Common gene variant doubles dementia risk, but only in men

Men who carry two copies of a common genetic variant are more than twice as likely to develop dementia as those without, according to new research.

The study, led by scientists in Australia, identified a strong association between dementia risk and the H63D variant in the HFE gene, a key regulator of iron metabolism. Notably, this increased risk was observed only in men, with no similar effect found in women carrying the same variant.

'Having just one copy of this gene variant does not impact someone's health or increase their risk of dementia,' said Professor John Olynyk, co-author of the study published in Neurology and clinician-researcher at Curtin Medical School in Perth. 'However, having two copies more than doubled the risk of dementia in men.'

The findings were based on data from over 12,000 older adults of European ancestry enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) trial, a large-scale study of healthy ageing. Participants had no history of dementia or cardiovascular disease at the start of the study and were tracked over a median of 6.4 years.

The HFE gene is most commonly tested to diagnose haemochromatosis, a condition that causes excess iron accumulation in the body. About one in three people carry one copy of the H63D variant, while around one in 36 carry two. Despite the variant's known role in iron regulation, the study found no link between high iron levels in the blood and dementia risk, suggesting other mechanisms are at work.

'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 said.

Dementia affects over 400,000 Australians, with men accounting for about one-third of cases – making the sex-specific nature of this genetic risk particularly noteworthy. The researchers suggest that broader screening of the HFE gene in men could help identify those at greater risk before symptoms arise.

'Understanding why men with the double H63D variant are at higher risk could pave the way for more personalised approaches to prevention and treatment,' said study co-author Professor Paul Lacaze from Monash University in Melbourne.

The research team now plans to investigate how the H63D variant may influence brain pathways and contribute to cognitive decline, with the ultimate goal of developing therapies that could mitigate its effects.