Harvard scientists may have found an answer to why some people
whose brains collect proteins strongly associated with Alzheimer's
don't get the disease.
It is one of the big scientific mysteries of Alzheimer's disease:
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 by Harvard scientists suggests 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.
"This is an extremely important study," said Li-Huei Tsai,
director of the Picower Institute for Learning and Memory at the
Massachusetts Institute of Technology, who was not involved in the
research but wrote a commentary accompanying the study. "This is the
first study that is really starting to provide a plausible pathway
to explain why some people are more vulnerable to Alzheimer's than
The research, published on Wednesday in the journal Nature,
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.
Experts said if other scientists could replicate and expand upon
the findings, the role of the protein, called REST, could spur
development of new drugs for dementia, which has so far been
virtually impossible to treat. But they cautioned that much more
needed to be determined, including whether the decline of REST was a
cause, or an effect, of brain deterioration, and whether it was
specific enough to neurological diseases that it could lead to
"You're going to see a lot of papers now following up on it,"
said Dr. Eric M. Reiman, executive director of the Banner
Alzheimer's Institute in Phoenix, who was not involved in the study.
"While it's a preliminary finding, it raises an avenue that hasn't
been considered before. And if this provides a handle on which to
understand normal brain aging, that will be great, too."
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.
"Why should a fetal gene be coming on in an aging brain?" he
He hypothesized that it was because in aging, as in birth, brains
encounter great stress, threatening neurons that cannot regenerate
if harmed. His team discovered that REST appears to switch off genes
that promote cell death, protecting neurons from normal aging
processes like energy decrease, inflammation and oxidative stress.
Analyzing brains from brain banks and dementia studies, the
researchers found that brains of 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. …