Six Gut Markers May Identify Early Cognitive Decline

Six blood metabolites produced by or associated with gut microbiota identified early cognitive impairment in a small study.

The circulatory metabolites — 5-hydroxyindole acetic acid, indole-3-propionic acid, choline, indoxyl sulfate, kynurenic acid, and kynurenine — distinguished cognitively healthy older adults from those with mild cognitive impairment with an area under the curve (AUC) of 0.79, reported David Vauzour, PhD, of the University of East Anglia in Norwich, England, and co-authors.

The metabolites also separated healthy controls from people with subjective cognitive impairment with an AUC of 0.75, Vauzour and colleagues wrote in Gut Microbes.

“This study shows that a small set of gut‑ and diet‑derived blood metabolites can reliably distinguish healthy aging from early cognitive decline, even at the very earliest stage,” Vauzour told MedPage Today.

The panel of six metabolites reflects early metabolic disruption along the gut-brain axis, he noted. “These results highlight that metabolic alterations appear long before cognitive decline is clinically apparent, offering a non‑invasive and scalable approach for early risk identification,” Vauzour said.

“Because circulating metabolites integrate both gut microbial activity and host physiology, they outperform microbiome‑only metrics and offer promising avenues for early detection, monitoring, and targeted intervention strategies,” he added.

Recent research showed that the composition of the gut microbiome correlated with amyloid and tau markers in people with asymptomatic Alzheimer’s disease. Growing evidence also suggests that changes to gut bacteria may be linked to dementia risk, noted Sheona Scales, PhD, of Alzheimer’s Research UK, which supported the study.

“While current blood tests for Alzheimer’s work by detecting levels of specific proteins linked with the disease, this research may offer a new avenue for future blood test development,” Scales wrote on the U.K. Science Media Centre website.

“This study can’t say whether people with early memory and thinking problems will go on to develop dementia, but it identifies an interesting area for further research,” she pointed out. “Given the study involved a relatively small group of people, larger and longer-term studies are needed to build on these findings and understand whether this type of test could be used alongside existing ones.”

Vauzour and co-authors studied 150 older adults: 50 cognitively healthy controls, 50 participants with subjective cognitive impairment, and 50 with objectively measured mild cognitive impairment.

Groups were matched on age, sex, and body mass index. The mean age across groups was 65.5 years and 54% were women. Blood and fecal sample data came from baseline measurements of two previously conducted clinical studies.

Participants were excluded if they had a history of significant neurologic, psychiatric, gastrointestinal, or metabolic disorders; chronic fatigue syndrome; or gallbladder abnormalities. Additional exclusion criteria included current or recent smoking, alcohol or drug dependency, and clinically significant depression or anxiety. Individuals were ineligible if they were taking antidepressants, antipsychotics, anticoagulants, or any medications affecting gastrointestinal function.

Mass spectrometry platforms analyzed 33 metabolites in serum — 13 tryptophan-related compounds, 15 bile acid compounds, three trimethylamine N-oxide-related metabolites, and two cresol metabolites. Microbiome analysis using 16S rRNA amplicon sequencing was used to detect bacterial taxa associated with metabolic changes.

The researchers used multiple linear regression and machine learning techniques to identify a metabolite panel capable of classifying early cognitive decline. Of the six metabolites in the panel, all except choline were products of tryptophan metabolism.

“The work underscores tryptophan metabolism as a key pathway disrupted early in cognitive decline, with protective metabolites decreasing and inflammatory or toxic metabolites increasing,” Vauzour said. “The observation that biological changes arise at the subjective cognitive impairment stage further supports the need to shift prevention efforts earlier in the disease trajectory.”

While the study adjusted for key covariates, metabolome profiles can be influenced by a plethora of environmental and biological factors, the researchers acknowledged. Metabolite changes may reflect physiological states associated with systemic inflammation, for example. “Thus, although our findings suggest relationships between the variables, we cannot infer causal relationships from this analysis alone,” they wrote.

Future work should validate these metabolite signatures in larger, independent cohorts and across more diverse populations, Vauzour suggested.

“Longitudinal studies are needed to determine whether these metabolic changes can predict conversion from subjective cognitive impairment to objective cognitive impairment, and eventually, dementia,” he stated. “Mechanistic studies, including microbiome manipulation or dietary interventions, could help clarify causal pathways and support the development of personalized, metabolite‑guided prevention strategies.”