Hemochromatosis Linked To Dementia In Men With European Ancestry

Men with European ancestry who are homozygous for HFE C282Y, the gene that causes hemochromatosis, were more likely to be diagnosed with dementia and to have more brain iron deposition in a retrospective study.

"It is vital that patients with hereditary hemochromatosis are diagnosed and treated earlier," Dr. Janice Atkins of the University of Exeter Medical School, UK, told Reuters Health by email. "Men with two faulty hemochromatosis genes were 83% more likely to develop dementia compared to those without the genes over 10 years of follow-up. Brain MRIs in a subset of (those) men found a build-up of iron in areas of the brain including the hippocampus and thalamus, known to be linked to memory."

Earlier diagnosis and treatment, she said, are also likely "to prevent substantial excess morbidity, including from dementia but also from liver disease, liver cancer, diabetes and osteoarthritis."

​

Clinicians should test more often for very high ferritin levels as the first step toward the diagnosis, she said.

As reported in theJournal of Alzheimer's Disease, previous work by the team found that men homozygous for HFE C282Y were more likely to develop liver cancer, arthritis and frailty than those without the faulty genes. The current analysis focused on dementia risk.

Dr. Atkins and colleagues analyzed hospital records of more than 335,000 people of European ancestry in the UK Biobank. Close to 3,000 participants (mean age, 64; about half, men) were homozygous for HFE C282Y.

As Dr. Atkins indicated, over a mean 10.5 years of followup, 25 of 1,294 homozygous men developed dementia - 83% more than for those without the variant. The association was similar after additionally adjustment for APOE genotype status (HR, 1.83).

No associations with dementia were seen in homozygote or heterozygote women.

Further analysis showed that while there were increased hazards for diagnosis of incident delirium among the homozygote men (HR 1.82), there were no associations with mild cognitive impairment, stroke, or transient ischemic attack.

In a subset MRI analysis, data on T2 signal loss due to iron accumulation were available for 78 men and 128 women homozygotes. T2 measures were substantially lower in homozygote men compared to those with neither variant across a number of brain regions, including the putamen, caudate and nucleus accumbens - but notably, as Dr. Atkins indicated, in two important cognitive regions: the thalamus (beta = - 0.90) and hippocampus (beta = - 0.32).

Associations were seen in women between p.C282Y homozygote status and T2 measures in the putamen, thalamus, caudate, and pallidum.

Dr. Atkins said, "We are working toward trials of earlier diagnosis and treatment for people with the hemochromatosis genes in the UK to pave the way to a screening program for this condition. The scientific community also needs to set up clinical trials of whether iron-removal therapies could slow dementia after it starts developing in those with the two faulty genes."

Dr. Rebecca Edelmayer, Alzheimer's Association Director of Scientific Engagement, commented in an email to Reuters Health, "There is some research to date that points to high iron accumulation as a risk factor for dementia, but it may be the liver damage or other inflammatory conditions that result from iron overload that increase risk. Much more research is needed, including intervention studies that investigate iron-reduction strategies."

"It's interesting to note that (homozygous) women didn't exhibit increased dementia incidence when we know women may be more vulnerable to Alzheimer's and dementia," she said.

"These findings aren't actionable until research shows that an iron-reduction intervention makes a difference in brain iron deposition and can be linked to benefits for cognition," she added. "Still, it's important that people get their iron levels checked as part of a regular blood workup in support of cardiovascular health. We are learning more through research that emphasizing good cardiovascular health across a life course may be an effective dementia risk-reduction strategy."

—Marilynn Larkin

Source