Vemuganti, V.; Kang, J. W.; Zhang, Q.; Martinez, R. A.; Harpt, J. L.; Harding, S. J.; Deming, Y.; Johnson, S. C.; Asthana, S.; Zetterberg, H.; Blennow, K.; Engelman, C.; Ulland, T. K.; Bäckhed, F.; Bendlin, B. B.; Rey, F. E.

The gut microbiome modulates metabolic, immune, and neurological functions and has been implicated in Alzheimer\'s disease (AD), though the specific mechanisms remain poorly defined. The bacterial metabolite imidazole propionate (ImP) has been previously associated with several AD comorbidities, such as type 2 diabetes and cardiovascular disease. Here, we show that elevated plasma ImP levels are associated with lower cognitive scores and AD biomarkers in a cohort of >1,100 cognitively unimpaired individuals. Metagenomic profiling identified gut bacteria encoding putative orthologs of the ImP-synthesizing enzyme, urocanate reductase (UrdA), whose abundance correlated with both cognitive measures and multiple AD biomarkers. Chronic ImP administration to mice activated neurodegenerative pathways, worsened AD-like neuropathology, and increased blood-brain barrier (BBB) permeability. Complementary in vitro studies showed that ImP compromised the integrity of human brain endothelial cells. Collectively, these findings implicate ImP in AD progression via both neurodegenerative and cerebrovascular mechanisms, identifying it as a potential target for early intervention.