The Role of Iron in Alzheimer’s Disease

Iron-induced brain inflammation may be implicated in Alzheimer’s disease
Michael Zeineh, Ph.D., M.D.

Stanford University School of Medicine, Stanford, CA

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2015, for 3 years

Funding Amount:


Lay Summary

Iron-induced brain inflammation may be implicated in Alzheimer’s disease

Might inflammation arising from iron that is converted into an active state in the brain be the third leg of the Alzheimer’s disease (AD) stool, joining the abnormal proteins “amyloid” and “tau” as the hallmarks of AD? Stanford investigators will use a combination of imaging techniques in preliminary steps to answering this question.

AD is characterized by abnormal accumulations of the protein called “amyloid” that builds up in spaces between brain cells, and by tangles within brain cells that consist of an abnormal form of the protein called “tau.” Together, these protein abnormalities eventually block brain cell communication. Cells degenerate and die. What has been elusive is exactly how cells and their communication connections (synapses) are destroyed. Increasingly, research has focused on the role in the brain that inflammation may play. Studies show that the amyloid protein can convert inactive iron in the brain into an active free-radical form that drives brain inflammation. Additionally, immune system microglial cells are located in areas of brain cell degeneration, especially in the “perforant” pathway that connects the whole brain with the hippocampus, which is involved in cognition including memory. This pathway’s degeneration is thought to be the earliest stage of AD, related to the loss of the memory that typically occurs in early AD.

Building on these findings, the Stanford radiologists imaged autopsied hippocampal tissue. They compared tissue from those who had AD prior to death to tissue from those who had not. They found activated iron in microglial cells only in the tissue samples from those with AD. This finding has led the Stanford investigators to hypothesize that inflammation that is associated with iron-laden microglial cells produces destruction of brain cells in AD, in synergy with amyloid and tau; and, that this degenerative process can be visualized using powerful 7T-MRI imaging.
They will test this hypothesis in autopsied AD brain tissue. First, they will quantify the amount of inflammation-inducing iron versus inactive iron in the hippocampus, using 7T-MRI microscopy combined with electron microscopy. They anticipate that about 50 percent of the iron will be in the activated state, supporting an inflammatory role for iron. Second, they will determine whether iron-containing microglial cells are located in the performant pathway (the earliest site of neurodegeneration in AD) using both MRI and a technique called CLARITY that shows proteins (such as amyloid and tau). They anticipate that in AD tissues, compared to unaffected tissues, there will be fewer nerve fibers in the perforant pathway and a greater concentration of iron, suggesting iron as a causal factor in neuron destruction. Thereafter, they will translate this tissue imaging methodology into 7T-MRI scanners that can be used to scan patients.

If these brain tissue MRI imaging techniques indicate that iron has a major role in triggering AD degeneration and if these techniques can be translated into human imaging, this research will take science a step closer to determining how AD neurodegeneration occurs.

Investigator Biographies

Michael Zeineh, Ph.D., M.D.

Dr. Michael Zeineh received a B.S. in Biology at Caltech in 1995 and obtained his M.D.-Ph.D. from UCLA in 2003. After internship also at UCLA, he went on to radiology residency and neuroradiology fellowship both at Stanford. He has been an assistant professor of radiology since 2010. Combining clinical acumen in neuroradiology with advanced MRI acquisition and image processing as well as histologic validation, Dr. Zeineh hopes to advance the care of patients with neurodegenerative disorders.