Microbiome functional gene pathways are indicative of cognitive performance in older adults at risk for Alzheimer's disease.

Disturbances in the gut microbiome are increasingly correlated with neurodegenerative disorders, including Alzheimer's disease. Multiple lines of emerging evidence are consistent with the microbiome's involvement in disease pathology in AD by triggering or potentiating systemic and neuroinflammation, thereby influencing disease pathology through the "microbiota-gut-brain axis." Currently, the copathologies contributing to cognitive decline and symptomatic progression in AD remain unknown and understudied. Changes in the gut microbiome composition may offer clues to potential systemic physiologic and neuropathologic changes that contribute to cognitive decline. Here, we recruited a cohort of 260 older adults (aged 60 y or older) living in the community and followed them over time, tracking objective measures of cognition, clinical information, and gut microbiome samples. Subjects were classified as healthy controls, exhibiting mild cognitive impairment, or having dementia based on clinical assessments. Using metagenomic sequencing and gene pathway analyses, we found that certain microbial-encoded metabolic pathways correlated with worse cognitive performance. Specifically, genes involved in the urea cycle, polyamine synthesis, or the metabolism of methionine and cysteine predicted worse cognitive performance. Our study suggests that the gut microbiome composition may be linked to cognitive impairment along the AD continuum and points to microbial metabolic pathways that may potentiate disease.