Researchers have discovered that a rare mutation inherited with the APOE4 gene variant protects against Alzheimer's, shedding new light on ways to counteract high-risk genes for the disease, according to a news release.
Nearly 30 years after the discovery of the first gene linked to the development of Alzheimer’s disease, scientists still don’t understand why some people who inherit high-risk genes go on to develop memory loss, confusion and cognitive decline, while others don’t.
Now, through analysis of massive genetic datasets, an international collaboration led by Michael Greicius, MD, Professor of Neurology at Stanford Medicine, has found a rare mutation that protects against Alzheimer’s in individuals who are genetically predisposed to the disease. Called the R251G variant, this mutation changes one amino acid (proteins are essentially long chains of varying amino acids) of a protein known as apolipoprotein E, or APOE.
“Our group has been interested in the genetics of APOE for a long time,” said Greicius, the Iqbal Farrukh and Asad Jamal Professor and senior author of the research, published in JAMA Neurology. How this gene works in Alzheimer’s is complex, Greicius said, because APOE codes for a protein that does many different things, including transporting fats and cholesterol in the blood and binding to neurons in the brain.
While the newly discovered mutation is rare — found in fewer than 1 in 1,000 individuals — its protective qualities could help researchers untangle a question that’s been plaguing them for decades: Why do certain variants of the APOE gene increase a person’s risk for developing Alzheimer’s as much as 10-fold, and how could new treatments reduce that risk?
Alzheimer’s disease is divided into two categories: late-onset, which strikes after age 65 and is the most common form of the disease, and early-onset, which can affect patients as early as the mid-30s. (Early-onset Alzheimer’s accounts for less than 5-10% of cases.) Unlike the early-onset form, which is determined almost entirely by genetics, late-onset Alzheimer’s is caused by a variety of genetic, environmental and other unknown factors.
The strongest genetic determinant of a person's risk for late-onset Alzheimer's is the APOE gene variant. Just like with other genes, every person inherits two copies of the APOE gene. There are three common variants of APOE, each carrying different levels of risk for developing Alzheimer's disease.
The most common variant, called APOE3, neither increases nor decreases one's chance for Alzheimer's. APOE2 is protective, and APOE4 carries an elevated risk for disease development. About 25% of people with European ancestry have one copy of APOE4, which more than doubles their chances of developing late-onset Alzheimer's. Another 2% to 3% of people have two copies of the variant, which renders them 8 to 10 times more likely to get the disease.
That’s what makes the discovery of this mutation so exciting. Although the R251G mutation is rare, it’s co-inherited with the high-risk APOE4 variant, meaning that every person with a copy of the R251G mutation also has a copy of the APOE4 variant. But unlike most people with APOE4, these individuals have no increased risk of developing Alzheimer’s: The single amino acid change caused by R251G neutralizes the risk normally caused by APOE4.
“Identifying genetic variants counterbalancing the risk of APOE4 may shed new light on its role in Alzheimer’s disease development,” said Stanford neurology researcher Yann Le Guen, PhD, who shares lead authorship of the paper with Stanford neurology researcher Michael Belloy, PhD. “This finding could help develop new drugs mimicking the effect of the protective genetic variant to reduce the risk of disease.”
