Alzheimer’s disease microbiome is associated with dysregulation of the anti-inflammatory p-glycoprotein pathway
Open accessAbstract
Studies of the intestinal microbiome and AD have demonstrated associations with microbiome composition at the genus level among matched cohorts. We move this body of literature forward by more deeply investigating microbiome composition via metagenomics and by comparing AD patients against those without dementia and with other dementia types. We also exploit machine learning approaches that combine both metagenomic and clinical data. Finally, our functional studies using stool samples from elders demonstrate how the c microbiome of AD elders can affect intestinal health via dysregulation of the P-glycoprotein pathway. P-glycoprotein dysregulation contributes directly to inflammatory disorders of the intestine. Since AD has been long thought to be linked to chronic bacterial infections as a possible etiology, our findings therefore fill a gap in knowledge in the field of AD research by identifying a nexus between the microbiome, loss of intestinal homeostasis, and inflammation that may underlie this neurodegenerative disorder.
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The AppNL-F and AppNL-G-F alleles impact the gut microbiome in ways that link to cognitive performance.
“Collectively, these results suggest that the AppNL-F and AppNL-G-F alleles impact the gut microbiome in ways that link to cognitive performance, and support the hypothesis that AD risk alleles may elicit their impact on cognition at least in part by altering the microbiome’s contribution to neurophysiology49–52.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [52]
The Results section reports that gut microbiome composition distinguishes older adults with Alzheimer’s disease from those without dementia, supporting a general microbiome–dementia association. It does not examine the AppNL-F or AppNL-G-F alleles or show that those alleles alter the microbiome in ways linked to cognitive performance. (LLM, conf=0.81)
Experimental — accuracy not yet measuredAD risk alleles may elicit their impact on cognition at least in part by altering the microbiome's contribution to neurophysiology.
“Collectively, these results suggest that the AppNL-F and AppNL-G-F alleles impact the gut microbiome in ways that link to cognitive performance, and support the hypothesis that AD risk alleles may elicit their impact on cognition at least in part by altering the microbiome’s contribution to neurophysiology49–52.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [52]
The Introduction and Discussion link the gut microbiome to Alzheimer’s disease and describe a possible pathway through intestinal inflammation, supporting the broad microbiome–neurophysiology hypothesis. But the paper compares elders by dementia status; it does not show that AD risk alleles alter the microbiome or that allele-driven changes affect cognitive performance. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRecent studies have shown dramatic changes in the GM of patients with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and schizophrenia.
“Furthermore, recent studies have shown dramatic changes in the GM of patients with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and schizophrenia (73–77).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [73]
A relevant contribution of gut microbiota is not restricted to neuroinflammatory and psychiatric disorders but also extends to brain development.
“Moreover, a relevant contribution of gut microbiota is not only restricted to neuroinflammatory and psychiatric disorders (23–32) but also to brain development (13).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [24]
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A peripheral signature of Alzheimer’s disease featuring microbiota-gut-brain axis markers
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Nutrition, gut microbiota, and alzheimer’s disease
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Regulation of microglial physiology by the microbiota
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The Role of Genetic, Environmental, and Dietary Factors in Alzheimer’s Disease: A Narrative Review
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Self-citation
- Authors
- Haran, J. P., Bhattarai, S. K., Foley, S. E., Dutta, P., Ward, D. V., Bucci, V., & McCormick, B. A.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- University of Massachusetts Dartmouth (US)
- Corresponding author
- Haran, John P.
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2019-06-25
- Volume
- 10
- Issue
- 3
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6509190
- OpenAlex
- W2944552216
- Cited by
- 412
- References
- 67
- Citations by year
- 2026: 45 · 2025: 62 · 2024: 53 · 2023: 74 · 2022: 77 · 2021: 53 · 2020: 43 · 2019: 5
- FWCI
- 14.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (1R15AI112985-01A1)
- National Science Foundation (1458347)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK056754)
- HHS | NIH | National Institute on Aging (1R03AG056356-01, 1K23AG057790-01A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, gut microbiota, P-glycoprotein, anti-inflammatory pathways, intestinal inflammation, intestinal homeostasis, chronic bacterial infection, dementia, metagenomics, machine learning, older adults, gut-brain axis
- MeSH terms
- Gastrointestinal Microbiome, Machine Learning, Aged, Aged, 80 and over, Alzheimer Disease, Bacteria, Dementia, Epithelial Cells, Feces, Female, Homeostasis, Humans, Inflammation, Intestines, Male, Prospective Studies, RNA, Ribosomal, 16S, ATP Binding Cassette Transporter, Subfamily B, Metabolic Networks and Pathways, Metagenomics, Dysbiosis
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