A significant breakthrough in neurogenetics has revealed that men who carry two copies of a specific genetic variant are twice as likely to develop dementia during their lifetime compared to women. The study, which analyzed extensive health data from thousands of older adults, sheds new light on the complex interplay between genetics, gender, and neurodegenerative disease, potentially opening doors for more targeted screening and personalized preventative care.
The findings, published in the prestigious medical journal Neurology, focus on the haemochromatosis (HFE) gene. While this gene is primarily known for its role in regulating iron levels within the human body, researchers have long suspected it might play a more clandestine role in brain health. By analyzing the genetic profiles and health outcomes of a massive cohort of elderly participants, the research team identified a stark disparity in how certain mutations of this gene affect the cognitive health of men versus women.
At the heart of the study is a variant known as H63D. The HFE gene is responsible for producing a protein that sits on the surface of cells and helps regulate the amount of iron that enters them. When this gene is mutated, it can lead to a condition known as haemochromatosis, where the body absorbs and stores too much iron, potentially damaging organs such as the liver and heart. However, the H63D variant is often considered a "milder" mutation compared to others associated with iron overload. Despite this reputation, the new research suggests that its impact on the brain may be far more significant than previously understood.
Professor John Olynyk, a co-author of the study from the Curtin Medical School, highlighted the prevalence of this genetic marker within the general population. According to the research, approximately one in three individuals carries a single copy of the H63D variant. While carrying one copy is common, it does not appear to negatively impact an individual’s health or elevate their risk for cognitive decline. The concern lies with those who inherit two copies of the variant—one from each parent.
"Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia," Professor Olynyk explained. "However, having two copies of the variant more than doubled the risk of dementia in men, but not women."
The discovery that this risk is gender-specific is one of the most striking aspects of the study. For reasons that researchers are still working to uncover, the presence of the double H63D variant appears to create a vulnerability in the male brain that is not mirrored in females. This statistical divergence suggests that biological or hormonal factors unique to men may interact with the genetic variant to accelerate the onset of dementia.
The research was made possible through the use of data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. ASPREE was a landmark, double-blind, randomized, placebo-controlled trial that monitored 19,114 healthy older individuals across Australia and the United States. While the primary objective of the ASPREE trial was to evaluate whether a daily low dose of aspirin could prolong healthy life in the elderly, the study inadvertently created an immense and invaluable repository of data. By tracking the health, genetics, and lifestyle factors of nearly 20,000 people over several years, the trial has provided a "treasure trove" of information that continues to fuel secondary research into the mechanisms of aging.
