The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease
Open accessAbstract
BACKGROUND: Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer's disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease. METHODS: In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer's clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein). RESULTS: ) and neuronal degeneration (total tau and neurofilament light chain protein). CONCLUSIONS: These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.
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Written from the paper’s full text.
TL;DR
CSF levels of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) were higher in individuals with MCI and AD dementia than in cognitively-unimpaired individuals, and higher CSF TMAO was associated with CSF markers of AD pathology and neuronal degeneration. The study supports a link between TMAO and AD but is cross-sectional and cannot establish causality.
Key findings
- In 410 participants (335 cognitively-unimpaired, 35 MCI, 40 AD dementia), CSF TMAO was elevated in AD dementia (β = 0.50, p < 0.0001) and MCI (β = 0.29, p < 0.05) compared with cognitively-unimpaired individuals, controlling for age, sex, and APOE ε4 genotype; TMAO did not differ between MCI and AD groups (β = 0.21, p = 0.12).
- Older age was associated with higher CSF TMAO (β = 0.02, p < 0.0001), while sex and APOE ε4 genotype showed no main effects.
- CSF TMAO was positively associated with p-tau (β = 0.09, p = 0.006), p-tau/Aβ42 (β = 0.11, p = 0.013), t-tau (β = 0.10, p = 0.01), and NFL (β = 0.085, p = 0.007), but not with Aβ42/Aβ40 (β = −0.003, p = 0.13) or neurogranin (β = 0.004, p = 0.92).
- Adding peripheral cardiovascular disease risk factors as covariates did not change these associations.
Methods
- Cross-sectional study of CSF collected from 414 individuals in the Wisconsin Alzheimer’s Disease Research Center clinical core and the Wisconsin Registry for Alzheimer’s Prevention; 4 individuals with nonneurodegenerative cognitive impairment were excluded, leaving 410 participants.
- Diagnostic groups were cognitively-unimpaired control (n = 335), MCI (n = 35), and AD dementia (n = 40), classified using 2011 NIA-AA criteria without biomarker data.
- CSF TMAO was quantified by untargeted UHPLC-MS metabolomics and expressed as scaled intensity units; multiple linear regression tested group differences controlling for age, sex, and APOE ε4 genotype, and separate linear regressions tested associations with CSF biomarkers controlling for age, sex, and CSF analysis batch.
Limitations
- The paper states that the study did not examine direct measures of central vascular disease and that future studies are needed to examine TMAO and cerebrovascular health; it also states that additional work is needed to determine the multifactorial pathways by which TMAO impacts the brain.
- The paper states that longitudinal studies are needed to determine whether elevated TMAO during mid-life predicts subsequent development or exacerbation of AD pathology.
- Evident from the text: the design is cross-sectional, so it cannot establish temporal or causal relationships; the sample was 97% Caucasian, and the control group tended to be younger and had a higher proportion of females than the MCI and AD dementia groups.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 12 cited sources checked · 0 supported · 0 flagged
- Findingown data
APOE ε4 genotype has no main effect on CSF TMAO.
“there were no main effects of sex or APOE ε4 genotype”
- Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
“APOE ε4 genotype | −0.02 (0.06) | −0.3 | 0.77”
Quote in the paperNot a substantial claim - Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
- Findingown data
CSF TMAO is not significantly associated with CSF Aβ42/Aβ40.
“No significant relationship between CSF TMAO and Aβ42/Aβ40 (β = − 0.003, p = 0.13; Fig. 2c) was observed.”
Quote in the paperNot a substantial claim - Findingown data
CSF TMAO is higher in individuals with AD dementia than in cognitively-unimpaired individuals, controlling for age, sex, and APOE ε4 genotype.
“CSF TMAO levels were elevated in individuals with AD dementia (β = 0.50, p < 0.0001) and MCI (β = 0.29, p < 0.05) compared to cognitively-unimpaired individuals (Fig. 1; Table 2), controlling for age, sex, and APOE ε4 genotype.”
- Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
“Control vs AD | 0.50 (0.11) | 4.7 | 4.1 × 10− 6***”
Quote in the paperSubstantial claim - Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
- Findingown data
CSF TMAO is not associated with CSF neurogranin.
“there was no relationship between CSF TMAO and CSF neurogranin (β = 0.004, p = 0.92; Fig. 2f).”
