Alzheimer’s disease (AD) is a progressive neurologic disorder that leads to the death of brain cells. People with this condition usually exhibit mild memory loss, impaired judgment, and vision (spatial) issues during the initial stages, but the symptoms gradually worsen over time.
Eventually, people with AD will lose their ability to carry on a conversation, lose their sense of direction, suffer serious memory impairment, exhibit changes in personality and behavior, and be totally dependent on others for their care. AD usually affects older people (65 years and over), but it can also affect people under age 65.
ApoE4: What Role Does It Play in Alzheimer’s Disease?
Since its discovery in the early 1900s by Dr. Alois Alzheimer (for whom the condition was named), scientists managed to come up with several theories that may explain how and why AD develops, and have concluded that the ApoE gene has something to do with its development.
The ApoE (apolipoprotein) is the gene responsible for transporting cholesterol across different cells and tissues and removing harmful amyloid plaques in the brain. It comes in three versions: ApoE2, ApoE3, and ApoE4.
- ApoE3 is the most common variant of the ApoE gene. It doesn’t seem to have any influence in increasing or reducing the risk of developing the condition.
- ApoE2 is the rarest form of the ApoE gene. Studies indicate that individuals carrying at least one allele of the ApoE2 gene have at least 40% reduced risks of developing AD.
- ApoE4, the version implicated in the development of the disease, is the least effective in removing plaque from the brain and is present in 10% to 15% of the population. Studies indicate that having one copy of the gene increases the risk by 2 to 3 times, while having two copies increases the risk by up to 12 times.
Aside from promoting the formation of amyloid-β in the brain, the presence of ApoE4 protein also leads to the overproduction of tau proteins. Why is this important? It is because the accumulation of tau proteins encourages the formation of clumps of varying sizes which eventually increases the risk of forming tangles and nerve cell degeneration.
A study conducted in the Washington University School of Medicine proved that the presence of ApoE4 increases the amount of tau-induced damage, while the lack thereof seems to have a protective effect against the damage inflicted by tau aggregates. The research also showed that the presence of the ApoE4 gene causes increased inflammation in the brain, which results in the shrinkage of the hippocampus, the area responsible for learning and memory.
Additionally, the presence of ApoE4 genes stimulates the activation of the microglial cells (the primary immune defense system in the central nervous system) which, in turn, activates the astrocyte cells in the brain. Further studies conducted by the same team of experts showed that tau accumulation triggers a strong inflammatory response which, in the presence of the ApoE4 genes, causes significant cell death in the brain.
Just recently, USC researchers discovered another factor that may contribute to the development of AD. Based on their findings, the presence of ApoE4 gene causes severe damage to the pericytes, those multi-functional cells embedded within the walls of the capillaries responsible for blood flow regulation and homeostasis.
When these capillaries are damaged, the blood-brain barrier is seriously compromised and the body is prompted to activate an inflammatory pathway, producing insane amounts of cyclophilin A (an inflammation-causing protein) in the process. This explains why ApoE4 carriers experience more serious leakages in their brain’s blood vessels and develop memory problems earlier compared to those who do not carry the gene.
Interestingly, another research showed that the presence or absence of ApoE4 does not fully determine who gets the disease. In a study conducted at the Baylor College of Medicine in Houston, researchers successfully identified 216 genes that may either increase ApoE2 carriers’ risk of developing AD or protect ApoE4 carriers from developing the disease.
