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Study of mouse neurons uncovers novel therapeutic role of removing a genetic variant in the treatment of Alzheimer’s disease

Removing a genetic risk factor from neurons reduces pathological hallmarks of Alzheimer’s disease in mice, according to an NIA-funded study. The results, published in Nature Aging, suggest that the activity of the APOE ε4 gene in neurons promotes the development of Alzheimer’s.

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Certain genes can increase the risk of developing dementia, including Alzheimer’s. One well-known gene that influences Alzheimer’s risk is the apolipoprotein E (APOE) gene. APOE comes in several forms, called alleles. The APOE ε4 allele is known as the strongest genetic risk factor for Alzheimer’s, but how it increases a person’s risk for the disease is not well understood. Some studies suggest that the activity of APOE ε4 in astrocytes, a type of glial cell, plays a role in harming the brain.

In this study, a research team from the Gladstone Institutes investigated the gene’s activity in neurons, the cells that send signals throughout the nervous system. Using genetic engineering, the scientists removed the APOE ε4 gene from the neurons of mice that already carried a disease-causing variant in tau, a protein that often forms damaging tangles in the brains of people with Alzheimer’s.

Removing the APOE ε4 gene from neurons reversed much of the damage seen normally in the brains of mice with the pathological tau variant. For example, removal of the neuronal APOE ε4 gene reduced cell death and the spread of tangles in the hippocampus, a brain region that is often damaged by Alzheimer’s. The disease also involves the loss of myelin, the insulation around nerves that helps them send signals to each other. Neuronal loss of APOE ε4 increased the presence of protective, myelinating cells to levels seen in brains of healthy control mice.

Likewise, removing neuronal APOE ε4 reduced the appearance of “reactive” glial cells to levels seen in the brains of control mice. In a healthy brain, one role of glial cells is to support neurons. In Alzheimer’s, these cells can become unhealthy and reactive, which contribute to neurodegeneration.

The researchers observed a similar trend when they analyzed the genetic activity of disease-associated brain cell populations. They found that removing the APOE ε4 gene in neurons shifted the genetic activity of several brain cell types, from a damaging to a protective state.

This study provides new insights into potential therapeutic targets for APOE ε4-related Alzheimer’s and helps illustrate how APOE ε4 is involved in many of the characteristics of the disease. More research is needed to better understand APOE ε4’s role in Alzheimer’s.

This research was supported in part by NIA grants R01AG071697, P01AG073082, R01AG061150, F31AG074672, and F31AG074690.

These activities relate to NIH’s Alzheimer’s and Related Dementias Research Implementation Milestone 2.E, “Create cross-disciplinary research programs aimed at understanding the integrative physiology of APOE and its pharmacogenetic effects on various pharmacological and non-pharmacological interventions.”

Reference: Koutsodendris N, et al. Neuronal APOE Ε4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nature Aging. 2023;3:275-296.

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