Tag Archives: metals

Genetic Evidence Suggests Iron is Linked to Alzheimer’s Disease

According to a recent study, people with a rare variant in the HFE gene are three times less likely to develop dementia than the general population.

You’ve probably heard that consuming enough iron is important for overall health. However, too much iron can also be a bad thing. In particular, people with Alzheimer’s disease often have abnormally high levels of iron in their brains. (See The Role of Metals in Alzheimer’s Disease). The question of whether iron is a cause or consequence in Alzheimer’s still remains unanswered.

In a paper published this week in PLoS One, a group of Italian researchers investigated whether the genes that control levels of iron in the body could be related to the risk of dementia. They recruited 765 subjects who had Alzheimer’s disease, vascular dementia, or mild cognitive impairment, as well as 1,086 healthy controls of a similar age. Then they took DNA samples from the subjects and looked at four different genes that are involved in iron metabolism.

They found that one gene called High Ferrum (HFE), which is responsible for controlling absorption of iron from the blood, was protective against dementia. Specifically, subjects who had a particular variant of the HFE gene were one-third as likely to develop Alzheimer’s disease or vascular dementia compared to subjects who didn’t have the protective variant. The effect was even stronger for mild cognitive impairment, which the HFE variant reduced the risk to only one-fifth.

The researchers then looked at another gene called APOE, which has previously been shown to be involved in Alzheimer’s disease. People with the APOE4 variant of this gene were more than four times as likely to have Alzheimer’s. However, in subjects who also possessed the protective HFE variant, the impact of APOE4 was completely attenuated, and their risk of Alzheimer’s was normal.

How could the HFE gene protect people from dementia? One possibility, known as the metal hypothesis of Alzheimer’s disease, suggests that iron makes amyloid-beta plaques more toxic. Amyloid-beta, a protein that accumulates in Alzheimer’s patients’ brains, can interact with various metal ions to become extra toxic. Normally metals are blocked from entering the brain by the blood-brain barrier, but this barrier tends to become leaky in older people. Thus the hypothesis suggests that influx of iron and other metals into the brain may cause amyloid-beta to aggregate and become more toxic, thus contributing to the development of Alzheimer’s.


The metal hypothesis suggests that the toxicity of beta-amyloid could be increased when it binds to metal ions. Image Source

However, the metal hypothesis can’t entirely explain these recent findings. For one thing, the variants in iron-controlling genes were also protective against vascular dementia, which does not involve amyloid-beta. In addition, the researchers did not observe any differences in blood iron levels based on these genetic variants, so it’s unclear exactly how these genes may be affecting iron metabolism. Future studies are needed to clarify if and how iron could be involved in Alzheimer’s and other types of dementia.


Enjoy this post? Help it to grow by sharing on social media!
Want more? Follow AlzScience via email, Facebook, or Twitter!

The Role of Metals in Alzheimer’s Disease

Small amounts of certain metals, such as zinc, copper, and iron, are necessary for our bodies to function properly. These are referred to as biometals. Other metals like aluminum are not needed for survival but can be tolerated by the body in low doses. However, for reasons that remain unclear, studies have shown that patients with Alzheimer’s disease often have an imbalance of these metal ions in their brains. Abnormally high concentrations of the aforementioned metals have been found inside of amyloid-beta plaques, the toxic protein deposits that are the hallmark of the Alzheimer’s brain [1]. This observation led some scientists to propose the metal theory of Alzheimer’s disease, which suggests that regular exposure to metals can lead to the development of Alzheimer’s [2]. In this article I briefly will evaluate the evidence for and against the metal theory, and describe how it may affect your life.


Aluminum was the first metal that was proposed as a possible cause for Alzheimer’s disease, leading to panic about the aluminum found in soda cans, cookwear, and many processed foods. Back in 1965, researchers showed that rabbits injected with aluminum developed toxic tau fibrils in their brains [3] [4]. Multiple studies have since verified this finding in mice, rats, cats, and monkeys [5].

More than sixty years after the initial experiments, we still have not come to a consensus on whether aluminum exposure can lead to Alzheimer’s. Studies have demonstrated that only levels of aluminum far exceeding those found in the body are capable of promoting amyloid-beta aggregation [6]. In addition, multiple studies have failed to find an association between exposure to aluminum (within normal safety guidelines) and risk of Alzheimer’s. On the other hand, experiments in which rats are chronically exposed to aluminum show accumulation of aluminum in their brains, particularly in the hippocampus (the brain’s memory center). These rats experienced memory impairments as a result of their aluminum exposure [5]. Overall, it’s possible that aluminum contributes in some form to the pathology of Alzheimer’s, but there is not enough evidence to conclude a causative relationship.

