Ruminococcus‐based metagenomic‐brain signature linked to cognitive performance and Alzheimer’s disease markers

Abstract Background The aim of this study was to identify a gut microbial signature associated with patterns of gray matter volume in AD, and to validate the microbial signature by testing it against measures of AD pathology and cognitive performance. Prior literature suggests that microbial species involved in bile acid production and inflammation may be implicated in the microbial signature. Method The sample comprised 204 Microbiome in Alzheimer’s Risk Study participants (22 AD, 10 MCI, and 172 CN; 129 Females, 78 APOE+) from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention. With shotgun metagenomic sequencing data and regional gray matter volumes calculated using T1‐weighted neuroimaging (Destrieux, Harvard Oxford subcortical atlases), sparse partial least squares regression was used to determine correlated sets of microbial features and gray matter regions that maximally explained the variance in the two datasets. General linear models were then used to link the derived microbial signature with an aggregated score of cognitive performance (PACC3), an estimated cognitive score (ADAS‐Cog‐13) derived using participants’ serum lipidomics, and amyloid and tau positivity status. Result Greater abundance of 14 microbial features dominated by Ruminococcus species was associated (r=0.39, p=7.7e‐09) with greater volume in 13 regions dominated by the hippocampus, amygdala, and temporal regions, which are implicated in AD (Figure 1). This relationship was especially strong among APOE ε4 carriers. Higher scores on the microbial signature (associated with higher gray matter volume) were also associated with pTau negative status, and with better performance on the PACC3 and estimated ADAS‐Cog‐13. Conclusion With roles in producing secondary bile acids and short chain fatty acids, Ruminococcus species may benefit the gut mucosal barrier and abrogate inflammatory mechanisms. This study suggests these microbes could protect against neurotoxic processes including tau hyperphosphorylation, resulting in preserved cortical volume and better cognitive performance. Funding : Alzheimer Gut Microbiome Project, NIA U19 AG063744