Fetal-brain protein reactivates in old age to fight dementia

Scientists have discovered that a gene-regulating protein that guards the developing brain of a fetus reboots 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 published Wednesday in the journal Nature, showed the protein, dubbed REST, is depleted in brains of people with Alzheimer's. It was found at a level three times higher in those who didn't become demented even when they had brain markings of the disease. Until now, REST wasn't known to play a role in the adult brain.

Experimental drugs to reduce proteins such as amyloid or tau that form the hallmark brain clumps of Alzheimer's have failed to stem cognitive decline. This finding supports the idea that targeting those proteins isn't enough to fight the disease. It also may explain why some people develop dementia as they age while others live long lives, 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 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 in fetal development and switched off in the brain after birth. A series of experiments by Yankner's team found that the protein suppresses genes involved in cell death and Alzheimer's progression, while turning on those that protect neurons from stress.

Over five million Americans have Alzheimer's disease, the most common type of dementia, a number projected to triple by 2050. The disease is the sixth-leading cause of death in the U.S. A March 6 study in Neurology found the disease may be underreported and could be the third-leading cause of mortality.

Since 1998, there have been over 100 attempts to develop an Alzheimer's drug and all failed.

The discovery of REST's potential role in the aging brain highlights the need for pursuing new directions in Alzheimer's research, said Maria Carrillo, vice president for medical and scientific relations at the Chicago-based Alzheimer's Association. The idea that the brain may harbor pathways, such as REST, to protect against cognitive decline is one of them. Still, any potential drug based on the today's findings is years away.

"Its' a fascinating take on the concept that's been around," she said. "There's not as much research in the neuroprotective aspects of aging. That is the most interesting aspect of this study, and it's important to pursue and continue research in this area."