Zinc, Copper, and Iron

The biometals zinc, copper, and iron play a variety of important roles in the brain, including cell signaling and neuroplasticity. However, too much of these metals may be harmful for our health. In cell cultures, physiological concentrations of zinc and iron (possibly copper as well, but this is less clear) can promote the formation of amyloid-beta plaques [7]. In addition, all three of these biometals can accelerate the aggregation of tau, another toxic protein found in Alzheimer’s disease. Copper and iron are also believed to contribute to oxidative stress [8]. Oxidative stress is a chemical process involving free oxygen radicals that gradually leads to cell damage and aging; the reason antioxidants are good for you is because they get rid of these free oxygen radicals.

Despite these results, there’s more to the biometals than meets the eye, particularly for zinc. The so-called “zinc paradox” arises from seemingly-contradictory evidence suggesting that zinc can also be neuroprotective in Alzheimer’s disease. When zinc binds to amyloid-beta, it changes the protein’s shape such that its toxicity is reduced. Thus it seems that zinc can stimulate amyloid-beta aggregation but also reduces the toxicity of these aggregates [9]. More research is needed to conclusively determine whether zinc is helpful or harmful in the long-run.

As a rule, most researchers agree that these biometals are likely involved in some way in the pathogenesis of Alzheimer’s disease, but there’s debate on whether they play a directly caustive role. It’s also unclear whether risk can be modulated by dietary or environmental exposure to these metals. For example, certain neurological events (such as a stroke or traumatic brain injury) can increase the levels of metal ions in the brain, so it’s possible that internal rather than external sources are to blame [10].

Other Metals

Though the four metals described above have been the main focus of Alzheimer’s metallobiology research, it’s possible that others could be involved as well. A small number of studies have drawn connections between Alzheimer’s and lead, cobalt, cadmium, and manganese, among others. Though there is not nearly enough evidence to make any definitive claims regarding the involvement of these metals in Alzheimer’s, they raise the possibility that the onset of Alzheimer’s could be exacerbated by chronic exposure to multiple metals simultaneously [11].

Metal Chelators as Alzheimer’s Drugs

If metals are indeed involved in the development of Alzheimer’s, it follows that metal chelators could be useful in the treatment of Alzheimer’s disease. Chelators are compounds that bind to metal ions and help to expel them from the body. Several types of chelators have been tested in animal and human trials for Alzheimer’s. Many of these drugs showed promise, but none have been approved for patient use, most often due to severe side effects. Current research is working to improve these early drugs and make them safer for widespread use [8].

Reducing Exposure to Metals

At present, there simply isn’t enough evidence to conclusively say that exposure to common metals can lead to Alzheimer’s disease. The most likely possibility is that metal exposure alone is not sufficient to cause Alzheimer’s, but it may contribute to disease pathology in combination with other factors including genetics, diet, exercise, and mental stimulation.

However, this does not necessarily mean that we shouldn’t take steps to reduce our exposure to metals. Just because there’s not enough evidence now, doesn’t mean more won’t arise in the future. Reducing daily exposure to metals is simple enough that no harm is done even if they turn out to be innocuous in the end. Here are a few easy tips you can consider [12]:

  • Unless instructed by a doctor, avoid vitamins or supplements contain very high levels of zinc, copper, or iron. Most people who consume a balanced diet have no need for biometal supplements. Shellfish, meats, and nuts are the best dietary sources of biometals. If you do choose to take supplements, do not exceed 100% of the daily recommended value.
  • If your drinking water comes from copper pipes or faucets, run the water for 15-30 seconds each morning before drinking.
  • Reduce your intake of red meat and highly processed foods.
  • The levels of aluminum or copper in cookwear are generally considered safe, but may increase when they are used to cook highly acidic foods (such as spicy foods or tomato sauce). Consider switching to glass or stainless steel.
  • Limit your use of antacids and aspirins that contain aluminum.
  • When baking, use parchment paper instead of foil.
Enjoy this post? Help it to grow by sharing on social media!
Want more? Follow AlzScience via email or like us on Facebook!