Quote in the paperNot a substantial claim - Findingown data
Sex has no main effect on CSF TMAO.
“there were no main effects of sex or APOE ε4 genotype”
- Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
“Sex | −0.02 (0.06) | −0.03 | 0.75”
Quote in the paperNot a substantial claim - Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
- Findingown data
CSF TMAO is higher in individuals with MCI than in cognitively-unimpaired individuals, controlling for age, sex, and APOE ε4 genotype.
“CSF TMAO levels were elevated in individuals with AD dementia (β = 0.50, p < 0.0001) and MCI (β = 0.29, p < 0.05) compared to cognitively-unimpaired individuals (Fig. 1; Table 2), controlling for age, sex, and APOE ε4 genotype.”
- Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
“Control vs MCI | 0.29 (0.11) | 2.6 | 0.01*”
Quote in the paperSubstantial claim - Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
- Findingown data
CSF TMAO is positively associated with CSF NFL.
“CSF TMAO was positively associated with both CSF t-tau (β = 0.10, p = 0.01; Fig. 2d) and CSF NFL (β = 0.085, p = 0.007; Fig. 2e)”
Quote in the paperSubstantial claim - Findingown data
CSF TMAO is positively associated with CSF t-tau.
“CSF TMAO was positively associated with both CSF t-tau (β = 0.10, p = 0.01; Fig. 2d) and CSF NFL (β = 0.085, p = 0.007; Fig. 2e)”
Quote in the paperSubstantial claim - Findingown data
CSF TMAO is positively associated with CSF p-tau/Aβ42.
“and p-tau/Aβ42 (β = 0.11, p = 0.013; Fig. 2b)”
Quote in the paperSubstantial claim - Findingown data
CSF TMAO is positively associated with CSF p-tau.
“there was a significant positive relationship between CSF TMAO and p-tau (β = 0.09, p = 0.006; Fig. 2a)”
Quote in the paperSubstantial claim - Findingown data
Older age is associated with higher CSF TMAO.
“Older age was associated with higher CSF TMAO (β = 0.02, p < 0.0001)”
- Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
“Age | 0.022 (0.004) | 6.1 | 5.6 × 10−8***”
Quote in the paperNot a substantial claim - Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
- Findingown data
CSF TMAO levels do not differ between MCI and AD dementia groups.
“CSF TMAO levels did not differ between the MCI and AD groups.”
- Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
“MCI vs AD | 0.21 (0.13) | 1.5 | 0.12”
Quote in the paperNot a substantial claim - Also stated in: § CSF TMAO is elevated in individuals with MCI and AD dementia · plain
- Interpretationown data
CSF TMAO is associated with CSF biomarkers of neuronal degeneration (t-tau and NFL).
“elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein).”
Quote in the paperSubstantial claim - Study design and conductown data
Including peripheral cardiovascular disease risk factors as covariates did not change the associations between CSF TMAO and CSF biomarkers.
“Including peripheral cardiovascular disease risk factors as covariates did not change these associations (see Additional file 1: Table S1).”
- Also stated in: § Discussion · plain
“controlling for peripheral vascular disease risk factors did not change the associations between CSF TMAO and biomarkers of AD and neurodegeneration”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Interpretationown data
TMAO may have an impact independent of vascular effects.
“suggesting that TMAO may have an impact independent of vascular effects.”
Quote in the paperSubstantial claim - Interpretationown data
TMAO is more closely related to tau pathology than amyloid deposition alone.
“potentially indicating that TMAO is more closely related to tau pathology than amyloid deposition alone.”
Quote in the paperSubstantial claim - Premisecitation
Mice treated with dietary TMAO show increased brain aging and cognitive impairment.
“mice treated with dietary TMAO show increased brain aging and cognitive impairment, likely due to increased oxidative stress, mitochondrial dysfunction, and inhibition of mammalian target of rapamycin (mTOR) signaling in the brain [11].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Li D, Ke Y, Zhan R, Liu C, Zhao M, Zeng A, et al. Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell. 2018;49:e12768–13. source
Not checked in the free run.
- Interpretationown data
These results provide additional evidence for an association between TMAO and AD.
“These results provide additional evidence for an association between TMAO and AD”
Quote in the paperSubstantial claim - Interpretationown data
Differences in TMAO between groups did not reflect underlying differences in cardiovascular disease status.
