Gut microbiome compositional and functional features associate with Alzheimer's disease pathology

Jea Woo Kang; Lora A Khatib; Margo B Heston; Amanda H Dilmore; Jennifer S Labus; Yuetiva Deming; Leyla Schimmel; Colette Blach; Daniel McDonald; Antonio Gonzalez; MacKenzie Bryant; Tyler K Ulland; Sterling C Johnson; Sanjay Asthana; Cynthia M Carlsson; Nathaniel A Chin; Kaj Blennow; Henrik Zetterberg; Federico E Rey; Alzheimer Gut Microbiome Project Consortium; Rima Kaddurah-Daouk; Rob Knight; Barbara B Bendlin

doi:10.1002/alz.70417

Gut microbiome compositional and functional features associate with Alzheimer's disease pathology

Alzheimers Dement. 2025 Jul;21(7):e70417. doi: 10.1002/alz.70417.

Authors

Jea Woo Kang¹, Lora A Khatib^{2

3}, Margo B Heston¹, Amanda H Dilmore², Jennifer S Labus^{4

5

6}, Yuetiva Deming¹, Leyla Schimmel⁷, Colette Blach⁸, Daniel McDonald², Antonio Gonzalez², MacKenzie Bryant², Tyler K Ulland^{1

9}, Sterling C Johnson¹, Sanjay Asthana¹, Cynthia M Carlsson¹, Nathaniel A Chin¹, Kaj Blennow¹⁰, Henrik Zetterberg^{1

10

11

12

13

14}, Federico E Rey¹⁵; Alzheimer Gut Microbiome Project Consortium⁷; Rima Kaddurah-Daouk^{7

16

17}, Rob Knight^{2

18

19

20

21}, Barbara B Bendlin^{1

22}

Affiliations

¹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
² Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
³ Neurosciences Graduate Program, University of California, San Diego, La Jolla, California, USA.
⁴ Integrative Biostatistics and Bioinformatics Core (IBBC) at the Goodman-Luskin Microbiome Center, Los Angeles, California, USA.
⁵ G. Oppenheimer Center for Neurobiology of Stress and Resilience, Los Angeles, California, USA.
⁶ UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁷ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA.
⁸ Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA.
⁹ Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
¹¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹² Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
¹³ UK Dementia Research Institute at UCL, London, UK.
¹⁴ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹⁵ Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹⁶ Duke Institute of Brain Sciences, Duke University, Durham, North Carolina, USA.
¹⁷ Department of Medicine, Duke University, Durham, North Carolina, USA.
¹⁸ Center for Microbiome Innovation, Joan and Irwin Jacobs School of Engineering, University of California, San Diego, La Jolla, California, USA.
¹⁹ Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California, USA.
²⁰ Halıcıoğlu Data Science Institute, University of California, San Diego, La Jolla, California, USA.
²¹ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
²² Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.

PMID: 40604345
DOI: 10.1002/alz.70417

Abstract

Background: The gut microbiome is a potentially modifiable risk factor for Alzheimer's disease (AD); however, understanding of its composition and function regarding AD pathology is limited.

Methods: Shallow-shotgun metagenomics was used to analyze the fecal microbiome of participants in the Wisconsin Microbiome in Alzheimer's Risk Study, leveraging clinical data and cerebrospinal fluid (CSF) biomarkers. Differential abundance and ordinary least squares regression analyses were performed to find differentially abundant gut microbiome features and their associations with CSF biomarkers of AD and related pathologies.

Results: Gut microbiome composition and function differed between individuals with and without AD dementia. The compositional difference was replicated in an independent cohort. Differentially abundant gut microbiome features were associated with CSF biomarkers of AD and related pathologies.

Discussion: These findings enhance our understanding of alterations in gut microbial composition and function in AD, and suggest that gut microbes and their pathways are linked to AD pathology.

Highlights: Gut microbiome composition and function differ between people with Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Co-occurring gut microbes show differential abundance across AD-related groups (AD vs CU, amyloid status+ vs amyloid status-, and apolipoprotein E (APOE) ε4 status+ vs APOE ε4 status-). Gut microbiome composition also differs between people with AD dementia and CU individuals in a larger validation cohort. Differentially abundant gut microbiome composition and function between AD and CU groups are correlated with cerebrospinal fluid biomarkers for AD and related pathologies.

Keywords: Alzheimer's disease; biomarkers; cerebrospinal fluid; composition; differential abundance; function; gut microbiome; pathology.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / cerebrospinal fluid
Alzheimer Disease* / microbiology
Alzheimer Disease* / pathology
Amyloid beta-Peptides / cerebrospinal fluid
Biomarkers / cerebrospinal fluid
Feces / microbiology
Female
Gastrointestinal Microbiome* / physiology
Humans
Male
Metagenomics

Substances

Biomarkers
Amyloid beta-Peptides

Abstract

MeSH terms

Substances

Grants and funding