Men carrying two copies of a common genetic variant face double the risk of dementia, according to new findings from the ASPREE trial.
New research has uncovered that men who carry a common genetic variant are twice as likely to develop dementia in their lifetime compared to women.
The study, published in Neurology, tapped into data from the large-scale ASPREE trial (ASPirin in Reducing Events in the Elderly) to explore the link between dementia and variants in the hemochromatosis (HFE) gene. This gene plays a crucial role in regulating iron levels in the body, but certain changes in it could have much bigger consequences for brain health.
Professor John Olynyk from Curtin Medical School, a co-author of the study, explained that about one in three people carry a single copy of the variant known as H63D. While common, it is the smaller group, around one in 36 people, who carry two copies that face a significantly higher risk.
“Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia. However, having two copies of the variant more than doubled the risk of dementia in men, but not women,” Professor Olynyk said.
“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.”
Gender Differences and Future Directions
Professor Olynyk said further research was needed to investigate why this genetic variant increased the risk of dementia for males but not females.
“The HFE gene is routinely tested for in most Western countries including Australia when assessing people for haemochromatosis – a disorder that causes the body to absorb too much iron. Our findings suggest that perhaps this testing could be offered to men more broadly,” Professor Olynyk said.
“While the HFE gene is critical for controlling iron levels in the body, we found no direct link between iron levels in the blood and increased dementia risk in affected men.
“This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body.”
Implications for Personalized Medicine
Co-author Professor Paul Lacaze, from Monash University, said the findings could help improve outcomes for people at risk of developing dementia.
“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 personalized approaches to prevention and treatment,” Professor Lacaze said.
“This study is a great example of how diverse Australian research groups and universities can collaborate effectively to learn more about these progressive diseases and ultimately improve health outcomes for people around the world.”
Reference: “Haemochromatosis Genotypes and Incident Dementia in a Prospective Study of Older Adults” by Chenglong Yu, Martin Delatycki, Sultana Monira Hussain, John James McNeil, Paul Lacaze and John K. Olynyk, 29 May 2025, Neurology.
DOI: 10.1212/WNL.0000000000213743
The ASPREE trial was a double-blind, randomized, placebo-controlled trial of daily low-aspirin in 19,114 healthy older people in Australia and the USA. Primarily undertaken to evaluate the risks versus benefits of daily low-dose aspirin in this cohort, it created a treasure trove of healthy ageing data that has underpinned a wealth of research studies.
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