₄₂ ratio (which incorporates both facets of AD pathology). Correlations were calculated separately for all 40 participants (All), 31 non-demented participants (ND), and 9 AD participants (AD). In general, genera identified as more abundant in AD were associated with greater AD pathology, while genera identified as less abundant in AD were associated with less AD pathology. Genera are ordered from most to least abundant. Shape and color of ellipses represent strength of Spearman’s rank correlation coefficients (rho). Bolded ellipse borders represent significant correlations (two-sided, p < 0.05 uncorrected).