One variant of the genes is a bigger risk factor for Alzheimer's. It's been a mystery how the genes cause brain damage.
A study has shown that faulty cholesterol processing in the brain can lead to defects in the sheaths that surround nerve fibres. According to preliminary results, these changes could cause deficits in memory and learning. Drugs that restore the brain's cholesterol processing may be able to treat the disease.
Gregory Thatcher is a chemical Biologist at the University of Arizona in Tucson.
Having two copies of APOE4 increases the chance of Alzheimer's by up to 12 times. The link between sticky plaques of amyloid and the brain is partially explained by interactions between the two. The interactions are only part of the story.
In today's Nature, Li-Huei Tsai and her colleagues report that the brain cells known as oligodendrocytes are made to accumulate cholesterol in the wrong places.
The cells are unable to cover nerve fibres in a protective wrapper due to this. The signalling of electrical impulses in the brain stops.
Some of the cells that provide immune protection for the brain have structural support. The new findings add to the mix.
Julia TCW is a neuroscience professor at Boston University in Massachusetts.
Working with MIT computational biologist Manolis Kellis, Tsai and her colleagues started by analyzing gene activity patterns in tissue from the prefrontal cortex, the brain's cognitive centre, of 32 deceased people who had two, one or no copies of ApoE4.
Many systems for metabolizing lipids were found to be abnormal when the researchers looked at brain cells affected by APOE4. There were defects in the way cholesterol was processed.
The team created cultures of human cells. The group found that cells with the ApoE4 variant were more likely to have cholesterol inside. The low amount of cholesterol they expelled made them less skilled at forming myelin sheaths.
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The researchers used the drug cyclodextrin to remove cholesterol. Myelin formation was restored with this help. The researchers found that in mice with two copies of the same drug, cholesterol was flushed out of the brain, and it improved the flow of cholesterol into myelin sheaths.
A person with Alzheimer's who took a similar form of cyclodextrin under a special drug-access programme as reported in 2020 is related to the mouse findings. The company says that the person's cognitive functions remained stable over the course of 18 months.
It might not be a good idea to use cyclodextrin to correct the brain's lipids. Leyla Akay is a co-author of the study. That depletes cholesterol from cells.
Now that the cholesterol dysregulation has been put on the Alzheimer's research map, better therapies could emerge. "This study shows the importance of cholesterol in the brain, and we now need to try all available strategies to target brain cholesterol."
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