Men who carry two copies of a common genetic variant are twice as likely to develop dementia than women with the same mutations, according to a new study from Australian researchers. This discovery has the potential to develop early detection and intervention methods to block how the variants affect the brain.
Researchers from Curtin University, Monash University, The University of Melbourne, The Royal Children’s Hospital, Murdoch Children’s Research Institute and Fiona Stanley Hospital have found that men with a pair of mutations in the hemochromatosis (HFE) gene – approximately one in 36 males – had double the incidence of dementia than those without, or women with, the variants.
It's estimated that one in three men have one variant, known as H63D, making it incredibly common. Having two, however, is the problem.
“Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia," said co-author Professor John Olynyk, from the Curtin Medical School. "However, having two copies of the variant more than doubled the risk of dementia in men, but not women."
Essentially, the HFE gene controls a protein found on cell surfaces that helps detect and regulate iron levels in the body. Mutations can cause genetic disorders – most commonly hemochromatosis, the genetic condition that sees the body absorb too much iron and can lead to organ damage. This is more common in men, but women can develop hemochromatosis later in life.
Using data from the double-blind, randomized, placebo-controlled daily low-aspirin trial (ASPirin in Reducing Events in the Elderly, or ASPREE), which assessed 19,114 healthy people in the US and Australia, the researchers found that there was a significantly higher risk of men developing dementia if they'd inherited the double H63D variant. But it wasn't linked to iron levels, as first suspected.
“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," said Olynyk. "This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body.”
Now that the link has been identified, scientists are moving on to unravel the mechanism that looks to be impacting brain health – and, in doing so, it could lead to interrupting what drives the process and in turn muting the variants' effect.
"Understanding why men with the double H63D variant are at higher risk could pave the way for more personalized approaches to prevention and treatment,” said co-author Professor Paul Lacaze from Monash University.
“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," added Olynyk.
Olynyk suggests that when diagnosing hemochromatosis in men, medical professionals should also be considering the wider health implications that this double H63D variant poses.
“The HFE gene is routinely tested for in most Western countries including Australia when assessing people for hemochromatosis," he said. "Our findings suggest that perhaps this testing could be offered to men more broadly.”
The research was published in the journal Neurology.
Source: Curtin University via Scimex
