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

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.

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.

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.

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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by the National Medical Research Council of Singapore (Grant/Award Number: MOH-000707-01) and the Singapore Ministry of Education Academic Research Fund (Grant/Award Number: NUHSRO/2024/028/T1/Seed-Sep23/06). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Domain-Specific Review Board of the Singapore National Healthcare Group gave ethical approval for this work (2018/01098 and 2010/00017). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Details added in Discussion, Title changed and Formatted for a Full paper rather than Short Report. Data Availability Anonymized datasets generated during and/or analyzed in the current study are available from the corresponding author upon reasonable request.