Researchers at the University of Colorado Anschutz and Pacific Northwest National Laboratory have found a new clue that may help explain why some people are more likely to develop Alzheimer’s disease. It suggests that a protein linked to the disease can change how the brain’s immune cells handle fat and trigger inflammation. Those changes could help explain how a well-known genetic risk factor for Alzheimer’s affects the brain.
The study was published this week in Alzheimer’s & Dementia.
The gene is called APOE, and one version, APOE4, is the strongest genetic risk factor for Alzheimer’s disease. But having APOE4 does not mean someone will develop Alzheimer’s. Scientists have spent decades trying to understand why.
“Our brains are mostly made of fat. But, because fat can’t get into the brain from the circulation, the brain has to make its own fat. It does this by sending fat carrying particles from one cell to another. This movement of fat around the brain keeps the cells healthy. ApoE acts like a belt holding these particles together. Our findings suggest that the way ApoE4 carries lipids causes cells to hang on to the fat, breaking the fat-cycle and causing cells to become very inflamed,” said Kimberley D. Bruce, PhD, senior author of the study and an associate professor in endocrinology at the CU Anschutz School of Medicine.
The researchers studied microglia, the brain’s immune cells.
“Microglia are so important in the fight against Alzheimer’s disease. Think of these cells like the brain’s cleanup and security crew. They help remove damaged material, watch for problems and respond when something goes wrong. When these cells aren’t able to perform these roles correctly, the brain loses its fight against Alzheimer’s disease,” said Bruce.
The team exposed human microglia to different forms of the ApoE protein. “When microglia were treated with ApoE4, they stored fat differently, developing fewer but larger fat droplets,” said Tsion Shiferaw, M.Sc., research professional at CU Anschutz and first author of the study, “They also had less mitochondria, the parts of cells that help turn fat into energy.”
Another important finding was that the protein’s effects on the cells depended on whether it was carrying fat, or whether it was fat-free. When ApoE4 was carrying fat, it changed how the cells stored and used fat and energy. When it was not carrying fat, it triggered a stronger immune response associated with inflammation. In other words, what the protein was carrying appeared to influence how the brain’s immune cells behaved.
Scientists already know that APOE4 increases a person’s risk of Alzheimer’s. What they don't know as well is how that risk actually plays out inside the brain. This study points to one possible answer.
The way ApoE4 handles fat may help determine whether the brain’s immune cells change how they use energy or become more inflammatory. That matters because inflammation and changes in how brain cells use and store fat have both been linked to Alzheimer’s disease.
The findings could give scientists a new way to study why APOE4 increases Alzheimer’s risk and, eventually, whether those effects can be prevented or changed.
“Our findings suggest that ApoE4 can affect microglia in different ways depending on whether it is carrying fat,” Bruce said. “In the future, we should be thinking about ways to make ApoE4 carry more fat, to preserve the function of these important (microglia) cells. We should also exposure treatments that can block the specific type of inflammation that fat-free ApoE4 seems to trigger, to reduce Alzheimer’s disease risk in people that carry the ApoE4 gene.”
It’s important to note that the study does not show that APOE4 causes Alzheimer’s disease and it does not provide a new treatment.
The researchers studied human brain immune cells in the laboratory. More work is needed to find out whether the same changes happen in people and whether they contribute to the development of Alzheimer’s disease.
Key Points
- APOE4 increases the risk of Alzheimer’s disease, but carrying the gene variant does not mean someone will develop the disease.
- Researchers found that ApoE4 changed how microglia, the brain’s immune cells, stored fat and used energy.
- The protein triggered different cellular effects depending on whether it was carrying fat, including a stronger inflammatory response when it was fat-free.
- The findings suggest new avenues for investigating ways to preserve microglial function and reduce harmful inflammation.
- The study examined human microglia in the laboratory. Further research is needed to determine whether these changes occur in people and contribute to Alzheimer’s disease. The findings do not establish a new treatment.