Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology

The gut microbiome influences metabolic, immune, and neuroinflammatory processes that are increasingly implicated in the pathophysiology of Alzheimer’s disease (AD). Alterations in microbial composition have been associated with cognitive decline, systemic inflammation, and disruptions in the gut-brain axis observed in AD. Despite a growing number of studies linking gut dysbiosis to AD-related brain changes, the underlying mechanisms remain poorly understood. The bacterial metabolite imidazole propionate (ImP) has been previously associated with dementia risk factors, including type 2 diabetes and cardiovascular disease, however, the impact of ImP on brain remains relatively unknown. Here, we show that elevated plasma ImP levels are associated with lower cognitive performance and biomarkers of AD pathology in a large cohort of cognitively unimpaired individuals (>1,100). Furthermore, high plasma ImP levels predicted accelerated progression of AD-related pathology. Metagenomic profiling of stool samples identified gut bacteria encoding predicted orthologs of the ImP-synthesizing enzyme, urocanate reductase (UrdA), whose abundance correlated with both cognitive measures and multiple AD biomarkers. Supporting the human observations, chronic ImP administration in AD mouse model activated neurodegenerative pathways, exacerbated AD pathology, and increased blood-brain barrier (BBB) permeability. Finally, in vitro studies showed that ImP compromised the integrity of human brain endothelial cells. Together, these findings implicate ImP in AD progression and position it as a potential target for early intervention.