Harvard researchers have found evidence that Alzheimer’s disease, long known for the toxic clumps and tangles that build up in the brain, may also be caused by the failure of a natural system that protects brain cells.
The protein deposits that are hallmarks of Alzheimer’s disease have turned out to be puzzlingly unreliable, suggesting the devastating illness might have additional causes. Studies have found the protein clumps clogging the brains of some people with no cognitive impairment.
In the new study, published Wednesday in the journal Nature, scientists identified a protein called REST that flips genes on and off and naturally increases during aging. REST, they found, represses genes involved in Alzheimer’s disease, and its levels are reduced in key brain areas of people diagnosed with Alzheimer’s or the mild cognitive impairment that precedes dementia.
In laboratory tests, REST protected brain cells from dying when exposed to a number of stresses, including the beta amyloid protein that accumulates 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,” said Bruce Yankner, a professor of genetics at Harvard Medical School.
The finding 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.
“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,” Yankner said. “The brain is a pretty tough organ and we should strive to find out what makes it so tough and capitalize on this.”
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.
“One of our concerns is the fact there are 5 million Americans living with Alzheimer’s disease, but we have no treatments to slow, stop, or prevent the disease,” said Dean Hartley, director of science initiatives for the Alzheimer’s Association. “It’s basic research like this that we think will be important not only to understand this disease, but the biggest risk factor for Alzheimer’s is aging—and that’s what intriging” about the new study’s focus.
Yankner did foundational work in the Alzheimer’s field, describing in the 1990s how the protein deposits that form in the brains of Alzheimer’s patients are toxic. In the intervening years, however, he has become broadly interested in what happens to the brain during aging.
It was a search for those changes that led his team to the REST protein. Yankner and colleagues used a computer program to search for genetic switches that might account for the characteristic differences in gene activity between the brains of young adults and older adults. The REST protein leaped out from the data.
Because genetic studies are not feasible in humans, the team created genetically manipulated 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. The scientists also found that among brain cells exposed to a toxin, cells with extra REST were less likely to die.
Next, they created roundworms that lacked proteins that are analogous to REST, and found that the ones lacking the protein were less likely to survive when subjected to an herbicide that causes oxidative stress. That suggested the REST mechanism for protecting brain cells is very basic to survival, because it had been conserved in starkly different species by evolution.
The researchers then analyzed human databases, including a study that has tried to eliminate some of the natural variability in people’s environment by studying clergy who have lived similar lifestyles. Those clergy in the Religious Orders Study had detailed cognitive assessments performed and also donated their brains for study after death.
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 laboratory tests in animals, suggested the protein was helping preserve cognitive abilities.
For years, experimental drugs aimed at the known pathological signs of Alzheimer’s disease have been largely 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 activate it.
Yankner cautioned that no one should try and take lithium to prevent memory loss, but said that it may help guide the development of drugs that can be tested in people. Jeffery Kelly, chairman of molecular medicine at Scripps Research Institute, said that what intrigues him about REST is that it is part of a signaling mechanism in cells that has been thoroughly studied in cancer research, thus it might make drug development quicker.
“What I love about this study, first and foremost, is it’s some good news for Alzheimer’s, and it connects that good news with an immediate therapeutic strategy,” Kelly said. “There aren’t a lot of steps between this” and the development of experimental drugs.
Li-Huei Tsai, director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, who was not involved in the study, said that the work could help fill in many questions about complex neurodegenerative diseases. Perhaps if researchers could understand patient’s natural levels of REST, they could target treatments to people based on whether they had high or low levels of the protein, similarly to how oncologists treating some cancers can tailor treatments based on the genetic cause of the cancer.
“I think this is an amazing, heroic piece of work,” Tsai said. “We always talk about why certain individuals get Alzheimer’s disease, and why some other people don’t. ... But so far nobody can really put a finger on, say, a particular biological pathway and say look, if you have higher activity of this pathway you can be more protected, or vice versa.
The Harvard study, she added, appears to do so.