Blood metabolites may reflect how lifestyle factors, medication use, and gut microbes intersect with cognition and brain structure years before dementia appears, according to a study published in Nature Aging on Jun. 25.
Researchers measured plasma levels of 1,387 metabolites in 1,082 participants from the Rotterdam study. They then assessed relationships between 991 frequent metabolites and both general cognition and magnetic resonance imaging (MRI) markers in 1,068 dementia-free middle-aged adults. The analysis found significant associations between 14 blood metabolites and cognitive performance.
Higher levels of uridine, 2-deoxyuridine, ergothioneine, two uncharacterized metabolites, and lower levels of seven sulfated xenobiotics plus two other uncharacterized compounds were associated with improved cognition. After adjusting for education level as well as smoking status, diabetes diagnosis, and hypertension history, these associations remained nominally significant but did not meet the threshold for statistical significance after correction for multiple testing.
For MRI markers of brain health such as white matter lesion volume and total brain volume, S-adenosylhomocysteine was associated with lesion volume while several other metabolites correlated with overall brain size. Replication analyses in independent samples from both older adults within the Rotterdam study cohort (RSI-4) and participants from the Alzheimer Gut Microbiome Project confirmed many findings: nine out of fourteen cognition-related metabolite associations were replicated in RSI-4; seven were replicated using three cognitive scores in AGMP; all fourteen showed significance in at least one replication test.
The researchers also found that sex differences may play a role: reduced glycocholate and taurocholate were linked to better cognition only among females, and higher N-acetyl-aspartyl-glutamate was beneficial only among males. However, these exploratory findings did not replicate across cohorts.
Regression analyses indicated that lifestyle features explained much of the variance observed among key blood metabolites related to cognition or MRI markers. Smoking emerged as a major factor influencing metabolite profiles associated with cognitive outcomes; body mass index (BMI), antidiabetic medication use or diabetes diagnosis itself, and alcohol intake were linked to changes in MRI marker-associated metabolites. Some metabolite levels also correlated significantly with specific gut microbial genera such as Fusicatenibacter and Romboutsia.
While mediation analysis suggested ergothioneine could partly explain negative effects of antacid use on cognition—mediating over thirty percent—the authors cautioned this does not establish causality nor immediate clinical implications without further longitudinal research.
