Haemochromatosis Genotypes and Incident Dementia in a Prospective Study of Older Adults

Variants in the homeostatic iron regulator (HFE) gene are prevalent among individuals of European ancestry and have been linked to an increased risk of dementia. This study aimed to evaluate the effects of HFE p.Cys282Tyr and p.His63Asp variants on serum ferritin levels and the incidence of dementia in a cohort of initially healthy older adults.

This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly trial. Participants had no history of cardiovascular disease, dementia, or cognitive decline at enrollment. Genotyping for HFE p.Cys282Tyr and p.His63Asp variants was conducted using microarrays, and baseline serum ferritin concentrations were measured in peripheral blood samples. Dementia diagnoses were confirmed by an adjudication committee over a median follow-up of 6.4 years. Associations were evaluated using Cox proportional hazards models adjusted for related covariates.

The study included 12,174 unrelated, healthy participants of European ancestry aged 70 years or older, comprising 5,583 men (45.9%) and 6,591 women (54.1%). The median age was 73.7 years (interquartile range [IQR]: 71.6-76.9) for men and 73.9 years (IQR: 71.7-77.5) for women. Compared with the wild-type group, men with p.Cys282Tyr+/+ (p = 0.048) and p.Cys282Tyr+/p.His63Asp + genotypes (p < 0.001) had significantly higher baseline ferritin levels. Women with p.His63Asp+/+ (p = 0.015) and p.Cys282Tyr+/p.His63Asp+ (p < 0.001) genotypes also exhibited elevated ferritin levels. No significant association was observed between baseline serum ferritin levels and dementia risk. However, men with p.His63Asp+/+ genotype had a significantly higher risk of incident dementia (adjusted hazard ratio = 2.39, 95% CI 1.25-4.57, p = 0.009) compared with those without HFE variations. This association was not observed in women.

Among initially healthy older adults, HFE p.His63Asp homozygosity was associated with a higher risk of incident dementia in men but not women. These findings highlight a potential sex-specific genetic risk factor for dementia and warrant further research into the underlying mechanisms linking p.His63Asp and dementia.