Contributions of HFE polymorphisms to brain and blood iron load, and their links to cognitive and motor function in healthy adults

Abstract

Background Brain iron overload is linked to brain deterioration, and cognitive and motor impairment in neurodegenerative disorders and normal aging. Mutations in the HFE gene are associated with iron dyshomeostasis and are risk factors for peripheral iron overload. However, links to brain iron load and cognition are less consistent and data are scarce. Aims and methods Using quantitative susceptibility mapping with magnetic resonance imaging, we investigated whether C282Y and H63D contributed to aging‐related increases in brain iron load and lower cognitive and motor performance in 208 healthy individuals aged 20‐79 years. We also assessed the modulatory effects of HFE mutations on associations between performance and brain iron load, as well as peripheral iron metabolism. Results Independent of age, carriers of either C282Y and/or H63D (HFE‐pos group, n = 66) showed a higher load of iron in putamen than non‐carriers (HFE‐neg group, n = 142), as well as higher transferrin saturation and lower transferrin and transferrin receptors in blood. In the HFE‐neg group, higher putaminal iron was associated with lower working memory. In the HFE‐pos group, higher putaminal iron was instead linked to higher executive function, and lower plasma transferrin was related to higher episodic memory. Iron‐performance associations were modest albeit reliable. Conclusion Our findings suggest that HFE status is characterized by higher regional brain iron load across adulthood, and support the presence of a modulatory effect of HFE status on the relationships between iron load and cognition. Future studies in healthy individuals are needed to confirm the reported patterns.

Contributions of the Catechol-O-Methyltransferase Val158Met Polymorphism to Changes in Brain Iron Across Adulthood and Their Relationships to Working Memory

“…Three blocks for each condition (1-, 2-, 3-back) were performed. Performance was calculated as proportion of false alarms subtracted from proportion of hits for 2- and 3-back only (for details about the tasks, see Kalpouzos et al, 2021 ).…”

HFE Mutations in Neurodegenerative Disease as a Model of Hormesis

“…HFE variants have been extensively investigated regarding their role in neurodegenerative disease due to the pathological effects of increased iron levels in the brain [ 119 ]. In cognitive impairment and dementia not associated with Alzheimer’s, Parkinson’s, or ALS, there are not many findings of increased risk due to HFE variants, but this may be due to a lack of investigation.…”

Brain iron content and cognitive function in patients with β-thalassemia

“… 76 In addition, human studies in patients with non- β-TM and cognitive impairment have demonstrated that brain iron deposition is correlated with cognitive impairment. 77 – 79 Currently, MRI is the most commonly used neuroimaging method for quantification of brain iron content in vivo , making it a crucial technique for evaluating brain iron overload in patients with β-TM. The key neuroimaging findings of brain iron accumulation in patients with β-TM with or without cognitive assessment are presented in Table 2 .…”