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Learning More About APOE4 and Alzheimer's Disease

Researchers from the Massachusetts Institute of Technology have started in-depth research of APOE4, a variant of the APOE gene.

APOE is a gene that provides instruction to produce the protein apolipoprotein E. The apolipoprotein combines with fats found in the body to create molecules known as lipoproteins. These molecules carry fats, cholesterol and other lipids through the body via the bloodstream.

The presence of APOE 4 increases the risk of early-onset Alzheimer's disease. Individuals can have no APOE4 variants or have one or two of the genetic variants. Having more APOE4 variants raises the risk of developing the disease.

Variants of APOE are found in over 50 percent of the population and are common among people living with Alzheimer's disease.

There are at least three variants of APOE. They are known as APOE2, APOE3 and APOE4.

Individuals with APOE4 are three times more likely to develop Alzheimer's disease than individuals without the variant.

APOE4 has been found to increase the development of beta-amyloid proteins, which cause the development of brain plaques.

Brain plaques are clusters of sticky chemical proteins that build up between nerve cells, blocking signals from passing from nerve to nerve.

The MIT researchers found that APOE4 has a significant influence on every cell type they studied involved in the pathology of Alzheimer's disease.

APOE4 had a notable influence in the development of amyloids.

To realize the influence of the APOE4 variant, the researchers used induced pluripotent stem cells, also known as iPSCs, and coaxed them into developing into different cell types found in the brain, such as neurons and astrocytes. IPSCs are stem cells that can be reprogrammed back to an embryonic-like state and then develop into many different types of cells.

"Induced pluripotent stem cells can develop into a wide range of cells," said Dr. Bill Johnson, a Dallas, Texas, stem cell physician.

After inducing the iPSCs into the different cell types, the study authors used the CRISPR/Cas9 gene editing tool to change the APOE3 variants found in the cells to APOE4.

In the created neurons, those cells that expressed APOE3 and APOE4 varied significantly in the expression of genes: 250 genes went down in rates of expression while 190 genes went up in the cells with APOE4.

In the astrocytes, the changes in gene expression were higher. In microglia, another type of cell created from the iPSCs by the MIT scientists, 1,100 genes showed reduced expression and 300 genes showed increased expression.

Neurons with the APOE4 variant developed more synapses, the junction between cells in which impulses pass. These cells also emitted more amyloid protein than neurons without the APOE4 variant.

APOE4 astrocytes also showed higher production of cholesterol than astrocytes with the APOE3 variant. These cells also had subdued ability to remove amyloid proteins from their environment compared to APOE3-containing cells.

The researchers also found that the microglia cells they created with the APOE4 gene were slow to remove amyloid proteins and pathogens such as viruses and bacteria compared to microglia with APOE3.

The researchers found in their study that the adverse effects of converting cells to the APOE4 gene could be reversed in brain cells created from iPSCS taken from a patient with late-onset Alzheimer's disease.

During the study, the MIT researchers also created 3D organoids from cells containing the APOE variants known to trigger early-onset Alzheimer's disease. These organoids contained high levels of amyloid aggregates.

After exposing the organoids to APOE3 microglia, many of the amyloid aggregates were cleared.

The MIT researchers hope their efforts will eventually develop into new therapies and intervention for individuals at risk of developing Alzheimer's disease.

According to the Alzheimer's Association, nearly 5.7 million Americans are living with Alzheimer's disease as of 2018. Eight percent of this number have APOE2, and 78 percent have APOE3. Fourteen percent of those living with Alzheimer's disease have APOE4.


Alz.org. 2018 Alzheimer's Disease Facts and Figures

R&D Magazine. New Study Sheds Light on Gene Linked to Alzheimer's. 1 June 2018.

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