Gut microbial taxa associations with cognitive functional measures in patients with Alzheimer’s Disease

Smita S. Ghare^1,2,3,5,6, Vasuk Gautam^1,5,6, Brandon C. Dennis^5,6, Paula M. Chilton^1,2,5,6, Jiyeon Lee^1,2,5,6, Fengyuan Li^1,2,5,6, Irina Smolenkova^5,6, Ashley Ezzo^5,6, Tasha M Santiago-Rodriguez⁴, Petrosino Joseph⁴, Lisa B.E.Shields^5,6, Marti Gardner⁶, Gerald Dryden^1,7, Christopher B Shields^5,6, and Shirish Barve^1,2,3,5,6

¹Department of Medicine, ²UofL Alcohol Research Center, ³UofL Hepatobiology COBRE, University of Louisville, School of Medicine, Louisville, KY 40202; ⁴Baylor College of Medicine, ⁵Norton Neuroscience Institute, ⁶Norton Healthcare, Louisville, KY 40202, ⁷Robley Rex VA Medical Center, Louisville, KY40206 .

Background: Alzheimer’s disease (AD) is associated with altered gut microbial diversity with shifts in key taxa. Gut microbiome alterations may play a mechanistic role in cognitive decline in AD and represent a potential target for therapeutic intervention. The present study reports the significant associations between gut microbiome and cognitive functional measures in AD patients.

Methods: A pilot study was conducted on participants in the Norton Neuroscience Memory Center cohort of Alzheimer’s disease (AD, n=18) compared to age matched controls with no cognitive impairment (NCI; n=11). Metataxonomic profiling of fecal samples were performed by 16S rRNA gene sequencing. Neurocognitive assessments were performed by Montreal Cognitive Assessment (MoCA) and Tablet-based Cognitive Assessment Tool Brain Health Assessment (TabCAT-BHA). Group-wise comparisons were made using Mann-Whitney U-test and non-parametric Spearman correlation models were used to evaluate the association between gut microbiome, and cognitive/memory measures.

Results: AD patients showed worse performance on TabCAT tasks and MoCA than control participants, demonstrating cognitive impairment. Taxonomic profiling of the gut microbiome showed that in comparison to controls, AD patients had significant reductions in percent relative abundance (%RA) of phylum Firmicutes, family Lachnospiraceae and genus Blautia, and increased %RA in phyla Bacteriodota and Proteobacteria, families Rikenellaceae, Oscillospiraceae and Tannerellaceae and genera Oscillibacter, and Parabacteroides. Spearman correlation analysis among controls showed significant positive correlation between Lactobacillaceae, Barnesiellaceae families and MoCA scores (Spearman r=0.69 and 0.74 and p<0.05). In comparison, in AD patients, although there was no significant differential change in %RA of Bacteroidaceae family, levels strongly correlated with memory/executive functions assessed by TabCAT (Spearman r=0.56 to 0.79 and p<0.01 to <0.0001), and with global cognitive performance assessed by MoCA (Spearman r=0.6933 and p=0.0003).

Conclusion: The current findings demonstrate that complex relationships between specific microbial taxa and cognitive functional measures are more significant than relative changes in bacterial abundance alone. Modulation of gut microbiota through interventions like diet, probiotics, or fecal microbiota transplantation may offer new strategies for the prevention and management of AD.