“suggesting that differences observed in TMAO between groups did not reflect underlying differences in cardiovascular disease status.”
Quote in the paperSubstantial claim - Study design and conductown data
There were no differences between groups with respect to cardiovascular disease risk factors including BMI, blood pressure, total cholesterol, HDL cholesterol, and fasting glucose.
“There were no differences between groups with respect to cardiovascular disease risk factors including BMI, blood pressure, total cholesterol, HDL cholesterol, and fasting glucose.”
Quote in the paperNot a substantial claim - Interpretationown data
CSF TMAO is associated with CSF biomarkers of AD pathology (p-tau and p-tau/Aβ42).
“elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein).”
Quote in the paperSubstantial claim - Interpretationown data
TMAO is not a primary driver of amyloid production.
“while TMAO may not be a primary driver of amyloid production”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 10
- May combine two claims. 4
Classified as probably not a substantial claim.
Study design and conductown dataLinear regression models for biomarker associations controlled for age, sex, and CSF analysis batch.
“each model included covariates of age, sex, and the nuisance covariate of CSF analysis batch (to account for batch variation).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAPOE ε4 genotype was more prevalent in the MCI and AD dementia groups.
“As expected, the APOE ε4 genotype was more prevalent in the MCI and AD dementia groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenBiomarker data were not used in determining clinical diagnosis.
“Biomarker data are not used in determining clinical diagnosis.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationTMAO is measurable in CSF, suggesting it reaches the CNS.
“A recent study [10] demonstrated that TMAO is measurable in cerebrospinal fluid (CSF), suggesting that this microbial-derived metabolite reaches the central nervous system (CNS), and may therefore be relevant to neurological function or disorders.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Del Rio D, Zimetti F, Caffarra P, Tassotti M, Bernini F, Brighenti F, et al. The gut microbial metabolite trimethylamine-N-oxide is present in human cerebrospinal fluid. Nutrients. 2017;9:1–7. https://doi.org/10.3390/nu9101053 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe Control group tended to be younger and had a higher proportion of females compared to the MCI and AD dementia groups.
“The Control group tended to be younger and had a higher proportion of females compared to the MCI and AD dementia groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAD pathology is characterized by extracellular beta-amyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein.
“Alzheimer’s disease (AD) pathology is characterized by extracellular beta-amyloid (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Scheltens P, Blennow K, Breteler MMB, De Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet. 2016;388:505–17. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningTMAO may impact vulnerable neurons and contribute to neurodegeneration.
“it may impact vulnerable neurons and contribute to neurodegeneration.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTMAO is related to axonal injury, but not dendritic degeneration.
“suggesting that TMAO is related to axonal injury, but not dendritic degeneration.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataLinear regression models for group differences controlled for age, sex, and APOE ε4 genotype.
“a multiple linear regression model was conducted in R (v3.5.0) to test the effect of age, sex, APOE ε4 genotype, and clinical diagnosis (Control, MCI, AD dementia) on CSF TMAO levels.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationA variety of genetic and environmental factors have been implicated in AD etiopathogenesis, including contributions from gut microbiota.
“A variety of genetic and environmental factors have been implicated in AD etiopathogenesis, including contributions from gut microbiota [13–15].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [13] Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802. source
Not checked in the free run.
- cites [14] Zhan X, Stamova B, Jin L-W, Decarli C, Phinney B, Sharp FR. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. 2016;87:2324–32. source
Not checked in the free run.
- cites [15] Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017;7:13537. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTMAO has been implicated in metabolic, cardiovascular, and cerebrovascular disease.
“The microbial-derived metabolite trimethylamine N-oxide (TMAO) has been implicated in metabolic [5], cardiovascular [6, 7], and cerebrovascular [8] disease.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [5] Gao X, Liu X, Xu J, Xue C, Xue Y, Wang Y. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. J Biosci Bioeng. 2014;118:476–81. source
Not checked in the free run.
- cites [6] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63. source
Not checked in the free run.
- cites [7] Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85. source
Not checked in the free run.
- cites [8] Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165:111–24. source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe relationship between TMAO and AD pathology has not yet been fully investigated in humans with Alzheimer's clinical syndrome.
