A protein, normally active in fetuses, may also protect the neurons in older people.

A protein, normally active in fetuses, may also protect the neurons in older people.

Along with symptoms of cognitive decline, Alzheimer’s disease patients often have an accumulation of plaques and tangles of proteins in parts of their brains. But one of the big scientific mysteries of Alzheimer’s disease is: Why do some people whose brains accumulate the plaques and tangles so strongly associated with Alzheimer’s not develop the disease?

Now, a series of studies published on March 19th 2014, in the journal Nature provides new clues that suggest a possible answer, one that could lead to new treatments if confirmed by other research.

The memory and thinking problems of Alzheimer’s disease and other dementias, which affect an estimated seven million Americans, may be related to a failure in the brain’s stress response system, the new research suggests. If this system is working well, it can protect the brain from abnormal Alzheimer’s proteins; if it gets derailed, critical areas of the brain start degenerating.

“It’s an amazing idea that neurons that you’re born with will function for 100 years or more, in a very high-stress situation … until the day a person dies,” said Bruce Yankner, a professor of genetics at Harvard Medical School who led the work. “The brain is a pretty tough organ and we should strive to find out what makes it so tough and capitalize on this.”

The research highlights a different approach to understanding neurodegenerative diseases: instead of focusing on the negative changes that cause disease, researchers looked for lapses in the brain’s protective mechanisms. The study focuses on a protein previously thought to act mostly in the brains of developing fetuses. The scientists found that the protein also appears to protect neurons in healthy older people from aging-related stresses. But in people with Alzheimer’s and other dementias, the protein is sharply depleted in key brain regions.

REST, a regulator that switches off certain genes, is primarily known to keep fetal neurons in an immature state until they develop to perform brain functions, said Dr. Bruce A. Yankner, a professor of genetics at Harvard Medical School and the lead author of the new study. By the time babies are born, REST becomes inactive, he said, except in some areas outside the brain like the colon, where it seems to suppress cancer.

While investigating how different genes in the brain change as people age, Dr. Yankner’s team was startled to find that REST was the most active gene regulator in older brains.

In laboratory tests, REST protected brain cells from dying when exposed to a number of stresses, including the proteins that form the plaque in the brains of Alzheimer’s patients.

“One very positive, optimistic note from this study is that it suggests that dementia can be resisted by some people, and it provides the first molecular inklings of how that might occur,” Yankner said.

Outside scientists said that the study was important and meticulously done, but warned that it is basic research and will need to be repeated. Translation of such insights into experimental treatments that can be tested in patients typically takes years.

Analyzing brains from brain banks and dementia studies, the researchers found that brains of young adults ages 20 to 35 contained little REST, while healthy adults between the ages of 73 and 106 had plenty. REST levels grew the older people got, so long as they did not develop dementia, suggesting that REST is related to longevity.

But in people with Alzheimer’s, mild cognitive impairment, frontotemporal dementia and Lewy body dementia, the brain areas affected by these diseases contained much less REST than healthy brains.

This was true only in people who actually had memory and thinking problems. People who remained cognitively healthy, but whose brains had the same accumulation of amyloid plaques and tau tangles as people with Alzheimer’s, had three times more REST than those suffering Alzheimer’s symptoms. About a third of people who have such plaques will not develop Alzheimer’s symptoms, studies show.

REST levels dropped as symptoms worsened, so people with mild cognitive impairment had more REST than Alzheimer’s patients. And only key brain regions were affected. In Alzheimer’s, REST steeply declined in the prefrontal cortex and hippocampus, areas critical to learning, memory and planning. Other areas of the brain not involved in Alzheimer’s showed no REST drop-off.

Because studies that involve genetic manipulation are not feasible in humans, the team created mice that lacked the REST protein. When the researchers compared month-old mice with and without REST, they had similar numbers of neurons in key brain areas. But by the time they were eight months old, more brain cells had degenerated and been lost in mice lacking the protein than in those with it.

In a follow-up experiment, the scientists found that among brain cells exposed to a toxin, cells that were forced to make higher than normal levels of REST were less likely to die.

The researchers found that higher levels of REST in the prefrontal cortex — a portion of the brain involved in decision-making, planning ahead, and coordinating activities — were correlated with greater ability to remember autobiographical information and events.

In addition, REST levels were significantly higher in study participants who had signs in their brain of Alzheimer’s disease but no recorded memory issues. That, along with the tests in animals, suggested the protein was helping preserve cognitive abilities.

For years, experimental drugs aimed at the pathological signs of Alzheimer’s disease have been ineffective, and Yankner thinks that perhaps this variability in people’s REST levels during aging could help explain those results. His team found that REST appears to be activated in response to stress, but further work needs to be done to understand precisely why some people have higher REST levels during aging and some do not.

Already, his group is searching for experimental drugs that can turn up REST levels, and he said one intriguing finding so far is that an approved drug, lithium, appears to increase REST production.

Yankner cautioned that no one should take lithium to prevent memory loss, but said that the drug might serve as a prototype in the development of drugs that can be tested in people.

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