Ironing out neurodegeneration: is iron intake important during the teenage years?

Keywords::

• Alzheimer's disease
• dietary iron
• HFE gene
• myelination
• neuroimaging

When did you last take an iron supplement? As a dietary supplement, iron has enjoyed varying popularity over the years; for decades, commercials for multivitamins enriched in iron have promised a remedy for ‘tired blood’. More recently, however, several studies began to link increasing iron levels as we age with a heightened risk of heart attack and cardiovascular disease [1]; these links remain controversial and are the target of intense research.

A recent study now reports that our iron levels when we are young affect the integrity of the brain years later – differences visible in brain scans [2]. This line of work also establishes new genetic links between iron, brain integrity and a gene that causes the commonest hereditary disease in the world – hemochromatosis. This iron overload disease affects one in every 200–300 people in the USA alone, according to the National Library of Medicine in 2010 [101].

Iron & the brain

Iron is an essential mineral in our daily life; it is a crucial component of hemoglobin, which carries oxygen in our blood from the lungs to the rest of the body. Even in North America and Europe, iron deficiency is still prevalent; it is the commonest nutritional deficiency worldwide and the leading cause of anemia. Abnormally low red blood cell counts can lead to countless complications throughout various organ systems of the body. Iron may be considered a ‘double-edged sword’: critical for brain development in early life, but a promoter of brain degeneration in old age.

Iron in neurodevelopment & degeneration

Iron enters the brain primarily when a specialized protein – called transferrin – transports it through the blood–brain barrier [3]. Most of the brain’s iron is found in oligodendrocytes, which maintain iron homeostasis in the brain. These cells also support myelination, which speeds neuronal transmission [4]. Even after adjusting for brain weight, iron concentrations are lowest at birth and increase throughout life [5], with complex and lasting effects on neurotransmitter systems, cognition and behavior.

Children with iron-deficient diets show poorer cognitive achievement [6]. In school-age children, vitamin and mineral supplements can increase cognitive performance, including nonverbal intelligence [7]. In rural areas where iron deficiency anemia is prevalent, iron supplements have also been shown to boost motor and language capabilities in children [8].

As we age, brain iron homeostasis and regulation can be disrupted, making us more vulnerable to a range of neurodegenerative diseases. Neuroimaging methods show abnormally high brain iron concentrations in patients with several neurodegenerative disorders including Alzheimer’s disease (AD). High iron concentrations may even cause neuronal death [9]. Brain regions with greatest iron stores include the basal ganglia, hippocampus and substantia nigra, and these show significant atrophy in patients with AD and Parkinson disease, compared with cognitively normal controls. But, why do the higher iron levels that help us in childhood, also promote brain degeneration later in life? A new study suggests these links might be traceable to common variants in our DNA, which affect how iron is used in the body and brain.

Does iron intake affect cognitive reserve?

No study to date has tracked iron intake from childhood into old age (to examine neurodegenerative complications), but adequate iron in the diet has been repeatedly linked to better cognition and scholastic achievement. Educational level is one of the most well-documented protective factors against AD [10]. Iron is critical for myelination, and some argue that myelin itself may increase the brain’s resilience to neuropathology later in life, by boosting our ‘cognitive reserve’ [11].

Iron building a better brain

In our recent study [2], adolescents with lower iron levels had poorer fiber integrity in the brain’s white matter. These differences were evident on specialized brain scans that reveal the fine structure of the brain’s neural pathways – diffusion tensor images – collected around 9 years after their iron status was assessed. As iron levels fluctuate throughout the day, we measured transferrin levels as a more stable proxy, to assess the long-term availability of iron to the brain. The liver produces more transferrin when iron levels are low, to mobilize what little iron is available. While we were unable to show better cognition in those with higher brain integrity – all our subjects were normal and not iron deficient – the direction of the results was foreshadowed by earlier work in molecular neuroscience. Lower iron levels (higher transferrin) are known to lead to hypomyelination [12]. However, do these results in a cognitively healthy, young population suggest that slight variations in iron levels early on affect the brain’s organization? In support of this, we found several regions prone to atrophy in neurodegenerative disorders such as the hippocampi and the midbrain were smaller in those with greater iron stores, but the caudate and basal ganglia regions were larger. The direction of these volumetric associations was mixed and unexpected, suggesting that iron may interact with the trajectory of brain development in complex ways.

