Reimagining Alzheimer’s (Part 8): APOE4 Removal Reduces Symptoms Of Alzheimer’s Disease

This article is the eighth installment in my series on Alzheimer’s disease. Read more about Alzheimer’s disease in part 1, part 2, part 3, part 4 , part 5, part 6, and part 7 of the series.

If you are a person who has inherited the APOE4 gene, new research in mice suggests that knocking out the APOE4 gene dramatically reduces the incidence of Alzheimer’s disease. The E4 variant of the APOE gene has proven to be the strongest known genetic risk factor for Alzheimer’s.

The study, published in Nature Aging, shows that when the APOE4 gene is knocked out in mice, typical Alzheimer’s disease symptoms are significantly reduced. The study provides a ray of hope that similar knockouts may eventually be achievable in humans. That day may come sooner than later with the advent of new gene editing technologies.

What symptoms did Koutsodendris et al. study? A primary characteristic of Alzheimer’s disease is the development of abnormal proteins called tau tangles. Tau tangles are linked to brain cell death and severe cognitive decline in Alzheimer’s patients.

Other symptoms of Alzheimer’s include inflammation in the brain gliosis which affects glial brain cells. Glial cells are responsible for providing neurons with support and act as immune cells in the brain. Gliosis occurs when the body creates significantly higher quantities of glial cells or abnormally large glial cells.

Now, Koutsodendris et al. have determined how APOE4 contributes to tau tangles, neuroinflammation, and gliosis among several other features of Alzheimer’s disease.

To do so, the researchers used gene-edited mice. In mouse models, researchers can emulate the features of human disease by replacing genes found in mice with equivalent genes found in humans. To determine how the E4 variant of the APOE gene impacts Alzheimer’s disease, Koutsodendris et al. were tasked with creating a line of mice that contained the human APOE gene.

To create their line of mice, Koutsodendris et al. replaced the mouse Apoe gene with the human APOE version. Each mouse either received two copies of the E3 variant or two copies of the high-risk E4 variant. The team also created a subset of each group of mice that did not produce APOE in neurons but could produce APOE in other cells. This would help Koutsodendris et al. determine the effects of removing APOE3 or APOE4 from the neurons.

The APOE mice were then crossbred with mice that contained a gene called MAPT. The presence of MAPT allows mice to develop tau tangles. The final APOE/MAPT mice contained both the human APOE gene and could develop tau tangles characteristic of Alzheimer’s disease in humans.

After creating their gene-edited mice, the researchers could begin exploring whether or not removing APOE4 from neurons impacts Alzheimer’s disease symptoms.

Koutsodendris et al. waited until the mice had aged before quantifying the levels of tau tangles in their brains. To do so, the researchers exposed the brain to a substance that stains tau tangles. This way, they could easily visualize the number of tangles in each mouse’s brain.

They soon found that E4 mice contain a significantly greater number of tau tangles than mice with the E3 variant. This proved that the team’s mouse model could accurately replicate the relationship between the E4 genetic risk factor and Alzheimer’s symptoms in humans.

Koutsodendris et al. also found that E4 mice with APOE4 removed from the neurons exhibit 80% fewer tau tangles than E4 mice with APOE4 protein in their neurons. This indicates that the removal of APOE4 in the neurons reduces the level of tau tangles in the brain dramatically.

While these results were optimistic, they did not account for a key characteristic of tau tangles—the tangles often migrate, promoting other tau proteins to tangle and aggregate.

To test whether removing APOE4 in neurons could hinder the migration of tau tangles throughout the brain, Koutsodendris et al. conducted a second experiment. This time they injected tau protein into a small region of the brain. After some time, they used the same staining technique to determine whether tau tangles could form and propagate to other regions of the brain.

The study found that mice with APOE4 removed from their neurons exhibit significantly less tau tangle migration compared to other E4 groups of mice. These results indicate that by removing APOE4 from the neurons, both the occurrence and migration of tau tangles are significantly reduced.

What about other symptoms of Alzheimer’s disease?

To determine whether removing APOE4 from neurons decreased neuronal death, Koutsodendris et al. measured the volume of each mouse’s brain over time. Mice whose brains decreased in volume indicated greater neuronal death than mice whose brains stayed the same volume throughout the experiment.

The experiment showed that neuronal death is significantly reduced in APOE4 knock-out mice. In contrast, mice with APOE3 removed did not experience a significant reduction in neurons compared to their control.

Additional experiments determined that the removal of APOE4 from neurons also positively impacts several other features of Alzheimer’s disease by reducing gliosis, improving the health of glial cells, and improving communication between neurons themselves.

What do these results mean? These remarkable results indicate that the removal of APOE4 could improve the biological symptoms of Alzheimer’s disease. Given the success of these experiments, there may also be a reason to suspect that the removal of APOE4 might protect the brain from cognitive decline.

The significant progress demonstrated by this paper not only supports the relationship between APOE4 and Alzheimer’s pathogenesis but offers a potential route for treatment. With CRISPR and other novel gene-editing technologies, it will be interesting to see whether gene-editing and the removal of APOE4 in humans eventually emerge as a potential treatment for Alzheimer’s disease.