Like the troublesome plaques and tangles of the demented brain, Alzheimer’s disease presents a knotted conundrum only now unravelling at the hands of science.

The memory and cognitive problems brought by Alzheimer’s and similar diseases may come as the result of a breakdown in the brain’s stress response system, which normally protects the aging brain from such wasting. Li-Huei Tsai, director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, praised the Harvard study as groundbreaking in a commentary published with the study in the journal Nature.

“This is an extremely important study,” Li-Huei Tsai said in a statement. “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 other people.”

In the study, Harvard researchers focused on a protein previously implicated in brain development during the fetal stage, finding that it also conferred protection from aging-related stresses in older people. But among patients with Alzheimer’s and similar dementias, the protein is nearly AWOL from key regions of the brain.

Study leader Bruce Yankner, a professor of genetics at Harvard Medical School says the new evidence — if validated — “opens up a new area in terms of treatment possibilities” for the five million Americans living with Alzheimer’s disease. “Our work raises the possibility that the abnormal protein aggregates associated with Alzheimer’s and other neurodegenerative diseases may not be sufficient to cause dementia,” he said in a statement. “You may also need a failure of the brain’s stress response system.”

Known as REST, the protein is active during fetal brain development but lies dormant until later in life, when called to duty to protect an aging brain. In lab experiments analyzing brain tissue from elderly patients, REST levels showed decline in the brains of those suffering mild cognitive impairment, but were nearly depleted in the key brain regions of those with Alzheimer’s.

"REST loss correlates very closely with memory loss, especially episodic or autobiographical memory, the type that typically declines early in Alzheimer's," Yankner said.

In such patients, REST is activated but then diverted away from its nuclear target in the brain, eventually engulfed and then destroyed in a process called autophagy. "The prevention of REST from getting to the nucleus may be the earliest phase in the loss of REST function,” Yankner said. “Our laboratory models suggest that this will make neurons much more vulnerable to a variety of stresses and toxic proteins.”

As for possible drug treatments, Yankner says lithium has been shown in the lab to boost REST functioning.

 

Source: Yankner BA, Lu T, Aron L, et al. Rest And Stress Resistance In Aging And Alzheimer’s Disease. Nature. 2014.