In search of Alzheimer’s clues from the few who have escaped genetic fate

ST. LOUIS (AP) – Doug Whitney inherited the same gene mutation at the unusually young age of 50 that gave his mother, brother and generations of other relatives Alzheimer’s disease.

Yet he’s a healthy 73, his mind still sharp. Somehow the man from Washington escaped his genetic destiny.

So did a woman in Colombia who escaped the similar fate of Alzheimer’s in her own family for almost three decades.

For scientists, these rare “outliers” weren’t just lucky. They offer an unprecedented opportunity to learn how the body can naturally resist Alzheimer’s.

“It’s often unique individuals that give us real breakthroughs,” said Dr. Eric McDade of Washington University in St. Louis, where Whitney’s DNA is located scoured for answers.

The hope: If researchers could figure out and mimic what protects these refugees, they could evolve better treatments — even preventive therapies — not just for families plagued by hereditary Alzheimer’s disease, but for everyone.

“We’re just learning about this approach to the disease,” said Yakeel Quiroz, a neuropsychologist at Massachusetts General Hospital who helped examine the Colombian woman. “One person can actually change the world – as in their case, how much we have learned from them.”

Quiroz’s team have a pretty good idea of ​​what was protecting Aliria Piedrahita de Villegas — an additional genetic oddity that appeared to counteract the damage done by her family’s Alzheimer’s mutation. But tests showed Whitney doesn’t have that protective factor, so something else must be shielding his brain.

Now scientists are on the lookout for even more Alzheimer’s escapees — people who might have simply assumed they didn’t inherit their family’s mutation because they’re healthy long after their loved ones always get sick.

“They just think it’s some kind of fluke, and they might actually be resilient,” said McDade, a researcher at Washington University network This is following about 600 members of several affected families – including Whitney, the fugitive.

“I think that made me very special. And they started poking and poking me and doing additional tests on me,” said the Port Orchard, Washington man. “I told them, you know, I’m here for anything you need.”

Answers can’t come fast enough for Whitney’s son Brian, who also inherited the devastating family gene. He’s reached the fateful age of 50 with no symptoms, but knows that’s no guarantee.

“I compare my genetics to a crime thriller,” said Brian Whitney, who is volunteering for studies at Washington University that involve testing an experimental preventive drug. “Our literal evidence is what they need to crack the case.”


More than 6 million Americans and an estimated 55 million people worldwide have Alzheimer’s disease. Simply getting older is the main risk – it’s usually a disease of people over the age of 65.

Less than 1% of Alzheimer’s disease is caused by inheritance of a single copy of a particular mutated gene. Children of an affected parent have a 50/50 chance of inheriting the familial Alzheimer’s gene. If they do, they are almost guaranteed to get sick at the same age as their parents.

This near certainty allows scientists to study these families and gain important information about how Alzheimer’s develops. It is now clear that silent changes in the brain occur at least two decades before the first symptoms – a potential window for intervention. Sticky amyloid begins to build up beneath the culprits, followed by neuron-killing tau tangles.

Instead, what happens in the brains of the resilient?

“That’s why I’m here,” said Doug Whitney, who has spent years giving blood and spinal fluid samples, brain scans and cognitive tests in search of clues. “It’s so important that people in my situation speak up.”

Whitney’s grandparents had 14 children, 10 of whom developed Alzheimer’s at an early age. His mother’s first red flag: Thanksgiving 1971, when she forgot the pumpkin pie recipe she’d always memorized.

“Five years later, she was gone,” Whitney said.

Back then, doctors didn’t know much about Alzheimer’s. It wasn’t until the 1990s that separate research teams proved that three different genes, when mutated, can each cause this unique inherited form of the disease. They both accelerate the abnormal buildup of amyloid.

Doug Whitney’s family could only watch and worry as his 50th birthday came and went. His older brother had started showing symptoms when he was 48. (Several other siblings were later tested and did not inherit the gene, although two still do not know.)

“We went through about 10 years when the kids called home and their first question was, ‘How’s Dad?'” recalls his wife, Ione Whitney. “When he turned 60, we were like, wow, we hit the coin toss.”

But not in the way he had hoped. In 2010, at the urging of a cousin, Whitney joined research in St. Louis. He also agreed to a genetic test, which he had expected would provide definitive assurance his children would not have the same worries – only to learn he had inherited the family mutation after all.

“He was kind of leveled by that result,” said Brian Whitney.

While Brian inherited the family gene, his sister Karen doesn’t – but she too is part of the same study, in the healthy comparison group.


Not only US researchers are on the trail of the answers. In South America, scientists are tracking a huge extended family in Colombia that shares a similar Alzheimer’s-causing variant. Carriers of this mutated gene begin to have memory problems in their early 40s.

In contrast, one family member – Piedrahita de Villegas – was classified as “extremely resilient” with no cognitive symptoms well into his 70s. Researchers flew the woman to Quiroz’s Boston lab for brain scans. And when she died of melanoma at the age of 77 with only mild signs of dementia, her brain was donated to Colombia’s University of Antioquia for further study.

Her brain was crammed with amyloid plaques, the hallmark of Alzheimer’s. But the researchers found very little tau – and oddly enough, it wasn’t in the memory center of the brain, but in an entirely different region.

Apparently something was affecting how and where dew formed. “What we don’t know exactly is why,” Quiroz said.

The DNA offered a suspect: an ultra-rare mutation in an unrelated gene.

This APOE gene comes in several variations, including one version notorious for increasing people’s risk of traditional old-age Alzheimer’s and another associated with a lower risk. Usually the APOE3 version that Piedrahita de Villegas wore makes no difference in dementia.

But remarkably, both copies of their APOE3 gene were altered by the rare “Christchurch” mutation – and researchers think the toxic tau was blocking it.

To prove this, Quiroz’s team used preserved cells from Piedrahita de Villegas and another Colombian patient to grow brain tissue in laboratory dishes. Cells with the Christchurch mutation developed less tau.

“We still have a lot to do, but we’re getting closer to understanding the mechanism,” Quiroz said.

This research is already having implications in an area that has long considered tackling amyloid as the most important step in treating Alzheimer’s.

Instead, “we may just need to block what’s downstream,” said Dr. Richard Hodes, Director of the National Institute on Aging.

And since Whitney, the Washington man, doesn’t have that extra mutation, “there may be multiple escape routes,” Hodes added.

In St. Louis, researchers are investigating another clue: Maybe something special about Whitney’s immune system protects his brain.

The results also fuel the search for other refugees for comparison. The Washington University team recently began investigating someone unrelated to Whitney. In Colombia, Quiroz said, researchers are investigating some other possible refugees.


This search for answers is not just work for scientists. Whitney’s son Brian estimates that he spends about 25 days each year undergoing various health checks and procedures, many far from his home in Manson, Washington, as part of Alzheimer’s research.

That includes being hooked up to a pump every two weeks that delivers an experimental anti-amyloid drug. He also gets regular brain scans to check for side effects.

It’s hard to live with the uncertainty and he sometimes has nightmares about Alzheimer’s. He tries to follow what he now knows as his parents’ mantra: “Make the most of life until 50 and everything after that is a bonus.”

He makes time for fishing and camping with daughter Emily, now 12, who has not yet been told about the family gene. He hopes there will be some answers when she’s grown up and can consider a test.

“When I’m having a bad day and decide maybe I shouldn’t continue[the research]I think about her and then it all goes away,” he said.


The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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