“While it has been hypothesized that TMAO could be associated with AD pathology [16], this relationship has not yet been fully investigated in humans with Alzheimer’s clinical syndrome (AD dementia) [17].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] Xu R, Wang Q. Towards understanding brain-gut-microbiome connections in Alzheimer's disease. BMC Syst Biol. 2016;10(Suppl 3):63. source
Not checked in the free run.
- cites [17] Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:535–62. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataAll statistical analyses accounted for batch variation.
“All CSF assays were performed in two batches (n = 192 samples in batch 1, n = 218 samples in batch 2), and all statistical analyses accounted for batch variation (see Statistical analysis).”
Quote in the paperSubstantial claim
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Dysbiosis-driven production of harmful metabolites such as TMAO from Enterobacteriaceae has been linked to cognitive decline and Aβ aggregation.
“Conversely, dysbiosis-driven production of harmful metabolites (e.g., trimethylamine-N-oxide [TMAO] from Enterobacteriaceae) has been linked to cognitive decline and Aβ aggregation [128].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [128]
The Background reports cognitive impairment in mice treated with TMAO, and the Conclusions report elevated CSF TMAO in people with mild cognitive impairment and AD dementia. But the Background and Discussion describe TMAO production as involving gut bacteria and host metabolism, not specifically Enterobacteriaceae or demonstrated dysbiosis-driven production. The Results find no significant association with the Aβ42/Aβ40 measure, and the Discussion does not establish a link to Aβ aggregation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTMAO levels are elevated in plasma and cerebrospinal fluid of individuals with mild cognitive impairment and Alzheimer's disease, and TMAO can traverse the blood-brain barrier and contribute to neurodegeneration by inducing microglial and astrocytic activation.
“Importantly, elevated levels of TMAO have been observed in the plasma and cerebrospinal fluid (CSF) of individuals with MCI and AD.409,410 Several studies have shown that TMAO has the ability to traverse the BBB and contribute to neurodegeneration by inducing microglial and astrocytic activation.411–414”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [410]
Elevated levels of TMAO have been reported in the plasma and CSF of individuals with MCI, AD, and PD.
“Studies have reported elevated levels of TMAO in the plasma and CSF of individuals with MCI, AD, and PD.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [410]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Overall fasting glucose is below every group mean
MinorThe exhaustive groups have fasting glucose means of 99, 99, and 100 mg/dl, but the reported overall mean is 97 mg/dl. Rounding cannot account for an overall mean below all three group means.
“| Fasting glucose (mg/dl) | 97 ± 20 | 99 ± 51 | 99 ± 15 | 100 ± 18 |”
“| N | 410 | 335 | 35 | 40 |”
Overall total cholesterol does not match the group means
MinorWeighting the group means by the reported group sizes gives about 196.8 mg/dl, rather than the reported overall mean of 195 mg/dl. The discrepancy exceeds what rounding to whole numbers can explain.
“| Total cholesterol (mg/dl) | 195 ± 37 | 199 ± 46 | 184 ± 44 | 190 ± 37 |”
“| N | 410 | 335 | 35 | 40 |”
Sex t statistic is inconsistent with its coefficient and standard error
MinorThe reported coefficient divided by its reported standard error is approximately −0.33, not −0.03. The listed p value of 0.75 is also consistent with a t statistic near −0.33.
Reported -0.03 · recomputed -0.333333
“| Sex | −0.02 (0.06) | −0.03 | 0.75 |”
Overall systolic blood pressure does not match the group means
MinorWeighting the group means by the reported group sizes gives about 126.3 mmHg, rather than the reported overall mean of 128 mmHg. Rounding the group means to whole numbers cannot bridge the difference.
“| Systolic blood pressure (mmHg) | 128 ± 17 | 125 ± 16 | 130 ± 18 | 134 ± 16 |”
“| N | 410 | 335 | 35 | 40 |”
Overall diastolic blood pressure is below every group mean
MinorThe three diagnostic groups exhaust the sample, yet their diastolic blood pressure means are 75, 76, and 75 mmHg while the overall mean is 74 mmHg. Even allowing for rounding to whole numbers, the overall mean cannot be that low.
