Impact of moderate alcohol consumption on brain iron and cognition: observational and genetic analyses

Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate 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. Multi-organ susceptibility-weighted magnetic resonance imaging was used to ascertain iron content of brain (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Observational associations between brain iron markers and self-reported alcohol consumption (n=22,254 UK Biobank participants) were compared with associations with genetically-predicted alcohol intake from two-sample Mendelian randomization (MR). 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 time of scan and in online follow-up. Alcohol consumption was associated with markers of higher iron in putamen ({beta}=0.09 standard deviation (S.D.) [95% confidence interval 0.07 to 0.10]), caudate ({beta}=0.06 [0.04 to 0.07]) and substantia nigra ({beta}=0.04 [0.02 to 0.05]), and lower iron in the thalami ({beta}= -0.05 [-0.06 to -0.03]). Quintile-based analyses found these effects in those consuming >7 units (56g) alcohol weekly. MR analyses provided some evidence these relationships are causal. A 1 S.D. higher genetically-predicted number of alcoholic drinks weekly associated with 0.25 [0.01 to 0.49] S.D. higher putamen susceptibility and 0.28 [0.05 to 0.50] S.D. higher hippocampus susceptibility. Genetically-predicted alcohol use disorder was causally related to higher putamen susceptibility (0.18 [0.001 to 0.35] S.D.), serum iron (0.12 [0.05 to 0.19] S.D.) and transferrin saturation (0.11[0.03 to 0.19] S.D.). Elevated liver iron was observed at just >11 units (88g) alcohol weekly (0.03 mg/g [0.01-0.05] higher c.f. <7 units (56g) weekly). Systemic iron levels partially mediated associations of alcohol intake with brain iron accumulation (proportion mediated: 32% [22 to 49]). Markers of higher basal ganglia iron were associated with accelerated age-related decline in executive function and fluid intelligence, and slower reaction times. This study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Even low levels of alcohol consumption were associated with iron accumulation in the brain, suggesting a potential mechanism for alcohol-related cognitive decline.