GUT MICROBIOME ALTERATIONS IN ALZHEIMER'S DISEASE AND THE RELATIONSHIP WITH CSF BIOMARKERS

Abstract

The etiology of dementia due to Alzheimer's disease (AD) is not completely understood. Recent studies suggest that alterations in human gut microbiota contribute to neurological conditions including multiple sclerosis and Parkinson's disease, yet the contribution of the gut microbiota to the development of AD neuropathology and dementia is unknown. We investigated this by examining gut microbiota among participants in the Wisconsin Registry for Alzheimer's Prevention and Wisconsin ADRC, with and without a clinical diagnosis of mild cognitive impairment (MCI) or AD. Secondary analysis examined the extent to which cerebrospinal fluid (CSF) biomarkers of AD were associated with the composition of the gut microbiome. Bacterial 16S rRNA gene sequencing was performed on DNA extracted from fecal samples collected from AD/MCI patients (n=16), age- and sex-matched control participants (n=18), and asymptomatic middle-aged participants (n=52). Sequence processing was performed in mothur, and richness, alpha, and beta diversity metrics were calculated using normalized OTU-level data. Metastats was used to detect differential abundance between AD/MCI and controls at the family taxonomic level. Among participants who had previously undergone lumbar puncture (n=31), we tested the relationship between microbiome phylogenetic diversity and CSF levels of Aβ42 and phosphorylated tau. The microbiome of AD/MCI participants showed significantly less richness and alpha diversity (Figure 1), and a significant difference in beta diversity compared to control participants. AD/MCI participants showed elevated abundance of Lachnospiraceae, Bacteroidaceae, and Streptococcaceae, with decreased levels of Ruminococcaceae (Figure 2). Among participants with CSF data, an interaction between diagnosis and phylogenetic diversity was observed for CSF phosphorylated tau and the ratio of ptau/Aβ42 (Figure 3). Decreased richness and alpha diversity in the microbiome of AD/MCI participants parallels results observed in other conditions associated with gut dysbiosis including diabetes and obesity. Moreover, we observed that decreased microbial diversity was associated with greater AD pathology in CSF. Additional work, including animal studies and longitudinal human studies, are needed to determine the potential contribution of gut microbiota to the development of AD. Gut microbiome in AD/MCI displays decreased richness (Abundance-based coverage estimator (ACE), Chaol) and alpha diversity (Shannon Index, Faith's Phylogenetic Diversity) metrics. *p<0.05. Relative abundance differences at family taxonomic level between AD/MCI and age- and sex-matched control participants as identified by Metastats. *p<0.05 (FDR). Relationship between gut microbiome phylogenetic diversity and CSF phosphorylated tau and the ratio of tau/Aβ42.