Tracing the iron effect to DNA

The people taking part in our study were all twins and most of them had genome-wide scans to assess around half a million variants in their DNA. As we were able to predict one twin’s brain integrity from the other twin’s iron levels, we knew that some common variation in their shared DNA was affecting both. With genome-wide scans, we set out to trace their brain differences back to a probable cause in the genome – an iron overload gene, called HFE (or ‘high iron’; ‘Fe’ in the gene name is based on the chemical symbol for iron). Although dietary intake of iron clearly affects iron levels in the body, iron overload disorder – or hemochromatosis – is the commonest genetic disorder in the world. It arises when the HFE gene has a mutation that damages the gene’s function and the body’s ability to regulate iron.

What is perhaps less known is that approximately one in five of Caucasians carries a variant in the HFE gene, the H63D variant (according to the HapMap project). Carriers of this variant have ‘genetically high’ iron availability; by sorting our subjects into those who had this genetic variant and those who did not, we saw higher brain integrity on brain scans in those with the high-iron variant.

This offers a clue to how this very commonly carried genetic variant affects the brain as well as iron regulation; this variant and a less common mutation in the same gene, HFE, have also been associated with neurological disorders, such as sporadic amyotrophic sclerosis [13]. AD patients with the H63D polymorphism have elevated plasma iron and transferrin levels [14], but this pattern is not detectable in healthy controls with the variant, suggesting that HFE and plasma iron levels play a role in AD. Currently, it is believed that HFE may even have protective implications in AD as reported by a meta-analysis [15].

Iron & gene expression in the brain

So far in our work, we had established a link between brain integrity and a common variant in an iron-regulating gene. Although we are either born with this variant or not, there is some evidence that the expression of other key genes also depends on our iron intake – even, to some extent – on maternal iron intake before we are born.

Neonatal iron deficiency arising from poor maternal diet is known to alter gene expression in the brain. Specifically, in the hippocampus, several AD-related genes (including Apbb1, C1qa, Clu, App, Cst3, Fn1 and Htatip) show altered expression in iron-deficient rats, relative to iron-sufficient controls. Neonatal iron deficiency may disregulate genes early on, perhaps altering disease risk later [16]. Intriguingly, common genetic variants in Alzheimer’s risk genes, including CLU [17], have been shown to alter brain integrity in healthy young adults. Remarkably, brain integrity can even be predicted now by genetic profiling of large numbers of people [18].

Clearly, both iron intake, and genetic variants that affect its availability, affect the brain throughout life. Careful attention to dietary iron levels – and how they interact with our genetic predisposition to regulate iron – may help offset iron’s role in promoting brain degeneration. Tests of gene-by-environment interactions for these risk factors, perhaps in larger neuroimaging studies, will shed light on these hypotheses.

Iron-rich foods for thought

Several iron-rich foods, such as spinach, breakfast cereals and fish, may offer sufficient iron for the brain, as well as other nutritional benefits. Folate and omega-3 fatty acids, also present in these foods, have been associated with benefits to the brain and cognitive function, in some but not all studies. Folate, a B vitamin found in high concentrations in spinach and breakfast cereals, can reduce homocysteine levels; those with high homocysteine levels showed reduced brain volumes, in a study of elderly individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) [19]. B vitamin supplementation does reduce homocysteine levels in patients with AD, but does not change the rates of cognitive decline [20]. Perhaps this underscores the need for adequate nutrition earlier, before the onset of disease. Additionally, fish consumption is associated with the preservation of brain structure, but healthy dietary factors are hard to isolate in observational studies, as healthy diet tends to be correlated with other health-promoting behaviors. Dietary supplements, in particular, are best taken with medical supervision. Even so, it is plausible that regular consumption of iron-rich foods, starting in childhood, may help to promote a healthy lifestyle and provide nutritional and cognitive benefits beyond those of iron alone.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.