Predictors of brain iron deposition in dementia and Parkinson's disease-associated subcortical regions: genetic and observational analysis in UK Biobank

BackgroundBrain iron in specific subcortical regions increases risk of dementia and Parkinsons Disease (PD). Genetic and environmental factors affect iron deposition, but the underlying mechanisms are unclear. ObjectiveIdentify risk factors and diseases associated with brain iron, and assess causality using genetics. Methods41,581 UK Biobank participants had MRI-estimated brain iron in four dementia or PD-associated subcortical regions (Caudate, Putamen, Substantia Nigra, Thalamus). We investigated common risk factors (including adiposity, blood pressure, health behaviours, and inflammation) and diseases observationally, using covariate-adjusted regression models, and genetically, with Mendelian randomization. ResultsParticipants diagnosed with Alzheimers disease, PD, or other diseases had higher brain iron. Anaemia, osteoporosis, and hyperparathyroidism were associated with lower brain iron. Higher BMI and blood pressure, history of smoking, and self-reported meat consumption, increased brain iron. Haematological parameters, inflammatory and kidney biomarkers, and calcium, were also associated. Genetics support causal effects of depression, type-2 diabetes, and 7 other diseases with increased iron, but not Alzheimers disease. Evidence supports a causal effect of osteoporosis on lower iron in the substantia nigra. We found causal associations between adiposity and proteins (such as IL-6 receptor and transferrin receptor) on subcortical brain iron. ConclusionsWe identified causal effects for liability to type-2 diabetes, depression, and other conditions, on subcortical iron deposition, but not to Alzheimers disease, supportive of dementia as a consequence of brain iron deposition, not a cause. The role of adiposity reducing interventions on brain iron should be investigated. Relationships between brain iron, osteoporosis, calcium, and hyperparathyroidism warrant further investigation.