Iron helps repair myelin damage in the brain, but accumulation of the element with aging may bring on iron toxicity, particularly in the hippocampus, a region affected early in Alzheimer's disease, researchers suggested.
MR imaging showed that Alzheimer's patients had increased levels of ferritin iron and tissue damage in the hippocampus, but not in the thalamus, a region affected only later in the disease, according to George Bartzokis, MD, of the Semel Institute for Neuroscience and Human Behavior at UCLA, and colleagues.
In addition, higher levels of iron in the hippocampus were associated with worse tissue integrity, they reported in the August issue of the Journal of Alzheimer's Disease.
Although iron is critical for cell function, too much can lead to oxidative damage. Levels of iron in the brain increase with age and are "abnormally elevated in gray matter structures in age-related degenerative diseases," researchers noted.
Post-mortem studies have indicated the brain stores more iron as it ages, and imaging studies by Bartzokis and others have shown increased levels of iron in the basal ganglia of patients with Parkinson's, Huntington's, and Alzheimer's.
A study in 2011 showed increased iron in the basal ganglia associated with advanced multiple sclerosis.
But it is the hippocampus -- a region of the brain associated with memory -- that has received the lion's share of attention in Alzheimer's pathology.
So Bartzokis and colleagues decided to see if the hippocampus -- like the basal ganglia in Parkinson's -- exhibited a correlation between increased levels of iron and tissue damage.
Their hunch was correct. The hippocampus exhibited elevated levels of iron and extensive tissue damage, while no such correlation existed the thalamus, which was used as a comparator.
The findings of Bartzokis and colleagues do not prove a causal relationship. That conclusion might come from a prospective study the researchers are currently conducting and whose results should be available next year.
"Our findings suggest that iron deposition and tissue damage are foundational to Alzheimer's," Bartzokis told MedPage Today. "But what is underappreciated is why the iron increases in the first place."
He noted that oligodendrocytes, which use iron to repair myelin throughout one's life, continue to be produced by the brain way into old age. The continual need for myelin repair into old age was not a problem when the average lifespan was around 60, he said.
"But now that people are living longer, the iron needed for cell repair, as well as iron waste byproducts, accumulate to a toxic level, which we have shown correlates with tissue damage in the very regions of the brain that are associated with certain degenerative diseases," Bartzokis said.
The brain has a "tremendous ability to package and repackage iron, which is essentially a way to manage its toxicity," Alan Lerner, MD, of University Hospitals of Case Western University in Cleveland, told MedPage Today.
"The study by Bartzokis and colleagues opens a window into some of the metal chemistry of the brain and its association with degenerative diseases," said Lerner, who was not involved in the study.
For the study, Bartzokis and colleagues recruited 31 patients with Alzheimer's (mean age 75) and 68 healthy controls (mean age 69). The split between men and women was fairly equal in both the study group and controls. Most of the participants were white.
There has been an emphasis within the last decade to focus on beta and tau amyloid, but it is unlikely that these by themselves actually cause the damage seen in Alzheimer's, Bartzokis said.
"Amyloid occurs normally at younger ages but aging is required for the degenerative diseases. Emerging evidence suggests that it is the metals in amyloid that are associated with Alzheimer's," he said.
Now that Bartzokis and colleagues have refined an imaging technique to identify iron in the brain accompanied by tissue damage associated with degenerative diseases, the next step -- after prospective findings -- would be to develop therapies.
"Chelation therapy as it currently exists is quite toxic and not a great idea," Bartzokis said. Instead, he suggested focusing on the phytochemicals in vegetables and fruits, which are not only antioxidants, but also iron chelators.
The study was limited by its cross-sectional design, the small number of Alzheimer's patients, and the lack of information on peripheral factors of iron loss or supplementation.
Might you now think twice about iron supplementation for your older patients? Add Your Knowledge to this topic by clicking the button below. -- Sanjay Gupta, MD
This work was supported in part by the National Institutes of Health and the RCS Alzheimer's Foundation.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner