New research published in Neurology has uncovered a significant gender disparity in dementia risk associated with a common genetic variant. Men carrying two copies of the H63D variant in the haemochromatosis (HFE) gene face more than double the lifetime risk of developing dementia compared to women with the same genetic profile.
Study Design and Prevalence
The investigation leveraged data from the ASPREE trial (ASPirin in Reducing Events in the Elderly), a major double-blind, randomized, placebo-controlled study involving 19,114 healthy older adults in Australia and the USA. Researchers analyzed whether variants in the HFE gene—crucial for regulating bodily iron levels—correlated with increased dementia risk.
“Approximately one in three individuals carries one copy of the H63D variant, while one in 36 carries two copies,” explained co-author Professor John Olynyk from Curtin Medical School. “Importantly, having a single copy shows no measurable health impact.”
Gender Disparity Emerges
The research revealed a striking gender-based difference: Men with two H63D copies exhibited a >200% increased dementia risk compared to women with identical genetics. This finding persisted despite no observed correlation between blood iron levels and dementia risk in affected men.
“This points to mechanisms beyond iron regulation,” noted Professor Olynyk. “We suspect inflammation and cellular damage causing brain injury might be pathways influenced by this gene variant.”
Clinical Implications and Future Research
The findings suggest potential clinical applications for existing genetic screening. Since HFE testing is already routine for haemochromatosis diagnosis in Western nations, researchers propose broader screening for men.
“With over 400,000 Australians living with dementia—one-third being male—this discovery could enable personalized prevention,” stated co-author Professor Paul Lacaze of Monash University. “Understanding why men with double H63D variants are vulnerable may unlock targeted interventions.”
Professor Olynyk emphasized the urgency of investigating the gender-specific mechanism: “While we cannot modify the gene itself, the biological pathways it triggers could become treatable targets with deeper understanding.”
Collaborative Science Driving Discovery
The ASPREE trial, initially designed to assess low-dose aspirin’s effects in healthy seniors, has generated a rich dataset enabling multiple health investigations. Professor Lacaze highlighted the study as “a testament to how cross-institutional Australian research collaborations advance global health outcomes against progressive diseases.”
Further research is underway to decode the biological reasons behind the male-specific dementia risk observed in dual H63D carriers.
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