Alzheimer's Disease Gene Removed From Human Neurons in Scientific Milestone

Gene therapy could become an option for Alzheimer's patients.

About 5.7 million people in the United States live with Alzheimer’s disease, but doctors have been slow to develop treatments for the neurodegenerative condition. The disease, which has a partially genetic basis, is characterized by a buildup of protein plaques in the brain that kill neurons. A groundbreaking study on the genes that cause those plaques to form, published in Nature Medicine on Monday, shows promising progress toward an effective therapy.

In the paper, researchers showed the results of an experiment in which they successfully neutralized a major genetic risk factor for Alzheimer’s disease in human neurons. Their goal was to get rid of a protein called apolipoprotein E4 (ApoE4), which is known to be involved in plaque formation. So, they took induced pluripotent stem cells that normally carry the gene for ApoE4, then edited that gene so that the cell would express a different, less harmful form of the protein. Their experiment worked, marking a scientific first: It’s a proof of concept that this gene can indeed be manipulated to make for less Alzheimer’s-friendly brain conditions. It’s a minor but significant step toward developing genetic therapies for people whose genes carry this risk factor.

The three images on the left show cultured human neurons that express ApoE4. You can see the greater amount of neurofibrillary tangles in these three images than in the one on the far right, which has been edited to express ApoE3, which is not associated with Alzheimer's.

Wang et al

ApoE4 is considered a risk factor for Alzheimer’s disease because it’s associated with the formation of neurofibrillary tangles, made of phosphorylated tau protein. These, in turn, form the plaques that characterize Alzheimer’s disease (they’re also formed as a result of traumatic brain injury). But for many people who live with Alzheimer’s disease, their condition is at least partially chalked up to a genetic predisposition that’s mediated by ApoE4.

In the experiment, scientists used gene editing to alter the expression of the human neurons to make them create ApoE3 instead of the harmful ApoE4. “Conversion of ApoE4 to ApoE3 by gene editing significantly lowered p-tau levels,” they write. “Our findings in [human induced pluripotent stem cell-derived] neurons provide a proof of concept that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related [Alzheimer’s disease].”

By demonstrating the first instance of genetic editing to lessen the harm of Alzheimer’s pathology, this study provides an important first step toward possible future therapies for people who show a genetic risk for Alzheimer’s disease. Future studies will likely try to pinpoint other genes involved in pathology so that treatment can take a multi-pronged approach.

Knowing what genes are involved with Alzheimer’s pathology opens up avenues for gene therapy, a form of treatment that involves inserting new genetic material into living cells through the use of viruses.

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