Title: Gut microbiome compositional and functional features associate with Alzheimer’s disease pathology
Legend: Heatmap illustrates the associations between gut microbiome functional features and CSF biomarkers in AD and related pathologies. The heatmap depicts the coefficients of regression analysis between the gut microbial pathways and CSF biomarkers. Coefficients are scaled by colors indicating the strength and direction of the associations, with red representing positive associations and blue representing negative associations. The intensity of the color corresponds to the magnitude (strength) of the coefficient. Microbial species and their associated pathway features are listed on the left of the plot and two groups (Top: more abundant in AD, denoted by the light pink bar; and Bottom: less abundant in AD or more abundant in CU, denoted by the light green bar) from DA analysis using BIRDMAn are displayed on the right of the plot. The biomarkers listed along the bottom include amyloid pathology (Aβ42/Aβ40), tau pathophysiology (p-tau181 and t-tau), neurodegeneration (NfL), synaptic dysfunction and injury (neurogranin and α-synuclein), inflammation (IL-6), and glial activation (S100B, GFAP, YKL-40, and sTREM2). It should be noted that a lower Aβ42/Aβ40 ratio is associated with a higher risk of having AD pathology, whereas higher levels of the rest of the CSF biomarkers are associated with a higher risk of having AD pathology. Asterisks indicate the level of statistical significance of the associations: **p < 0.01, and *p < 0.05 (uncorrected). Aβ, amyloid beta; AD, Alzheimer’s disease; BIRDMAn, Bayesian Inferential Regression for Differential Microbiome Analysis; CSF, cerebrospinal fluid; CU, cognitively unimpaired; DA, differential abundance; GFAP, glial fibrillary acidic protein; IL, interleukin; NfL, neurofilament light protein; p-tau, phosphorylated-tau; S100B, S100 calcium binding protein B; sTREM2, soluble triggering receptor expressed on myeloid cells 2; t-tau, total-tau; YKL-40, chitinase-3-like protein 1.
Citation: Kang, J. W., Khatib, L. A., Heston, M. B., Dilmore, A. H., Labus, J. S., Deming, Y., Schimmel, L., Blach, C., McDonald, D., Gonzalez, A., Bryant, M., Ulland, T. K., Johnson, S. C., Asthana, S., Carlsson, C. M., Chin, N. A., Blennow, K., Zetterberg, H., Rey, F. E., Alzheimer Gut Microbiome Project Consortium, … Bendlin, B. B. (2025). Gut microbiome compositional and functional features associate with Alzheimer’s disease pathology. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 21(7), e70417. https://doi.org/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.
Investigator: Barbara B. Bendlin, PhD
About the Lab: The mission of the Bendlin Lab is to take a multidisciplinary, collaborative, and inclusive approach to understand the factors that contribute to healthy and pathological brain aging. As a part of the Wisconsin Alzheimer’s Disease Research Center, we share the goal of improving the lives of those affected by Alzheimer’s disease. The Bendlin Lab strives to foster a non-discriminatory, diverse, and inclusive research and academic environment. Our research projects, supported by multiple NIA/NIH grants, donors, and private funding agencies, study brain structure and function in midlife and in older adults using a wide array of neuroimaging, biomarker, and genomic analyses. With a focus on education and outreach, the Bendlin Lab engages with students, staff, participants, and individuals in the community to promote greater awareness and understanding of Alzheimer’s disease.