Gene Editing Suggested as a Potential Solution to Alzheimer’s Disease Through Rare Mutation Discovery

Potentially preventing or delaying the onset of Alzheimer’s disease by suppressing a gene variation associated with increased risk.

The apolipoprotein E (APOE) gene is responsible for producing a protein that aids in transporting cholesterol around the body, and it comes in three different forms. The most significant genetic risk factor for Alzheimer’s disease is a variation called APOE4.

Having a single copy of the APOE4 gene (one from each parent) increases the risk of acquiring Alzheimer’s disease by more than twofold, and having two copies of the gene (one from each parent) increases the risk by eight to tenfold.

Many people who carry two alleles of APOE4 have a really high likelihood of having Alzheimer’s disease by the time they reach their 80s, according to research by Tara Spires-Jones of the University of Edinburgh, UK. Two copies of APOE4 are present in about 2% of the population.

Researchers have pondered the possibility of altering APOE4 genetically to determine if doing so lessens the likelihood of developing Alzheimer’s disease. However, due to the important role played by the protein encoded by this gene (apolipoprotein E), it is probably not safe to entirely disable it. Spires-Jones explains that its significance lies in its ability to transport cholesterol to the brain’s neurons. “Knocking down APOE could mean less risk of Alzheimer’s, but you might affect your heart or blood vessels.”

According to Joachim Herz of the University of Texas Southwestern Medical Centre, the mechanism by which APOE4 raises Alzheimer’s risk remains unknown. He speculates that this is because the APOE4 variation causes the protein to behave erratically or produce a less functioning form of itself.

In order to better understand the potential consequences of altering APOE4 in humans through genetic engineering, researchers Michael Greicius at Stanford University in California and his colleagues have scoured data from people with so-called loss-of-function mutations to APOE4 genes. According to Herz, APOE genes with a loss of function are exceedingly rare.

Two older adults were identified to have at least one of these APOE4 loss-of-function genes when the team investigated the Alzheimer’s Disease Sequencing Project database, which contains information on more than 36,000 people whose entire genomes have been sequenced.

They were both adults, but while one was judged cognitively normal at age 79 and the other died at over 90, there were no evidence of a protein called amyloid in the brain of the latter.

This protective effect from an incorrectly functioning gene supports the theory put forth by Greicius and coworkers that APOE4 raises the chance of developing Alzheimer’s disease by causing the related protein to behave abnormally.

A loss-of-function gene mutation may have raised the risk of Alzheimer’s disease if it caused the APOE4 gene to create a protein with diminished function. According to Herz, “loss-of-function APOE is advantageous” and the article supports this idea.

According to Greicius and coworkers, this represents the first human genetic data suggesting that targeting APOE4 may be an effective strategy for treating or preventing Alzheimer’s disease.

However, Herz cautions that the study’s results should be interpreted with caution because of the tiny sample size.

FAQs

Q1: What is the APOE4 gene, and how is it related to Alzheimer’s disease?

A1: The APOE4 gene variant is a significant genetic risk factor for Alzheimer’s disease, increasing the risk of developing the condition.

Q2: How does having one or two copies of the APOE4 gene affect Alzheimer’s risk?

A2: Having one copy increases the risk by more than twofold, while having two copies increases the risk by eight to tenfold.

Q3: Can the APOE4 gene be altered to reduce Alzheimer’s risk?

A3: Researchers are exploring the possibility, but due to the gene’s role in transporting cholesterol to the brain, complete disabling may have adverse effects.

Q4: Why is APOE4 significant in Alzheimer’s research?

A4: It is believed that APOE4 causes the related protein to behave abnormally, contributing to Alzheimer’s risk.

Q5: What recent discovery suggests a potential strategy for treating Alzheimer’s disease?

A5: Rare loss-of-function mutations in APOE4 genes found in older adults suggest that targeting APOE4 may be a viable approach to treating or preventing Alzheimer’s disease.