Scientists have discovered that a gene-regulating protein that guards the developing brain of a fetus reactivates in old age and may protect against dementia, a finding that could open a new path in Alzheimer’s research.
The research — by Harvard University scientists and published Wednesday in the journal Nature — showed that the protein, called REST, is depleted in brains of people with Alzheimer’s. It was found at a level three times as high in people who didn’t experience dementia even when their brains had markings of the disease. Until now, REST wasn’t known to have a role in the adult brain.
Experimental drugs to reduce proteins such as amyloid or tau — which form the hallmark brain clumps of Alzheimer’s — have failed to stem cognitive decline. The new finding supports the idea that targeting those proteins isn’t enough to halt the disease. It also may explain why some people develop dementia as they age while others live long lives, remaining lucid into their 90s or 100s, said Bruce Yankner, the study’s lead researcher.
“There’s a long-standing puzzle in neurology why a large percentage of the aging population when they die have enough abnormalities in the brain to classify as Alzheimer’s,” though they don’t develop the dementia, said Yankner, a professor of genetics at Harvard Medical School in Boston. “In addition to trying to remove toxic proteins, which many clinical trials do with limited success, we may need to augment the brain’s natural defense.”
Until now, the REST protein was thought to be active only during fetal development and to switch off in the brain after birth. Experiments by Yankner’s team found that the protein suppresses genes involved in cell death and Alzheimer’s progression and turns on those that protect neurons from stress.
More than 5 million Americans have Alzheimer’s disease, the most common type of dementia, and the number is projected to triple by 2050, according to the Alzheimer’s Association. The disease is the sixth-leading cause of death in the United States, according to the Centers for Disease Control and Prevention. A March 6 study published in Neurology found the disease may be underreported as a cause of death and could be the third-leading cause of mortality.
In the Harvard brain-tissue tests, researchers found that the REST protein, mildly detectable in early adulthood, “lit up like stars” in samples from people in their 70s and 80s, Yankner said. The study measured REST in brain samples from adults ages 20 to 35 and 73 to 106.
When researchers examined REST in brain samples from individuals with Alzheimer’s, they found that the protein was almost absent from cells of the prefrontal cortex and hippocampus, regions of the brain critical for such functions as memory, concentration and decision-making.