The story of APOE in Alzheimer’s and other diseases

This article is the third in my series on Alzheimer’s disease. Read more about Alzheimer’s disease at Part 1 And the Part 2 from the series.

Alzheimer’s disease is a serious disease that affects approximately 6 million people in the United States. Interestingly, some people have a much higher chance of developing Alzheimer’s disease than others, especially as they age. The main risk factor for Alzheimer’s disease is based on a single gene called apolipoprotein E (APOE). By having two copies of a particular APOE variant called APOE4, you become twenty times more likely to get the disease. Although APOE4 is not the only genetic cause of Alzheimer’s disease, it is the most prevalent. For this reason, APOE requires some special attention to what it is and how it works.

Housekeeping Jobs for APOE


APOE proteins are an essential component of our bodies’ ability to process fats/fats. APOE proteins collect fats circulating in the body and help distribute them through cells. In the brain, APOE is produced by cells called astrocytes. Astrocytes are one of the most abundant cells in the brain and play a supporting role for neurons and their signaling. When APOE proteins are formed in the brain, they collect various body fats to form lipid complexes. Next, the APOE proteins bind to the receptors on the surface of the cells. This allows the cells to ingest the floating fats and use them to make structural components of the cells or to store them as free energy.


One of the secondary responsibilities of APOE is that it helps the body process and distribute cholesterol. Much like how protein distributes fat to cells, APOE is also responsible for collecting and distributing floating cholesterol among cells in the body. Cholesterol is an essential component of cell membranes and can help cells produce hormones in the body. It is also a major determinant of heart disease.


While processing lipids and cholesterol are very important functions of APOE, studies have indicated that APOE may play an important role in regulating inflammation as well. Recent research indicates that APOE regulates one of the primary inflammatory pathways in the brain – the classic complement cascade – by binding to a protein complex called C1q.

When the classical complement cascade is activated, a series of proteins including C1q begin to bind/interact with each other. This activity sends a signal to distant inflammatory immune cells and communicates with the site of infection. While sending a signal to distant immune cells, proteins in the classical complement cascade will simultaneously tag or label infected cells to be eliminated by the immune cells. Once inflammatory immune cells are recruited to the site of infection, immune cells take over and eliminate any of the infected cells that have been marked by complementary cascade proteins. By binding to the C1q complement chain, APOE can effectively stop inflammatory reactions in the brain.

Variations in the APOE gene

APOE may play an essential role in the body, but what does it have to do with Alzheimer’s disease? There are three known types of the APOE gene: APOE2, APOE3, and APOE4. Each of these variants has its own important physiological consequences for whoever carries it. This is especially important for those who have two copies of the same variable.


Currently, the APOE4 variant is the largest known risk factor for Alzheimer’s disease. Those who have only one copy of the APOE4 variant are three times more likely to develop Alzheimer’s disease during old age.

This risk is significantly increased for those with two copies of the APOE4 variant. As mentioned, those with two copies of the APOE4 variant are twenty times more likely to develop Alzheimer’s disease. Having two copies of the APOE4 variant also increases the risk of early Alzheimer’s disease. Early Alzheimer’s disease affects people between the ages of 30 and 60.


The APOE3 variant is the most common version of the gene and is considered neutral. The APOE3 variant was not associated with any risk of disease.


APOE2 is the rarest variant and its physiological consequences are somewhat unknown. Interestingly, studies have indicated that APOE2 may play a protective role against Alzheimer’s disease. There is evidence to suggest that having a single copy of the APOE2 gene can reduce the risk of Alzheimer’s disease. Other studies have found that APOE2 is associated with a higher risk of diseases such as type 2 diabetes and psoriasis.

The evolutionary origins of APOE variants

Where did these variables come from? About 7.5 million years ago, humans and primates split into two unique species. The APOE4 variant was one of the first APOE variants found in the human line but not in primates. Over the next hundred thousand years, the APOE gene continued to mutate and create the other two major APOE variants present in the modern era.

These mutations began approximately 220,000 years ago. The APOE4 variant underwent a single amino acid substitution mutation. The building blocks of proteins in the body are amino acids. When one amino acid is changed, it can affect the overall function and structure of the protein. For APOE4, an uncharged amino acid cysteine ​​was replaced by a positively charged amino acid arginine. This led to major physical changes and later formed the APOE3 variant.

After 140,000 years, the APOE3 variant underwent an additional amino acid substitution mutation. This mutation involved replacing a different positively charged amino acid arginine with a neutral, uncharged amino acid cysteine. This additional mutation led to the APOE2 variant of the gene.

Physiological consequences of APOE variants across the population

Although scientists have demonstrated that different APOE variants can increase or decrease the risk of certain diseases, it is important to note that none of the APOE variants are associated with the onset of Alzheimer’s disease 100% of the time. This means that while the APOE4 variant significantly increases the risk of Alzheimer’s disease, not everyone who has one or two copies of the APOE4 variant will develop Alzheimer’s disease. In fact, among those who have two copies of the APOE4 variant, 40% show no symptoms of Alzheimer’s disease at all.

This observation is particularly true across different populations. For example, while the Nigerian population has the highest proportion of individuals with the APOE4 variant, it has one of the lowest incidences of Alzheimer’s disease.

This indicates that there are many other genetic or biological factors that play a role in determining whether an individual has Alzheimer’s disease.

Final comments

While none of the APOE variants are 100% associated with Alzheimer’s disease, if your family members have Alzheimer’s disease, it is recommended that you undergo genetic testing to understand your APOE profile. Genetic testing is relatively simple and can be done with a simple blood or saliva test. Then DNA is isolated from these samples and specific genes can be detected within the DNA.

There is more research to be done on APOE variants and how they affect the onset of Alzheimer’s disease. Fortunately, the basic knowledge and science that exists today allow us to understand the risks of developing Alzheimer’s disease and hopefully prepare for the future.

Leave a Comment