Plasma Trimethylamine N-Oxide (TMAO): Associations with Cognition, Neuroimaging, and Dementia
Open accessAbstract
BACKGROUND: The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine - have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain. METHODS: In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function. RESULTS: Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses. CONCLUSIONS: Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.
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A large-scale study found no significant association between TMAO levels and cognitive decline.
“However, the effects of TMAO on brain function remain inconclusive, as a large-scale study found no significant association between TMAO levels and cognitive decline [67].”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [67]
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The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders
Młynarska, E., Barszcz, E., Budny, E., Gajewska, A., Kopeć, K., Wasiak, J., Rysz, J., & Franczyk, B. (2025) · Nutrients · doi:10.3390/nu17071135 · Cited by 44 · see citing works
- Authors
- Yaqub, A., Vojinovic, D., Vernooij, M. W., Slagboom, P. E., Ghanbari, M., Beekman, M., van der Grond, J., Hankemeier, T., van Duijn, C. M., Ikram, M. A., & Ahmad, S.
- Affiliations
- Erasmus MC (NL)
- Leiden University Medical Center (NL)
- Leiden University (NL)
- Corresponding author
- Ikram, M. Arfan
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2024-05-20
- Volume
- 16
- Issue
- 1
- Pages
- 113-113
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC11103865
- OpenAlex
- W4398137527
- Cited by
- 37
- References
- 52
- Citations by year
- 2026: 22 · 2025: 11 · 2024: 4
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Deltaplan Dementie from ZonMW Memorabel (73305095005)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- trimethylamine N-oxide, choline, L-carnitine, betaine, cognition, dementia risk, brain atrophy, white matter hyperintensities, cerebral small vessel disease, gut-brain axis, renal dysfunction, structural MRI
- MeSH terms
- Aged, Brain, Choline, Cognition, Dementia, Female, Humans, Magnetic Resonance Imaging, Male, Methylamines, Middle Aged, Prospective Studies, Biomarkers, Neuroimaging
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