Metabolomic Markers in Cognition


By Betsy Redmond, PhD, MMSc, RDN

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Impaired cognition and Alzheimer’s disease (AD) may first manifest with distinctive metabolic dysfunctions beginning decades prior to disease manifestation. Disease classification methods primarily investigate structural and functional connectivity patterns of brain regions, requiring complex neuroimaging. Metabolomic markers are currently being investigated as they may provide early insight into patients at high risk for AD or impaired cognition.1, 2 


Kynurenine/Tryptophan Ratio (KTR) 

Kynurenine is the main stable product of tryptophan and is the central node of the pathway. Kynurenine can be metabolized into hydroxykynurenine, degraded to anthranilic acid, or deaminated to kynurenic acid. The ratio of kynurenine to tryptophan (the KTR) is thought to estimate indolamine 2,3 dioxygenase (IDO) activity and associated inflammation. Under normal conditions, the tryptophan 2,3-dioxygenase (TDO) enzyme is utilized; but under inflammatory conditions, IDO predominates.

Increased KTR has been associated with obesity, kidney disease, cancer, AIDS, pregnancy, as well as reduced cognition, neurodegenerative disease, and psychotic disorders.3 In a European biobank study, researchers found urinary KTR higher in the AD group. Additionally, the KTR had a significant negative correlation with the Mini-Mental State Exam (MMSE), a test of cognitive function.4 Weight loss resulted in a decreased KTR and CRP (C-reactive protein). Probiotics have also been shown to lower the KTR.5-7


The Castor Ratio

One research study divided adults into two groups, either cognitively healthy or clinically probable AD, based on beta amyloid42/Tau ratios in cerebrospinal fluid (n=101). Urine dicarboxylic acids (DCA) of carbon length 3–10, along with an MRI and neuropsychological studies, were assessed. The urine measures of DCAs had an 82% ability to predict cognitively healthy participants. In AD, compared to controls, urine C4 (succinic acid) and C5 (glutaric acid) were lower, and C7 (pimelic acid) + C8 (suberic acid) + C9 (azelaic acid) were higher. A higher ratio of C4 + C5/C7 + C8 + C9 was associated with better cognitive outcome.8

  • Dysfunctional brain mitochondria in AD may account for reduced C4 and C5. C4 is the most abundant DCA, making up 40% of the total.
  • As tissue loss progresses in AD, the fragile double bonds in unsaturated fatty acids within the brain may be oxidized and excreted in the urine. Levels of C7-C9 positively correlated with CSF Tau levels, and higher levels were associated with lower hippocampal volume.


Cortisol

Corticosteroids are known to impact brain function. Increased cortisol may negatively impact cognition and has been associated with dementia and AD in older adults.9 About 1% of plasma cortisol is excreted in the urine. A morning spot urine sample gave comparable results to 24-hour collection samples.10 


Equol

Equol is a metabolite produced by certain gut microbiota from the substrate daidzein, a soy isoflavone. Research has suggested that equol is antiatherogenic and improves arterial stiffness. Equol may prevent coronary heart disease and cognitive impairment/dementia. Equol producers, compared to non-producers, had a significantly lower prevalence of coronary artery calcium, which predicts future cardiovascular (CV) events, independent of CV risk factors (n=743). 

Compared to its precursor daidzein and other soy isoflavones, equol has been noted to have higher antioxidant properties, greater or similar affinity to estrogen receptor beta (which is expressed more in the vasculature and brain than in reproductive tissues), and a greater ability to increase mitochondrial activities. Equol-producing status appears to be determined by the presence of specific equol-producing bacteria and not genetics.11 


References

1.         Yan T, et al. Early-Stage Identification and Pathological Development of Alzheimer’s Disease Using Multimodal MRI. J Alzheimers Dis. 2019;68(3): p. 1013-1027.

2.         Webster JM, et al. Leveraging Neuroimaging Tools to Assess Precision and Accuracy in an Alzheimer’s Disease Neuropathologic Sampling Protocol. Front Neurosci. 2021; 15: p. 693242.

3.         Sorgdrager FJH, et al. Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target. Front Immunol. 2019; 10: p. 2565.

4.         Whiley L, et al. Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer’s disease. Alzheimers Res Ther. 2021; 13(1): p. 20.

5.         Christensen MHE, et al. Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery. PLoS One. 2018; 13(2): p. e0192169.

6.         Kazemi A, et al. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Clin Nutr. 2019; 38(2): p. 522-528.

7.         Purton T, et al. Prebiotic and probiotic supplementation and the tryptophan-kynurenine pathway: A systematic review and meta analysis. Neurosci Biobehav Rev. 2021; 123: p. 1-13.

8.         Castor KJ, et al. Urine dicarboxylic acids change in pre-symptomatic Alzheimer’s disease and reflect loss of energy capacity and hippocampal volume. PLoS One. 2020; 15(4): p. e0231765.

9.         Ouanes S, Popp J. High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature. Front Aging Neurosci. 2019; 11: p. 43.

10.       Al Sharef O, et al. An HPLC method for the determination of the free cortisol/cortisone ratio in human urine. Biomed Chromatogr. 2007; 21(11): p. 1201-6.

11.       Sekikawa A, et al. Effect of S-equol and Soy Isoflavones on Heart and Brain. Curr Cardiol Rev. 2019; 15(2): p. 114-135.