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 (β=0.09 standard deviation (S.D.) [95% confidence interval 0.07 to 0.10]), caudate (β=0.06 [0.04 to 0.07]) and substantia nigra (β=0.04 [0.02 to 0.05]), and lower iron in the thalami (β= -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. ### Competing Interest Statement BR has consulted for Axcella Therapeutics in the past. AR is employed by Perspectum Ltd. The other authors declare no competing financial interests. ### Funding Statement This work was undertaken using UK Biobank application numbers 55929 & 8107. AT is supported by a Wellcome Trust () fellowship (216462/Z/19/Z). CW is funded, in part, by the China Scholarship Council (CSC, ). KPE is funded by the UK Medical Research Council ( , G1001354 & MR/K013351/1) and the European Commission (, Horizon 2020 732592). CM is supported by the Oxford NIHR Biomedical Research Centre and the Oxford BHF Centre of Research Excellence. JG, DL and HZ are supported by the US Department of Veterans Affairs ( , I01CX001849). SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society ( , 204623/Z/16/Z). S.Bell was supported by the British Heart Foundation ( , RG/16/4/32218) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). MH is supported by the Wellcome Trust and NIHR Oxford Biomedical Research Centre. SS is supported by a Wellcome Trust Collaborative Award 215573/Z/19/Z. KLM is supported by a Wellcome Trust Senior Research Fellowship 202788/Z/16/Z. This work was also supported by the Li Ka Shing Centre for Health Information and Discovery, NIH grant (, TN: R01EB026859), the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014), and a Wellcome Trust award (TN: 100309/Z/12/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank data is available for researchers through successful data application. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is available through a successful UK Biobank application.