Summary: New research shows that men who inherit two copies of a common HFE gene variant face more than double the lifetime risk of developing dementia, while women with the same genotype do not appear to be affected. The H63D variant, associated with hereditary haemochromatosis, is relatively common—present in roughly one in 36 people as a double copy.
The study did not find a direct link between elevated blood iron levels and dementia risk, suggesting other biological mechanisms—such as inflammation or neural cell damage—may explain the association. These results could inform more targeted dementia prevention strategies, especially for men who carry this genetic profile.
Key Facts:
- Sex-specific association: Men who are homozygous for the H63D variant (two copies) have a significantly increased dementia risk; this effect was not observed in women.
- Not explained by serum iron: The increased risk does not appear to be driven directly by higher blood iron (ferritin) levels, pointing to alternative biological pathways.
- Potential clinical implication: Routine testing of HFE variants—already performed when assessing haemochromatosis—might be considered more broadly in men to identify those at higher dementia risk and guide early prevention.
Source: Curtin University
New evidence links an HFE gene variant to a higher dementia risk in men
Published in Neurology, the study analyzed genetic and clinical data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial to evaluate whether variants in the haemochromatosis (HFE) gene are associated with later-life dementia. The HFE gene plays a key role in regulating iron absorption and storage in the body.
Co-author Professor John Olynyk from Curtin Medical School noted that about one in three people carry a single copy of the H63D variant, which typically has no known health impact. Around one in 36 individuals carry two copies (homozygous). In this study, men who were homozygous for H63D experienced more than twice the risk of developing dementia compared with men without the variant, while women with the same genotype showed no similar increase.
“Carrying one copy of the H63D variant does not appear to increase dementia risk,” Professor Olynyk said. “However, men with two copies had a markedly higher risk. The variant itself cannot be changed, but understanding the brain pathways it influences could reveal treatments that prevent or limit the damage that leads to dementia.”
Professor Olynyk emphasized that although HFE testing is commonly used when evaluating people for haemochromatosis in many Western countries, the new findings suggest there may be value in broader testing among men to identify those at elevated dementia risk.
Importantly, the study found no consistent relationship between baseline serum ferritin (a blood marker of iron storage) and the subsequent development of dementia. This indicates that the increased risk associated with H63D homozygosity is unlikely to be driven solely by excess circulating iron. The researchers propose that other mechanisms—such as chronic inflammation, oxidative stress, or cell damage—may link the genotype to neurodegeneration.
Co-author Professor Paul Lacaze of Monash University highlighted the potential public health implications. “With more than 400,000 Australians currently living with dementia—about a third of whom are men—identifying genetic subgroups at higher risk could support more personalized prevention and earlier intervention strategies,” he said.
The ASPREE trial, a large double-blind, randomized, placebo-controlled study of low-dose aspirin in 19,114 healthy older adults in Australia and the USA, provided the longitudinal, well-characterized dataset used for this analysis. Participants enrolled with no history of cardiovascular disease, dementia, or cognitive decline, and were followed for a median of 6.4 years.
This research was a collaborative effort involving Curtin University, Monash University, The University of Melbourne, The Royal Children’s Hospital, Murdoch Children’s Research Institute, and Fiona Stanley Hospital.
About this genetics and dementia research news
Author: Yasmine Phillips
Source: Curtin University
Contact: Yasmine Phillips – Curtin University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Haemochromatosis genotypes and incident dementia in a prospective study of older adults” by John Olynyk et al. Neurology
Abstract
Haemochromatosis genotypes and incident dementia in a prospective study of older adults
Background and Objectives
Variants in the homeostatic iron regulator (HFE) gene are common among people of European ancestry and have previously been implicated in dementia risk. This study examined how two specific HFE variants—p.Cys282Tyr and p.His63Asp (often called H63D)—relate to baseline serum ferritin levels and the incidence of dementia in a cohort of initially healthy older adults.
Method
Researchers conducted a prospective longitudinal analysis using data from the ASPREE trial. Participants had no prior cardiovascular disease, dementia, or cognitive decline at enrollment. Genotyping for p.Cys282Tyr and p.His63Asp variants was performed using microarray technology, and baseline serum ferritin concentrations were measured from peripheral blood samples. Dementia cases were adjudicated by an expert committee over a median follow-up of 6.4 years, and associations were assessed with Cox proportional hazards models adjusted for relevant covariates.
Results
The analytic sample included 12,174 unrelated, healthy participants of European ancestry aged 70 years or older (5,583 men and 6,591 women). Median ages were similar for men and women. Some genotypes, such as p.Cys282Tyr homozygosity and compound heterozygosity, were associated with higher baseline ferritin in men and women. However, baseline serum ferritin did not predict dementia risk in this cohort.
Crucially, men who were homozygous for p.His63Asp (H63D+/+) had a significantly higher risk of developing dementia (adjusted hazard ratio = 2.39, 95% CI 1.25–4.57, p = 0.009) compared with men without HFE variants. This association was not observed among women.
Discussion
In this population of initially healthy older adults, homozygosity for the p.His63Asp (HFE H63D) variant was linked to an increased risk of incident dementia in men but not in women. The lack of a direct association with serum ferritin suggests that other biological mechanisms—potentially involving inflammation, oxidative stress, or cellular injury—may underlie this sex-specific genetic risk. Further research is needed to clarify the pathways involved and to evaluate whether targeted screening or interventions could reduce dementia risk in affected men.