Metabolism of the antioxidant Ergothioneine as a Plasma Biomarker of Cognitive Reserve
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
IMPORTANCE
The biological mechanisms underlying resilience against Alzheimer’s disease (AD) pathology are under active investigation. The association between diet-derived antioxidants and cognitive reserve is unknown.
OBJECTIVE
To investigate whether plasma L-ergothioneine (ET), its metabolite L-hercynine (Hcy), as well as their ratio (Hcy: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 longitudinal cohort study consisted of dementia-free participants of varying clinical severity recruited from memory clinics and the community in Singapore from August 2010 to July 2019. Analyses were conducted in February 2025. All participants underwent annual neuropsychological assessments for up to 5 years, with a mean [SD] follow-up of 52 [15] months.
EXPOSURES
Plasma ET, Hcy, Hcy:ET and phosphorylated tau (p-tau181 and p-tau217).
MAIN OUTCOMES AND MEASURES
The main outcomes were cognitive decline, defined by annual change in CDR Sum of Boxes (CDR-SB), and risk of incident cognitive decline, defined as CDR Global Score (CDR-GS) increments of ≥0.5 at follow-up. Linear regression analyses tested for interaction effects of plasma ET, Hcy and Hcy:ET on the association between plasma phosphorylated tau and cognitive decline, while Cox proportional hazards models were fitted to estimate hazard ratios (HRs) of incident cognitive decline.
RESULTS
259 dementia-free participants (mean [SD] age, 72 [8] years; 50% females; median [IQR] baseline CDR-SB, 0 [1]) were included. Plasma Hcy:ET significantly moderated associations between plasma p-tau181 and cognitive decline, whereby only High Hcy:ET attenuated the detrimental effects of plasma p-tau181 on cognitive decline (High Hcy:ET β, 0.0976; 95% Confidence Interval [CI] = −0.444 to 0.639 vs. Low Hcy:ET β, 0.849; 95% CI, 0.318 to 1.38). Among participants with high risk of amyloid pathology (defined by a three-range cutoff of p-tau181), those with Low Hcy: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 Hcy:ET (HR=0.87; 95% CI = 0.33 to 2.26) over the follow-up period.
CONCLUSIONS
Identification of plasma Hcy:ET as a biomarker of cognitive reserve against amyloid pathology suggests potential beneficial effects of ET metabolism. Further studies are needed to assess ET-mediated antioxidant and other neuroprotective mechanisms as potential therapeutic targets in delaying or moderating AD-associated cognitive decline.
