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Are some of us protected from Alzheimer's?

In the battle to cure Alzheimer's disease, the two hallmark proteins that clog the brains of people with the deadly dementia - amyloid and tau - have received most of the attention.

Bruce Yankner researches gene regulator’s role in the disease.
Bruce Yankner researches gene regulator’s role in the disease.Read moreHandout

In the battle to cure Alzheimer's disease, the two hallmark proteins that clog the brains of people with the deadly dementia - amyloid and tau - have received most of the attention.

But dementia experts have long known that some people whose brains were riddled with these misfolded proteins still had good cognitive function throughout their lives.

What if something was protecting them?

Bruce Yankner, a Harvard University professor of genetics and neurology, came to the University of Pennsylvania recently to talk about a gene regulator called REST that he believes may help explain why human brains are able to work as long as they do, and why some of us stay sharp into our 90s while others begin having thinking and memory problems much earlier.

His work shows that REST, which is diminished in people with dementia, suppresses genes that promote cell death and protects neurons from stress and amyloid toxicity.

It may provide a different avenue for combatting Alzheimer's, considered by some estimates the most expensive disease in the United States.

Yankner was chosen to receive this year's Joseph A. Pignolo Award in Aging Research, named for the father of a Penn physician. He spoke to fellow researchers at Penn's Smilow Center last week.

In his speech, Yankner said the lack of success so far in finding effective treatments "behooves us to step back and think some more about some of our basic assumptions about the pathogenesis of Alzheimer's disease."

REST is active in the brain during fetal development, then goes dormant until it is reactivated as people age, Yankner said.

His team has studied it in people, mice, and worms. He could not yet discuss detailed results from some of his most recent and still-unpublished work.

REST functioning has been associated with slowing cell death while promoting DNA damage repair and proper neurotransmitter signalling.

Research in people found a correlation between good cognitive function and fewer signs of Alzheimer's pathology with high levels of REST inside neurons in key brain areas. People with the highest levels of REST had very little cognitive decline at the end of their lives while those in the bottom 20 percent for REST had a steep decline.

Yankner said that REST may explain what Alzheimer's researchers have thought of as a "cognitive reserve," the fact that some people seem able to function even with evidence of Alzheimer's. Some brains may be able to mount a more effective defense.

Curing Alzheimer's disease will not be as simple as raising REST levels. Yankner's team has found that REST had reactivated in people with dementia, but had not made its way to the correct location, the nuclei of neurons. Amyloid and tau may somehow prevent that.

Yankner is studying how factors that may delay Alzheimer's onset or improve function in the early stages - exercise and the Mediterranean diet - influence the REST pathway. "Our hope is that REST may provide an independent index or marker to help optimize a regimen to maintain brain health and prevent Alzheimer's disease," he said.

sburling@phillynews.com

215-854-4944

@StaceyABurling