A recent study by a team comprising researchers from the National University of Singapore (NUS) and the National University Health System (NUHS) revealed that low levels of ergothioneine in blood plasma may predict an increased risk of cognitive impairment and dementia, suggesting possible therapeutic or early screening measures for cognitive impairment and dementia in the elderly.

The research teams were led by Professor Barry Halliwell from the Department of Biochemistry under the NUS Yong Loo Lin School of Medicine and Associate Professor Christopher Chen and Mitchell Lai, PhD, from the Memory, Ageing, and Cognition Centre under NUHS. The results of their most recent study were published in the scientific journal Antioxidants.

Earlier Studies on Ergothioneine and its Role in Human Health

In 2005, scientists discovered a transporter specific for ergothioneine—a unique diet-derived compound—that facilitates the uptake and accumulation of ergothioneine in the body.

Halliwell and his team demonstrated that ergothioneine is avidly retained in the human body following oral supplementation, and in preclinical models, ergothioneine is transported to almost all organs, although higher levels can be found in specific cells and tissues such as the blood cells, eyes, liver, lungs, and even the brain.

Earlier work by Halliwell demonstrated the potent antioxidant properties of ergothioneine and later its ability to protect cells from a range of different forms of stress and toxins. As its main dietary source is in mushrooms, it was found that increasing consumption of mushrooms such as golden, oyster, shiitake, and white button mushrooms is associated with a reduced risk of mild cognitive impairment in elderly Singaporeans.

A study by Halliwell’s team in 2016 showed lower ergothioneine levels in blood plasma among participants with mild cognitive impairment. This was verified in a much larger group of cognitively impaired participants with and without dementia, in collaboration with Lai and Chen. The findings of this study were published in Free Radical Biology and Medicine in 2021.

However, evidence of whether a low level of ergothioneine in blood plasma can predict the progression of cognitive impairment and dementia was unknown.

The most recent study by the NUS-NUHS research team addresses these gaps in ergothioneine research by demonstrating the potential of ergothioneine as a predictive biomarker for cognitive impairment and dementia in elderly Singaporeans.

Ergothioneine as a Predictive Marker for Cognitive Impairment and Dementia

In the latest study published in August 2022, the research team recruited 470 elderly patients and followed them for up to five years at the Memory, Aging and Cognition Centre. The researchers measured ergothioneine levels in the blood plasma of the participants and followed their cognitive and functional abilities at different time points. They then examined the link between low ergothioneine levels and the risk of cognitive and functional decline over time.

“Before this study, there was little evidence that ergothioneine levels in the blood can predict the risk of developing cognitive issues. The current study is significant because it measured the ergothioneine levels of elderly participants before developing dementia. Our findings demonstrate that if your ergothioneine levels are low, your risk of developing cognitive problems increases,” says Halliwell.

The researchers showed that participants with lower levels of ergothioneine displayed poorer cognitive performance at the start of the study and an accelerated rate of decline in cognitive and functional abilities over the follow-up period.

The team also observed structural changes in the brain seen from MRI (magnetic resonance imaging) scans of the participants, which suggested that the association between a low ergothioneine level in blood and cognitive decline was due to underlying disease pathology. These structural changes, including reduced cortical thickness, lower hippocampus volume, and white matter hyperintensities, are characteristic of neurodegenerative disease.

“This points to the possibility of using a simple blood test to detect ergothioneine levels for early screening in the elderly to identify those who may have higher risk of cognitive decline,” says Halliwell. He added that low ergothioneine levels are also associated with a number of other age-related diseases such as frailty, cardiovascular disease, and macular degeneration, so ergothioneine may have a more general role in maintaining health.

Understanding the Ergothioneine and Disease Relationship

Based on this study, which showed that plasma ergothioneine levels in the blood can be a predictive biomarker for the risk of cognitive and functional decline, the research team hopes to gather further evidence of ergothioneine’s preventive and therapeutic potential through a double-blinded placebo-controlled clinical trial.

For this clinical trial, the team is currently recruiting volunteers who are patients over the age of 60 years with mild cognitive impairment to participate. The researchers will provide study volunteers with either pure ergothioneine supplements or a placebo over a specified period to assess the effect and causal relationship of ergothioneine supplementation on elderly patients with mild cognitive impairment.

“If the deficiency in ergothioneine is leading to an increased risk of cognitive decline, then we would have the potential to intervene, and that is what we are trying to find out by undertaking this clinical trial,” says Irwin Cheah, PhD, senior research fellow from the NUS Department of Biochemistry.

Despite being interrupted abruptly by the COVID-19 pandemic, the team still managed to restart the clinical trial recently and pick up the progress where they left off. Through this clinical trial, the team hopes to understand further the potential preventive and therapeutic capabilities of ergothioneine in preventing or delaying cognitive impairment and dementia.

Featured image: Prof Barry Halliwell (left) and Irwin Cheah, PhD, (right), together with their collaborators from the National University Health System, have discovered that low levels of ergothioneine in blood plasma may predict an increased risk of cognitive impairment and dementia. Photo: National University of Singapore