Abstract
Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective:To estimate p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort.Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2* measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2* measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.
Highlights
Iron has been linked to dementia and other neurodegenerative diseases, with roles in oxygen transport, myelin production plus synthesis and metabolism of neurotransmitters [1,2,3]
T2∗ measures were substantially lower in male p.C282Y homozygotes compared to those with neither variants across a number of brain regions including the putamen, caudate, and nucleus accumbens, but notably within important cognitive regions: the thalamus and hippocampus
We aimed to estimate hemochromatosis genotype associations with brain Magnetic resonance imaging (MRI) measures and incident dementia in the UKB community genotyped cohort, with a specific focus on male HFE p.C282Y homozygotes, who develop the majority of hemochromatosis related physical diseases
Summary
Iron has been linked to dementia and other neurodegenerative diseases, with roles in oxygen transport, myelin production plus synthesis and metabolism of neurotransmitters [1,2,3]. Iron accumulation in specific brain areas is found in Alzheimer’s disease (the most common form of dementia), beyond normal accumulations seen in aging [5], and these iron accumulations are associated with amyloid plaques and tau aggregation [5]. The variants can result in iron overload and iron deposition in many tissues [8]. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimate p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2∗ measures (lower values indicating more iron). Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes
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