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Peer-reviewedCC BYNature Communications

Gut bacterial metabolite imidazole propionate potentiates Alzheimer’s disease pathology

  • Vaibhav Vemuganti1,2,3,4
  • Jea Woo Kang5,4,6
  • Qijun Zhang2,7,4
  • Eric R. McGregor8,7,4
  • James R. Hilser9,4,6
  • Ruben Aquino-Martinez2,7,4
  • Sandra Harding5,4,6
  • Joseph Lawrence Harpt2,4,6,10
  • Katharina R. Beck11,4,6,10
  • Hailey Bussan2,12,13,14,15,16,17,18
  • Jessamine F. Kuehn2,19,20,21,22,23,24
  • Yuetiva Deming5,25,4
12 more authors
  • Rachel Studer5,26,4
  • Sterling C. Johnson5,27,28,29,30,31
  • Sanjay Asthana5,27,4,6,10
  • Henrik Zetterberg32,33,14,34,35,36,5,37,4
  • Kaj Blennow33,34,38,39
  • Corinne D. Engelman40
  • Hooman Allayee9
  • Rozalyn M. Anderson8
  • Tyler Kent Ulland5
  • Fredrik Bäckhed11
  • Barbara B. Bendlin
  • Federico E. Rey
40 affiliations
  1. 1Cellular and Molecular Pathology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA
  2. 2Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
  3. 3Cellular and Molecular Pathology Graduate Training Program, University of Wisconsin-Madison
  4. 4Madison, WI, USA
  5. 5Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
  6. 6Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison
  7. 7Department of Bacteriology, University of Wisconsin-Madison
  8. 8Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
  9. 9Division of Cardiology, Department of Medicine, David Geffen School of Medicine of UCLA, Los Angeles, California, USA
  10. 10Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin
  11. 11Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
  12. 12Centre for Brain Research, Indian Institute of Science; Bangalore, India
  13. 13Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital; Mölndal, Sweden
  14. 14Department of Neurodegenerative Disease, UCL Institute of Neurology; Queen Square, London, UK
  15. 15Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Mölndal, Sweden
  16. 16Hong Kong Center for Neurodegenerative Diseases; Inn, 6, oHK, Hong Kong, China
  17. 17UK Dementia Research Institute at UCL; London, UK
  18. 18Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison; Madison, WI, USA
  19. 19Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital
  20. 20Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg
  21. 21Hefei, P.R. China
  22. 22Mölndal, Sweden
  23. 23Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC
  24. 24Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University
  25. 25Department of Population Health Sciences, University of Wisconsin-Madison
  26. 26Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison
  27. 27Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
  28. 28Kongens Lyngby, Denmark
  29. 29Microbiome Health Initiative and the National Food Institute, Technical University of Denmark
  30. 30Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology; Gothenburg, Sweden
  31. 31Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg
  32. 32Centre for Brain Research, Indian Institute of Science, Bangalore, India
  33. 33Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  34. 34Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  35. 35Hong Kong Center for Neurodegenerative Diseases, Inn,6,oHK, Hong Kong, China
  36. 36UK Dementia Research Institute at UCL, London, UK
  37. 37Department of Medical Microbiology and Immunology, University of Wisconsin-Madison
  38. 38Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China
  39. 39Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
  40. 40Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
Open at sourceDOICite

Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{vemuganti2026bacterial,
  title = {{Gut bacterial metabolite imidazole propionate potentiates Alzheimer’s disease pathology}},
  author = {Vaibhav Vemuganti and Jea Woo Kang and Qijun Zhang and Eric R. McGregor and James R. Hilser and Ruben Aquino-Martinez and Sandra Harding and Joseph Lawrence Harpt and Katharina R. Beck and Hailey Bussan and Jessamine F. Kuehn and Yuetiva Deming and Rachel Studer and Sterling C. Johnson and Sanjay Asthana and Henrik Zetterberg and Kaj Blennow and Corinne D. Engelman and Hooman Allayee and Rozalyn M. Anderson and Tyler Kent Ulland and Fredrik Bäckhed and Barbara B. Bendlin and Federico E. Rey},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74744-z},
  url = {https://doi.org/10.1038/s41467-026-74744-z},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Gut bacterial metabolite imidazole propionate potentiates Alzheimer’s disease pathology
AU  - Vaibhav Vemuganti
AU  - Jea Woo Kang
AU  - Qijun Zhang
AU  - Eric R. McGregor
AU  - James R. Hilser
AU  - Ruben Aquino-Martinez
AU  - Sandra Harding
AU  - Joseph Lawrence Harpt
AU  - Katharina R. Beck
AU  - Hailey Bussan
AU  - Jessamine F. Kuehn
AU  - Yuetiva Deming
AU  - Rachel Studer
AU  - Sterling C. Johnson
AU  - Sanjay Asthana
AU  - Henrik Zetterberg
AU  - Kaj Blennow
AU  - Corinne D. Engelman
AU  - Hooman Allayee
AU  - Rozalyn M. Anderson
AU  - Tyler Kent Ulland
AU  - Fredrik Bäckhed
AU  - Barbara B. Bendlin
AU  - Federico E. Rey
PY  - 2026
DA  - 2026/06/26
JO  - Nature Communications
DO  - 10.1038/s41467-026-74744-z
UR  - https://doi.org/10.1038/s41467-026-74744-z
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.
SN  - 2041-1723
ER  -