“| Diastolic blood pressure (mmHg) | 74 ± 9 | 75 ± 9 | 76 ± 10 | 75 ± 9 |”
“| N | 410 | 335 | 35 | 40 |”
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Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort Study
Rawlings, A. M., Sharrett, A. R., Schneider, A. L. C., Coresh, J., Albert, M., Couper, D., Griswold, M., Gottesman, R. F., Wagenknecht, L. E., Windham, B. G., et al. (2014) · Annals of Internal Medicine · doi:10.7326/m14-0737 · Cited by 447 · see citing works
Evans, A. M. (2014) · Journal of Postgenomics Drug & Biomarker Development · doi:10.4172/2153-0769.1000132 · Cited by 387 · see citing works
Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet
Gao, X., Liu, X., Xu, J., Xue, C., Xue, Y., & Wang, Y. (2014) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2014.03.001 · Cited by 360 · see citing works
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Self-citationThe Wisconsin Registry for Alzheimer's Prevention: A review of findings and current directions
Johnson, S. C., Koscik, R. L., Jonaitis, E. M., Clark, L. R., Mueller, K. D., Berman, S. E., Bendlin, B. B., Engelman, C. D., Okonkwo, O. C., Hogan, K. J., et al. (2017) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2017.11.007 · Cited by 306 · see citing works
Self-citationTrimethylamine‐<i>N</i>‐oxide promotes brain aging and cognitive impairment in mice
Li, D., Ke, Y., Zhan, R., Liu, C., Zhao, M., Zeng, A., Shi, X., Ji, L., Cheng, S., Pan, B., et al. (2018) · Aging Cell · doi:10.1111/acel.12768 · Cited by 304 · see citing works
Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of aging cohort
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Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels
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Microglial immunophenotype in dementia with Alzheimer’s pathology
CFAS, M., Minett, T., Classey, J., Matthews, F. E., Fahrenhold, M., Taga, M., Brayne, C., Ince, P. G., Nicoll, J. A. R., & Boche, D. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0601-z · Cited by 219 · see citing works
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Towards understanding brain-gut-microbiome connections in Alzheimer’s disease
Xu, R., & Wang, Q. (2016) · BMC Systems Biology · doi:10.1186/s12918-016-0307-y · Cited by 175 · see citing works
The Gut Microbial Metabolite Trimethylamine-N-Oxide Is Present in Human Cerebrospinal Fluid
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Where Vascular Meets Neurodegenerative Disease
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Self-citationTrimethylamine-N-oxide and its biological variations in vegetarians.
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The gut microbiome in neurological disorders
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Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction
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Self-citationThe Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment
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Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia
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Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress
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Gut-microbiota derived bioactive metabolites and their functions in host physiology
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Gut Microbiota-Derived Metabolite Trimethylamine N-Oxide as a Biomarker in Early Parkinson’s Disease
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- Authors
- Vogt, N. M., Romano, K. A., Darst, B. F., Engelman, C. D., Johnson, S. C., Carlsson, C. M., Asthana, S., Blennow, K., Zetterberg, H., Bendlin, B. B., & Rey, F. E.
- Affiliations
- University of Wisconsin–Madison (US)
- Cleveland Clinic (US)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Bendlin, Barbara B.
- Rey, Federico E.
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2018-12
- Volume
- 10
- Issue
- 1
- Pages
- 124-124
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC6303862
- OpenAlex
- W2906377431
- Cited by
- 471
- References
- 42
- Citations by year
- 2026: 55 · 2025: 74 · 2024: 66 · 2023: 72 · 2022: 73 · 2021: 66 · 2020: 41 · 2019: 23
- FWCI
- 22.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (F30 AG059346, P50 AG033514, R01 AG027161, R01 AG021155, R01 AG037639, R01 AG054047)
- National Center for Advancing Translational Sciences (UL1TR002373)
- Alzheimerfonden (AF-553101, AF-646211)
- Torsten Söderbergs Stiftelse
- Hjärnfonden (FO2015-0021)
- Västra Götalandsregionen (ALFGBG-139671)
- H2020 European Research Council (681712)
- University of Wisconsin-Madison Microbiome Initiative (MSN209613-AAC3569)
- Swedish State Support for Clinical Research (ALFGBG-441051)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- trimethylamine N-oxide, Alzheimer's disease, gut microbiota, gut-brain axis, cerebrospinal fluid biomarkers, mild cognitive impairment, neurodegeneration, tau protein, amyloid-beta, neurofilament light chain, neurogranin, APOE ε4
- MeSH terms
- Gastrointestinal Microbiome, Aged, Alzheimer Disease, Female, Humans, Male, Methylamines, Middle Aged, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, tau Proteins, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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