Zeamer, Abigail LLai, YushuanSanborn, VictoriaLoew, EthanTracy, MatthewJo, CynthiaWard, Doyle VBhattarai, Shakti KDrake, JohnathanMcCormick, Beth ABucci, VanniHaran, John P2025-04-072025-04-072025-03-10Zeamer AL, Lai Y, Sanborn V, Loew E, Tracy M, Jo C, Ward DV, Bhattarai SK, Drake J, McCormick BA, Bucci V, Haran JP. Microbiome functional gene pathways predict cognitive performance in older adults with Alzheimer's disease. bioRxiv [Preprint]. 2025 Mar 10:2025.03.06.641911. doi: 10.1101/2025.03.06.641911. PMID: 40161798; PMCID: PMC11952313.2692-820510.1101/2025.03.06.641911401617982025.03.06.641911https://hdl.handle.net/20.500.14038/54311This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Disturbances in the gut microbiome is increasing correlated with neurodegenerative disorders, including Alzheimer's Disease. The microbiome may in fact influence disease pathology in AD by triggering or potentiating systemic and neuroinflammation, thereby driving disease pathology along the "microbiota-gut-brain-axis". Currently, drivers of cognitive decline and symptomatic progression in AD remain unknown and understudied. Changes in 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 (age 60+) living in the community and followed them over time, tracking objective measures of cognition, clinical information, and gut microbiomes. Subjects were classified as healthy controls or as having mild cognitive impairment based on cognitive performance. Those with a diagnosis of Alzheimer's Diseases with confirmed using serum biomarkers. Using metagenomic sequencing, we found that relative species abundances correlated well with cognition status (MCI or AD). Furthermore, gene pathways analyses suggest certain microbial metabolic pathways to either be correlated with cognitive decline or maintaining cognitive function. Specifically, genes involved in the urea cycle or production of methionine and cysteine predicted worse cognitive performance. Our study suggests that gut microbiome composition may predict AD cognitive performance.enThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.http://creativecommons.org/licenses/by-nc-nd/4.0/ADAS-CogAlzheimer’s DiseaseClinical Dementia Rating (CDR) ScaleCognitionCysteineMethionineMicrobiomeMild Cognitive ImpairmentNIH ToolboxUrea cyclePreprint