Screening 991 blood metabolites against cognitive performance and brain MRI markers in 1,082 dementia-free middle-aged participants (Rotterdam Study), this analysis identified 14 metabolites with replicated associations to cognition and 22 linked to structural MRI measures. Ergothioneine — a dietary antioxidant concentrated in mushrooms and certain seafoods — showed the strongest single effect. Critically, antacid use correlated with both lower ergothioneine levels and worse cognition, with ergothioneine statistically mediating 31.5% of that medication-associated cognitive deficit. The combined metabolite signature of cognition mirrored that of incident Alzheimer's disease in longitudinal follow-up. Lifestyle, clinical variables, and medications collectively explained up to 28.6% of metabolite variance.
This is a landmark systems-level finding. Ergothioneine has been gaining traction in longevity research as a potential "longevity vitamin" — it has dedicated human transporters (SLC22A4), accumulates in mitochondria, and declines with age — yet rarely appears in large population studies with this mechanistic granularity. The antacid-ergothioneine-cognition pathway is particularly actionable: proton pump inhibitors and H2 blockers are among the most overprescribed drug classes globally, and this mediational finding gives plausible biological grounding to prior observational signals linking antacid use to dementia risk. Limitations include the cross-sectional primary design, predominantly European cohort, and the fact that mediation analysis cannot establish causality. Still, the replication across independent cohorts and the longitudinal AD signal elevate this beyond incremental — it is among the most comprehensive metabolome-brain mapping exercises in midlife populations to date.
