Associations Between Moderate Alcohol Consumption, Brain Iron, and Cognition in UK Biobank Participants: Observational and Mendelian Randomization Analyses
Research Summary
Why was this study done?
- There is growing evidence that even low dose alcohol consumption negatively impacts the brain, but the mechanisms underlying this are unclear.
- One possibility is that accumulation of iron in the brain could contribute, as higher brain iron has been described in numerous neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease.
- So far, there have been no studies investigating if brain iron levels differ by level of alcohol consumption.
What did the researchers do and find?
- In 20,965 participants in a United Kingdom cohort study, the researchers explored relationships between self-reported alcohol use and brain iron levels, measured using magnetic resonance imaging.
- The study assessed the association of alcohol intake with blood and liver iron and cognitive measures associated with higher brain iron.
- Alcohol consumption above 7 units (56 g) weekly was associated with markers of higher iron in the basal ganglia, which in turn was associated with worse cognitive function.
- These observational findings were further supported by analyses using genetic variants as proxies for alcohol consumption.
Abstract
Background
Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in low-dose alcohol users is unknown.
The objectives of this study were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits.
Methods
Observational associations between brain iron markers and alcohol consumption (n = 20,729 UK Biobank participants) were compared with associations with genetically predicted alcohol intake and alcohol use disorder from 2-sample mendelian randomization (MR).
Alcohol intake was self-reported via a touchscreen questionnaire at baseline (2006 to 2010). Participants with complete data were included. Multiorgan susceptibility-weighted magnetic resonance imaging (9.60 ± 1.10 years after baseline) was used to ascertain iron content of each brain region and liver tissues, a marker of systemic iron.
Main outcomes were susceptibility (χ) and T2*, measures used as indices of iron deposition. Brain regions of interest included putamen, caudate, hippocampi, thalami, and substantia nigra. Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis.
Cognition was assessed at the scan and in online follow-up (5.82 ± 0.86 years after baseline). Executive function was assessed with the trail-making test, fluid intelligence with puzzle tasks, and reaction time by a task based on the “Snap” card game.
Mean age was 54.8 ± 7.4 years and 48.6% were female. Weekly alcohol consumption was 17.7 ± 15.9 units and never alcohol users comprised 2.7% of the sample. ‘
Findings
Alcohol consumption was associated with markers of higher iron (χ) in putamen, caudate, and lower iron in the thalami. Quintile-based analyses found these associations in those consuming >7 units (56 g) alcohol weekly.
MR analyses provided weak evidence these relationships are causal.
Genetically predicted alcoholic units weekly positively associated with putamen and hippocampus susceptibility; however, these associations did not survive multiple testing corrections.
Weak evidence for a causal relationship between genetically predicted alcohol use disorder and higher putamen susceptibility was observed; however, this was not robust to multiple comparisons correction.
Genetically predicted alcohol use disorder was associated with serum iron and transferrin saturation. Elevated liver iron was observed at just >11 units (88 g) alcohol weekly c.f. <7 units (56 g). Systemic iron levels partially mediated associations of alcohol intake with brain iron. Markers of higher basal ganglia iron associated with slower executive function, lower fluid intelligence, and slower reaction times.
The main limitations of the study include that χ and T2* can reflect changes in myelin as well as iron, alcohol use was self-reported, and MR estimates can be influenced by genetic pleiotropy. It is unclear how the study findings generalize to other populations, particularly those which are more ethnically diverse and socioeconomically deprived.
Conclusions
This study represents the largest investigation of low dose alcohol consumption and iron homeostasis to date. Alcohol consumption above 7 units weekly is associated with higher brain iron. Iron accumulation represents a potential mechanism for alcohol-related cognitive decline.
In the largest study to date, we found drinking greater than 7 units of alcohol weekly associated with iron accumulation in the brain,” said Anya Topiwala from the University of Oxford, who was the lead researcher of the study, as per MSN.
Higher brain iron is in turn linked to poorer cognitive performance. Iron accumulation could underlie alcohol-related cognitive decline.”
Anya Topiwala, University of Oxford
What do these findings mean?
- These findings suggest that low dose alcohol consumption is associated with higher iron levels in the brain.
- Brain iron accumulation represents a potential mechanism for alcohol-related cognitive decline.
The brain is very sensitive to changes in iron metabolism,” said Dr. Emma Laing, a clinical professor at the University of Georgia and national spokesperson for the Academy of Nutrition and Dietetics, as per MSN.
Abnormally high iron in the brain has been associated with oxidative stress, which leads to neuronal damage and cell death.”
Dr. Emma Laing, clinical professor, University of Georgia and national spokesperson, Academy of Nutrition and Dietetics