People who inherit one very rare gene mutation are virtually guaranteed to develop Alzheimer's before they turn 50.
Except for Doug Whitney.
"I'm 75 years old, and I think I'm functioning fairly well," says Whitney, who lives near Seattle. "I'm still not showing any of the symptoms of Alzheimer's."
Now a team of scientists is trying to understand how Whitney's brain has defied his genetic destiny.
"If we are able to learn what is causing the protection here, then we could translate that to therapeutic approaches and apply that to the more common forms of the disease," says Dr. Jorge Llibre-Guerra, an assistant professor of neurology at Washington University School of Medicine in St. Louis.
One possibility is high levels of heat shock proteins found in Whitney's brain, the team reports in the journal Nature Medicine.
There are hints that these proteins can prevent the spread of a toxic protein that is one of the hallmarks of Alzheimer's, Llibre-Guerra says.
A genetic surprise
Early-onset Alzheimer's is everywhere in Whitney's family.
His mother and 11 of her 13 siblings all had the disease by about age 50. "None of them lasted past 60," Whitney says.
Whitney's wife, Ione, saw this up close.
"We went home for Thanksgiving, and his mom couldn't remember the pumpkin pie recipe," she says. "A year later when we went back, she was already wandering off and not finding her way back home."
The affected family members all carried a mutated version of a gene called presenilin 2. The variant causes a person's brain to accumulate beta amyloid and phosphorylated tau proteins, the hallmarks of Alzheimer's.
When Whitney turned 60 and still had no symptoms, he assumed he didn't have the mutation. But he wanted to help others. So he volunteered for a study of families with early Alzheimer's.
"I submitted my blood samples and to my great surprise, it came back positive for the Alzheimer's gene," Whitney says. "It was quite a shock."
It was also a shock for scientists. Whitney was only the third person known to have escaped the effects of a presenilin mutation.
The first two came from a group in Colombia with mutations to the presenilin 1 gene. Whitney is the only person known to have resisted a mutation in the presenilin 2 gene, which is found on a different chromosome.
All three had lots of beta-amyloid in their brains. But surprisingly, they didn't have much phosphorylated tau.
This form of tau is a misfolded protein that tends to appear in one brain area, then spread. But in Whitney's brain, tau was confined to a small area involved in visual perception.
"One key element of the disease is having the tau protein spread through the brain," Llibre-Guerra says. "That was not happening."
The scientists set about trying to understand why.
They don't have a definitive answer yet. But they are intrigued by the high levels of heat shock proteins in Whitney's brain.
These proteins help protect brain cells from high temperatures and other forms of stress. They also seem to prevent healthy tau from misfolding into the toxic, phosphorylated form associated with Alzheimer's.
"It may be the case that those proteins are preventing more tau to be misfolded, and then spread through the brain," Llibre-Guerra says.
Protection from hot work?
Scientists told Whitney that the high levels of heat shock proteins in his brain might be the result of his life experience.
"I spent 20 years in the Navy, most of it in the hot spots, like the engine rooms of ships—110 degrees is nothing on a ship," he says.
That environment may have caused an increase in heat shock proteins, which were able to limit the spread of tau and prevent the onset of Alzheimer's.
The scientists studying Whitney aren't sure if that's all, or even part, of the explanation. But they are hoping that the paper on Whitney will encourage other researchers to look for answers.
In the meantime, Whitney plans to continue making his brain and body available to scientists. Later this year, he will return to Washington University in St. Louis, where he has undergone repeated brain scans, blood draws, lumbar punctures, and even provided a sample of bone marrow.
Whitney's hope is that scientists will learn something that helps protect other brains from Alzheimer's.
"I would love to see that happen," he says, "while I'm still around."
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