Metabolism of the neuroprotectant ergothioneine as a blood-based biomarker of cognitive resilience to amyloid pathology

Abstract Background The mechanisms underlying cognitive resilience to Alzheimer’s disease (AD) pathology are under active investigation. The association between dietary micronutrients with neuroprotective properties and cognitive resilience is currently unknown. Objective To investigate whether plasma L-ergothioneine (ET), its metabolite L-hercynine (HC), as well as their ratio (HC:ET, as an index of ET metabolism) affect the association between plasma markers of brain amyloid pathology (phosphorylated tau species) and cognitive decline. Design, setting and participants This study consisted of 259 dementia-free participants (mean age [SD] = 72 [8] years; 50% females) recruited from memory clinics and the community in Singapore from August 2010 to July 2019 as part of a larger, ongoing longitudinal cohort study on dementia, with analyses performed in February 2025. Measurements All participants of this study were dementia-free at baseline (median Clinical Dementia Rating-Sum of Boxes (CDR-SB) [IQR] scores = 0 [1]), had blood collected for measurements of plasma ET, HC, HC:ET, p-tau181 and p-tau217, and underwent annual neuropsychological assessments for up to 5 years (mean follow-up [SD] = 52 [15] months). The main cognitive outcomes were cognitive decline, defined by annual change of CDR-SB, and risk of incident cognitive decline, defined as Global CDR scores (CDR-GS) increments of ≥ 0.5 at follow-up. Linear regression analyses tested for interaction effects of plasma ET, HC and HC:ET on the association between plasma p-tau and cognitive decline, while Cox proportional hazards models were fitted to estimate hazard ratios (HRs) of incident cognitive decline. Results Plasma HC:ET significantly moderated associations between plasma p-tau181 and cognitive decline, whereby only High HC:ET attenuated the detrimental effects of plasma p-tau181 on cognitive decline (High HC:ET β = 0.0976; 95% Confidence Interval [CI] = -0.444 to 0.639 vs. Low HC:ET β = 0.849; 95% CI, 0.318 to 1.38). Among participants with high risk of amyloid pathology, those with Low HC:ET had approximately twofold increased risk of cognitive decline (Hazards ratio [HR] = 1.96; 95% CI = 1.01 to 3.79) compared to participants with High HC:ET (HR=0.87; 95% CI = 0.33 to 2.26) over the follow-up period. Conclusions Identification of plasma HC:ET as a biomarker of cognitive resilience to amyloid pathology suggests potential beneficial effects of ET metabolism. Further studies are needed to elucidate ET-mediated neuroprotective mechanisms as potential therapeutic targets in delaying or moderating AD-associated cognitive decline.