Doug Whitney inherited the same Genetic mutation that caused Alzheimer’s in his mother, brother and other relatives for several generations, at the unusually young age of 50. Whitney is 73 years old and still mentally sharp.
Somehow, he evaded his genetic destiny. Scientists search for clues to Alzheimer’s among Whitney and a few others who eluded his apparent genetic fate.
The same was true of a woman in Colombia who evaded a similar fate of Alzheimer’s from her own family for nearly three decades.
For scientists, these few “fugitives” weren’t just lucky: they offer an unprecedented opportunity to understand how the body might naturally resist Alzheimer’s.
“It’s these unique people that really allow us breakthroughs,” said Dr. Eric McDade of Washington University in St. Louis, where they are poring over Whitney’s DNA for answers.
The hope: if researchers could discover and mimic what protects these fugitives, they could develop better treatments —and even preventative therapies—not just for families affected by hereditary Alzheimer’s, but for everyone.
“We’re just beginning to learn about this approach to disease,” said Massachusetts General Hospital neuropsychologist Yakeel Quiroz, who helped study the Colombian woman. “A real person can change the world, as in her case, (because) how much we have learned from her.”
Quiroz’s team has a pretty good idea of what protected Aliria Piedrahita de Villegas: an additional genetic quirk that apparently counteracted the damage of her family’s Alzheimer’s mutation. But the tests showed that Whitney doesn’t have that protective factor, so something else must be shielding her brain.
Now, scientists are looking for more Alzheimer’s fugitives, people who simply assumed they didn’t inherit the mutation from their family because they’re healthy long past the age when their loved ones got sick.
“They think it’s just like winning the lottery, and it may in fact be resilient,” said McDade, a researcher for a University of Washington network that tracks about 600 members of various affected families, including Whitney, the fugitive.
“I guess that made me pretty special. And they started poking and poking me and doing additional tests,” the Port Orchard, Washington, man said. “I told them: you know, I’m here for whatever you need.”
The answers may not be long in coming for Whitney’s son, Brian, who also inherited the devastating family gene. He has reached the fateful age of 50 without symptoms, but he knows that is no guarantee.
“I compare my genetics to being a murder mystery”said Brian Whitney, who is volunteering for studies at the University of Washington that include testing an experimental preventive drug. “Literally, our body of evidence is what they need to crack the case.”
More than 6 million Americans and approximately 55 million people worldwide have Alzheimer’s. The main risk is simply getting older, since it is generally a disease of people over 65 years of age.
Less than 1% of Alzheimer’s is caused by inheriting a single mutated copy of a particular gene
Children of an affected parent have a 50-50 chance of inheriting the familial Alzheimer’s gene. If so, they will almost certainly get sick at about the same age as their parent.
That near certainty allows scientists to study these families and gain crucial information about how Alzheimer’s develops.
It is now clear that silent changes occur in the brain at least two decades before the first symptoms, opening a potential window for intervention.
Among the culprits, sticky beta-amyloid begins to accumulate, followed by neuron-killing tangles of tau proteins.
What happens instead in the brain of the resilient?
“That’s why I’m here,” said Doug Whitney, who for years has given blood and spinal fluid samples, brain scans and cognitive tests in search of clues. “It’s very important that people in my situation make themselves known.”
Whitney’s grandparents had 14 children, 10 of whom developed early-onset Alzheimer’s. The first red flag for her mother: Thanksgiving Day 1971, when she forgot the pumpkin pie recipe she had always made by heart.
“Five years later, he was gone,” Whitney said.
Back then, doctors didn’t know much about Alzheimer’s. It wasn’t until the 1990s that different research teams demonstrated that each of three different genes, when mutated, can cause this uniquely inherited form of the disease. Each of them accelerates the abnormal accumulation of beta-amyloid.
Doug Whitney’s family could only watch and worry as his 50th birthday came and went. His older sister had started showing symptoms at age 48. (Some other siblings were tested later and didn’t inherit the gene, though two still don’t know.)
“We spent about 10 years where kids would call home and their first question would be, ‘How’s Daddy?'” his wife, Ione Whitney, recalled. “By the time he turned 60, we were like, wow, we beat him on the flip of a coin.”
But not in the way he expected. In 2010, at the urging of a cousin, Whitney joined the St. Louis investigation. She also agreed to undergo a genetic test that she hoped would provide reassurance that her children would not face the same concern, only to discover that he had inherited the family mutation after all.
“He fell apart with that result,” Brian Whitney said.
While Brian inherited the family gene, his sister Karen did not, but she is also part of the same study, in the healthy comparison group.
American researchers aren’t the only ones tracking the answers. In South America, scientists are tracking a huge extended family in Colombia that shares a similar variant that causes Alzheimer’s. Carriers of this mutated gene begin to show memory problems from the age of 40.
In contrast, Piedrahita de Villegas, a member of the family, was estimated to have “extreme resistance” without cognitive symptoms until her 70s. Investigators took the woman to Quiroz’s Boston lab for brain scans. And when she died of melanoma at age 77—with only mild signs of dementia—she donated her brain to Colombia’s University of Antioquia for further examination.
His brain was littered with beta-amyloid plaques characteristic of Alzheimer’s disease, but the researchers found very few tau proteins, and strangely, they weren’t in the brain’s memory center but in a very different region.
Clearly something affected how and where the tau protein was formed. “What we don’t know for sure is why,” Quiroz said.
The DNA offered a suspect: an extremely rare mutation in an unrelated gene.
That gene, called apolipoprotein E, or APOE, has several variations, including a version notorious for increasing people’s risk for traditional old-age Alzheimer’s and another that is associated with a lower risk.
Usually, the APOE3 variation that Piedrahita de Villegas had does not affect dementia at all. But remarkably, both copies of her APOE3 gene were altered by a rare mutation called “Christchurch,” which the researchers think is what blocked the toxic tau protein.
To begin testing, Quiroz’s team used cells preserved from Piedrahita de Villegas and another Colombian patient to grow brain tissue in Petri dishes. Cells with the Christchurch mutation developed less tau protein.
“We still have more work to do, but we are getting closer to understanding the mechanism,” Quiroz said.
That research already has implications for a field that has long seen fighting beta-amyloid as the key step in treating Alzheimer’s.
Instead, perhaps “we just need to block what is in the final stage,” said Dr. Richard Hodes, director of the US National Institute on Aging.
And since Whitney, the man from Washington, doesn’t have that extra mutation, “there may be multiple avenues of escape,” Hodes added.
In St. Louis, investigators investigate another lead: Maybe there’s something special about Whitney’s immune system that protects her brain.
The findings also prompt the search for more fugitives to compare. The University of Washington team recently began studying one who is not related to Whitney. In Colombia, Quiroz said investigators are investigating other possible fugitives.
That search for answers is not just a job for scientists. Whitney’s son Brian estimates that he spends about 25 days a year undergoing various health checkups and procedures, many of them away from his home in Manson, Wash., as part of Alzheimer’s research.
That includes connecting every two weeks to a pump that delivers an experimental drug to fight beta-amyloid. He also undergoes periodic brain scans to check for side effects.
Living with uncertainty is hard and sometimes he has nightmares about Alzheimer’s. She tries to follow what she now knows was her parents’ mantra: “Get the best in life until you’re 50, and everything after that is a bonus.”
He takes plenty of time to go fishing and camping with his 12-year-old daughter Emily, who has yet to be told about the family gene. She hopes there will be some answers by the time she is an adult and she can consider getting tested.
“When I’m having a bad day and decide maybe I shouldn’t continue (with the investigation), I think about her and then it all falls away,” he said.
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