By mining this data, the collaborative team of researchers from Curtin University, Monash University, The University of Melbourne, and several other leading Australian medical institutions was able to isolate the impact of the H63D variant with a high degree of statistical confidence. The scale of the ASPREE cohort allowed the team to look past general trends and identify specific risks associated with rare genetic combinations, such as the one in 36 people who carry two copies of the H63D variant.
One of the most surprising findings of the study involves the role of iron itself. Given that the HFE gene is the primary regulator of iron, the researchers initially expected to find that high iron levels in the blood were the smoking gun linking the genetic variant to dementia. However, the data told a different story.
"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," Professor Olynyk said. This finding is significant because it suggests that the H63D variant may be causing damage through pathways that are independent of systemic iron levels. Rather than a simple case of "iron poisoning" the brain, the mutation may be triggering more localized and complex cellular issues.
"This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body," Professor Olynyk added. If the variant leads to chronic low-grade inflammation or makes brain cells more susceptible to oxidative stress, it could explain the gradual neurodegeneration observed in these patients. Understanding these specific pathways is now a priority for the research team, as it could lead to the development of therapies designed to counteract the damage caused by the variant.
The implications for public health are substantial, particularly regarding how the medical community approaches genetic screening. In many Western countries, including Australia, testing for the HFE gene is already a routine part of clinical practice when a patient is suspected of having haemochromatosis. Because the test is already established and widely available, the researchers suggest it could be utilized more broadly to identify men who are at a higher risk for cognitive decline.
"Our findings suggest that perhaps this testing could be offered to men more broadly," Professor Olynyk noted. By identifying high-risk individuals decades before the onset of symptoms, clinicians might be able to implement preventative strategies, monitor cognitive health more closely, and eventually provide targeted treatments as they become available.
The need for such personalized approaches is underscored by the growing prevalence of dementia globally and within Australia. Currently, more than 400,000 Australians are living with dementia. While the disease is often associated with women due to their longer average lifespans, men account for approximately one-third of all cases. For these men, understanding the genetic drivers of their condition is a critical step toward better care.
