Blood Metabolite Ergothioneine Linked to Cognition and Alzheimer's Risk in Midlife

Metabolic changes in the blood are increasingly recognized as windows into brain health, yet the specific metabolites that matter — and what shapes them — have remained poorly characterized at midlife, before dementia symptoms emerge.

This large study from the Rotterdam Study examined 991 blood metabolites in 1,082 dementia-free, middle-aged adults. Researchers correlated these metabolites with both cognitive test performance and structural brain MRI measures. They also quantified how much of each metabolite's variability could be explained by genetics, gut microbiome composition, lifestyle, medications, and clinical conditions.

Twenty-two metabolites were associated with MRI brain measures, and fourteen showed replicated associations with cognition across two independent older-adult cohorts. Critically, the metabolite signature of current cognitive performance closely mirrored the signature seen in people who later developed incident Alzheimer's disease — suggesting these midlife markers carry genuine predictive weight. Ergothioneine, a dietary antioxidant concentrated in mushrooms, emerged as the single most impactful metabolite for cognition. Antacid use was independently linked to lower ergothioneine levels and worse cognitive scores, with ergothioneine statistically mediating 31.5% of that medication-related cognitive decline.

Lifestyle factors, clinical comorbidities, and medications collectively were the strongest determinants of these cognition-associated metabolites, explaining up to 28.6% of their variance — exceeding the contributions of genetics or the gut microbiome alone.

The implications are significant: if antacid use suppresses ergothioneine, clinicians may want to consider the neurological trade-offs of long-term proton pump inhibitor or antacid prescribing. The findings also raise the possibility of dietary intervention — increasing mushroom or ergothioneine intake — as a modifiable strategy for brain health. Caveats include the cross-sectional design for the primary cohort and the fact that the full paper was not available for review.