Dementia Risk Doubles in Men With Two Copies of HFE Variant
Men with two copies of a common HFE gene variant have over twice the dementia risk compared to women.
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A new study published in Neurology has found that men who carry two copies of a common variant in the HFE gene face more than twice the lifetime risk of developing dementia compared to women with the same genetic profile.
HFE gene
The HFE gene provides instructions for making a protein that regulates iron absorption in the body. Mutations in this gene, such as H63D, are linked to conditions like hereditary haemochromatosis.The research drew on data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, which enrolled over 19,000 healthy older adults in Australia and the United States. Researchers used this dataset to explore associations between variants in the HFE gene – essential for iron regulation in the body – and dementia risk.
A closer look at the H63D variant
Approximately one in three individuals carries one copy of the H63D variant in the HFE gene, while ~1 in 36 carries two copies. The study found no increased risk of dementia in individuals with a single copy of the variant. However, males with two copies showed a more than two-fold increased risk of developing dementia, a pattern not observed in females.
“While the genetic variant itself cannot be changed, the brain pathways which it affects – leading to the damage that causes dementia – could potentially be treated if we understood more about it.”
Dr. John Olynyk.
The HFE gene is routinely screened in Western healthcare settings during assessments for hereditary haemochromatosis, a disorder that leads to excessive iron accumulation in the body. Despite this association with iron regulation, researchers found no direct link between elevated blood iron levels and dementia risk in men with the double H63D variant. This suggests that other biological pathways, such as those related to inflammation or cellular damage, may play a role.
Haemochromatosis
A genetic disorder that causes the body to absorb too much iron from food. The excess iron is stored in organs, leading to damage if untreated.Implications for research and health assessments
The sex-specific nature of the findings raises questions about potential underlying mechanisms that may protect females or increase susceptibility in males. Further studies are needed to understand these differences.
“More than 400,000 Australians are currently living with dementia, with around a third of those being men. Understanding why men with the double H63D variant are at higher risk could pave the way for more personalised approaches to prevention and treatment.”
Dr. Paul Lacaze.
The ASPREE trial, initially conducted to assess the risks and benefits of daily low-dose aspirin use, has become a significant source of longitudinal health data in aging populations. This latest analysis underscores the value of leveraging such datasets to investigate genetic and environmental contributors to neurodegenerative diseases.
Reference: Yu C, Delatycki M, Hussain SM, McNeil JJ, Lacaze P, Olynyk JK. Haemochromatosis genotypes and incident dementia in a prospective study of older adults. Neurology. 2025;104(12):e213743. doi: 10.1212/WNL.0000000000213743
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