Interestingly, there was no direct link found between iron and dementia, and it only appears to impact men.
Up to one in three people have two copies of a gene variant which, according to a recent Melbourne study, more than doubles the risk of dementia in men.
Haemochromatosis resulting from mutations to the homeostatic iron regulator (HFE) gene is one of the most frequent inherited causes of iron overload in humans and is routinely tested for when conducting haemochromatosis investigation.
The researchers have published their findings in Neurology this month.
They say that male HFE p.His63Asp homozygosity is a potential sex-specific genetic risk factor for dementia that warrants further investigation.
While the gene is critical for controlling iron levels, they found no direct link between iron in the blood and increased dementia risk, and the mechanism of this association remains unclear.
The study included more than 12,000 healthy participants of European ancestry from Australia and the US aged 65 years or older. Participants had no history of cognitive decline, dementia, cardiovascular disease, independence-limiting physical disability or other life-threatening illnesses at enrolment.
During a median follow-up of six and a half years, there were almost 500 cases of dementia, split evenly between men and women. Homozygous p.His63Asp men had an adjusted hazard ratio for dementia of 2.39, an association which was not seen in women or heterozygous men.
Researchers explained that homozygosity was not associated with an increase in brain iron levels but they did find an increase in hepatic iron concentrations, as well as brain H-ferritin and L-ferritin.
“p.His63Asp has been linked to increased brain ferritin levels and neuroinflammatory signalling. This suggests that brain iron homeostasis and inflammation, rather than systemic iron burden, may drive dementia risk,” researchers said.
They noted that the association in men but not women may reflect iron homeostasis and neuroprotection differences between sexes.
“Estrogen helps regulate iron metabolism and reduces oxidative stress, potentially mitigating the effects of iron-induced neurotoxicity in females. In addition, men typically have higher iron levels and a stronger proinflammatory microglial response, which may amplify oxidative stress and neurodegeneration,” they wrote.
Clinical Professor Dimity Pond of the Wicking Dementia Centre in Tasmania told Haematology Republic that the findings suggest more careful attention should be paid to men who are homozygous.
“Those with two copies of the gene do not necessarily have iron overload,” she said.
“It is elevated iron that usually triggers us to look for haemochromatosis, so we may be missing those with this genetic risk factor.”
However, she said that routine GP screening such as MMSE or MOCA tended to result in fewer false positives if the focus was on known risk factors and symptoms, as advocated by the RACGP Red Book.
“We know that another gene, APOE4, is associated with dementia but it is not recommended to screen for this because cost outweighs benefits at a population level. There are other rarer genes also associated with dementia,” she said.
The association between male p.His63Asp homozygosity and increased dementia risk was independent of APOE4 and APOE2 alleles in the study.
Professor Pond said that as the cost of genetic testing comes down, it may become cost effective to do this sort of screening in future.
“I think personally, I will continue to focus my dementia screening on those with risk factors, including if I already know that my male patients have haemochromatosis, but not looking for it just for this purpose,” she said.
