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A rare mutation protects against Alzheimer's disease, Stanford-led research finds

Michael Greicius headshot

By Hadley Leggett

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 May 31. 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?