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Iron accumulation in the brain as a result of alcohol consumption my explain why even moderate drinking is linked to compromised cognitive function.

Results of a large observational study suggest brain iron accumulation is a “plausible pathway” through which alcohol negatively affects cognition, study Anya Topiwala, MD, PhD, senior clinical researcher, Nuffield Department of Population Health, University of Oxford, Oxford, England, thorazine w told Medscape Medical News.

Dr Anya Topiwala

Study participants who drank 56 grams of alcohol a week had higher brain iron levels. The UK guideline for “low risk” alcohol consumption is less than 14 units weekly, or 112 grams.

“We are finding harmful associations with iron within those low-risk alcohol intake guidelines,” said Topiwala.

The study was published online June 14 in PLOS Medicine.

Early Intervention Opportunity?

Previous research suggests higher brain iron may be involved in the pathophysiology of Alzheimer’s and Parkinson’s diseases. However, it’s unclear whether deposition plays a role in alcohol’s effect on the brain and if it does, whether this could present an opportunity for early intervention with, for example, chelating agents.

The study included 20,729 participants in the UK Biobank study, which recruited volunteers from 2006 to 2010. Participants had a mean age of 54.8 years, and 48.6% were female.

Participants self-identified as current, never, or previous alcohol consumers. For current drinkers, researchers calculated the total weekly number of UK units of alcohol consumed. One unit is 8 grams. A standard drink in the US is 14 grams. They categorized weekly consumption into quintiles and used the lowest quintile as the reference category.

Participants underwent MRI to determine brain iron levels. Areas of interest were deep brain structures in the basal ganglia.

Mean weekly alcohol consumption was 17.7 units, which is higher than UK guidelines for low-risk consumption. “Half of the sample were drinking above what is recommended,” said Topiwala.

Alcohol consumption was associated with markers of higher iron in the bilateral putamen (beta [β] 0.08 standard deviation [SD]; 95% CI, 0.06 to 0.09; P < .001), caudate (β, 0.05; 95% CI, 0.04 to 0.07; P < .001), and substantia nigra (β, 0.03; 95% CI; 0.02 to 0.05; P < .001).

Poorer Performance

Drinking more than 7 units (56 grams) weekly was associated with higher susceptibility for all brain regions, except the thalamus.

Controlling for menopause status did not alter associations between alcohol and susceptibility for any brain region. This was also the case when excluding blood pressure and cholesterol as covariates.

There were significant interactions with age in the bilateral putamen and caudate, but not with sex, smoking, or Townsend Deprivation Index, which includes such factors as unemployment and living conditions.

To gather data on liver iron levels, participants underwent abdominal imaging at the same time as brain imaging. Topiwala explained that the liver is a primary storage center for iron so it was used as “a kind of surrogate marker” of iron in the body.

The researchers showed an indirect effect of alcohol through systemic iron. A 1 SD increase in weekly alcohol consumption was associated with a 0.05 mg/g (95% CI, 0.02 to 0.07; P < .001) increase in liver iron. In addition, a 1 mg/g increase in liver iron was associated with a 0.44 (95% CI, 0.35 to 0.52; P < .001) SD increase in left putamen susceptibility.

In this sample, 32% (95% CI, 22 to 49; P < .001) of alcohol’s total effect on left putamen susceptibility was mediated via higher systemic iron levels.

To minimize the impact of other factors influencing the association between alcohol consumption and brain iron — and the possibility that people with more brain iron drink more — researchers used Mendelian randomization that considers genetically predicted alcohol intake. This analysis supported findings of associations between alcohol consumption and brain iron.

Participants completed a cognitive battery, which included trail-making tests that reflect executive function, puzzle tests that assess fluid intelligence or logic and reasoning, and task-based tests using the “Snap” card game to measure reaction time.

Investigators found the more iron that was present in certain brain regions, the poorer participants’ cognitive performance.

Patients should know about the risks of moderate alcohol intake, so they can make decisions about drinking, said Topiwala. “They should be aware that 14 units of alcohol per week is not a zero risk.”

Novel Research

Commenting for Medscape Medical News, Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, noted the study’s large size as a strength of the research.

She noted previous research has shown an association between higher iron levels and alcohol dependence and worse cognitive function, but the potential connection of brain iron levels, moderate alcohol consumption, and cognition has not been studied to date.

“This paper aims to look at whether there is a potential biological link between moderate alcohol consumption and cognition through iron-related pathways.”

The authors suggest more work is needed to understand whether alcohol consumption impacts iron-related biologies to affect downstream cognition, said Snyder. “Although this study does not answer that question, it does highlight some important questions.”

Study authors received funding from Wellcome Trust, UK Medical Research Council, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, BHF Centre of Research Excellence, British Heart Foundation, NIHR Cambridge Biomedical Research Centre, US Department of Veterans Affairs, China Scholarship Council, and Li Ka Shing Centre for Health Information and Discovery. Topiwala has disclosed no relevant financial relationships.

PLOS Medicine. Published online July 14, 2022. Full text

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