TY - JOUR
T1 - Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology
AU - Vemuganti, Vaibhav
AU - Kang, Jea Woo
AU - Zhang, Qijun
AU - McGregor, Eric R.
AU - Hilser, James R.
AU - Aquino-Martinez, Ruben
AU - Harding, Sandra
AU - Harpt, Joseph Lawrence
AU - Beck, Katharina R.
AU - Bussan, Hailey
AU - Kuehn, Jessamine F.
AU - Deming, Yuetiva
AU - Studer, Rachel
AU - Johnson, Sterling C.
AU - Asthana, Sanjay
AU - Zetterberg, Henrik
AU - Blennow, Kaj
AU - Engelman, Corinne D.
AU - Allayee, Hooman
AU - Anderson, Rozalyn M.
AU - Ulland, Tyler K.
AU - Bäckhed, Fredrik
AU - Bendlin, Barbara B.
AU - Rey, Federico E.
PY - 2026
Y1 - 2026
N2 - The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, this study links ImP to hallmarks of neurodegeneration and suggests that targeting ImP may represent a potential strategy to modify ADRD risk.
AB - The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, this study links ImP to hallmarks of neurodegeneration and suggests that targeting ImP may represent a potential strategy to modify ADRD risk.
U2 - 10.1038/s41467-026-74744-z
DO - 10.1038/s41467-026-74744-z
M3 - Journal article
C2 - 42362546
SN - 2041-1723
VL - 17
JO - Nature Communications
JF - Nature Communications
M1 - 8017
ER -