Searching for clues to Alzheimer’s disease from the few who escape genetic fate

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

Still, he’s a healthy 73, his mind still sharp. Somehow, the Washington man escaped his genetic fate.

So did a Colombian woman who dodged her own family’s similar Alzheimer’s fate for nearly three decades.

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

“It’s often unique individuals who really provide us with breakthroughs,” said Dr. Eric McDade of Washington University in St. Louis, where Whitney’s DNA is being scanned. for the answers.

The hope: if researchers could discover and imitate everything that protects these escapees, they could develop better treatments – even preventative therapies – not just for families plagued by hereditary Alzheimer’s disease, but for everyone.

“We’re just discovering this approach to disease,” said neuropsychologist Yakeel Quiroz of Massachusetts General Hospital, who helped study the Colombian woman. “One person can really change the world – like in her case, everything we learned from her.”

Quiroz’s team has a pretty good idea of ​​what protected Aliria Piedrahita de Villegas — an additional genetic oddity that apparently countered the damage caused by her family’s Alzheimer’s disease mutation. But the tests showed that Whitney didn’t have that protective factor, so something else had to be protecting her brain.

Now, scientists are on the hunt for even more Alzheimer’s disease escapees – people who may have just assumed they didn’t inherit the mutation from their family because they are in good health long after the age at which their loved ones always fall ill.

“They just think it’s kind of luck of the draw and they may actually be resilient,” said McDade, a network researcher at the University of Washington. which follows approximately 600 members of several affected families – including Whitney, the escapee.

“I guess that made me pretty special. And they started pushing and pushing and doing more tests on me,” the Port Orchard, Washington man said. “I told them, you know, I’m here for whatever you need.”

The answers can’t come fast enough for Whitney’s son Brian, who also inherited the devastating family gene. He has reached the fateful age of 50 without symptoms but knows that is not guaranteed.

“I liken my genetics to a murder mystery,” said Brian Whitney, who is volunteering for studies at the University of Washington that include testing an experimental preventive drug. “Our literal bodies of evidence are what they need to solve the case.”


More than 6 million Americans and approximately 55 million people worldwide have Alzheimer’s disease. Just getting older is the biggest risk – it’s usually a disease of people over 65.

Less than 1% of Alzheimer’s cases are caused by the inheritance of a single copy of a particular mutated gene. The children of an affected parent have a 50% chance of inheriting the family gene for Alzheimer’s disease. If they do, they are almost guaranteed to get sick around the same age as their parents.

This near certainty allows scientists to study these families and gain key insights into how Alzheimer’s disease forms. It is now clear that silent changes occur in the brain at least two decades before the first symptoms appear – a potential window for intervention. Among the culprits, sticky amyloid begins to build up, followed by neuron-killing tau tangles.

What happens instead in the brains of resilient people?

“That’s why I’m here,” said Doug Whitney, who for years gave blood and spinal fluid samples and underwent brain scans and cognitive exams, looking for clues. “It’s so important that people in my situation come forward.”

Whitney’s grandparents had 14 children, and 10 of them developed early-stage Alzheimer’s disease. The first red flag for her mother: Thanksgiving 1971, when she forgot the pumpkin pie recipe she had always made from memory.

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

At the time, doctors didn’t know much about Alzheimer’s disease. 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 each accelerate the abnormal buildup of amyloid.

Doug Whitney’s family could only watch and worry as his 50th birthday came and went. Her older brother had started showing symptoms at age 48. (Some other siblings were later tested and didn’t inherit the gene, though two still don’t know.)

“We went through about 10 years when the kids would call home their first question was, ‘How’s Dad?'” recalls his wife Ione Whitney. “By the time he turned 60 we went, wow, we beat the draw.”

But not as he had hoped. In 2010, prompted by a cousin, Whitney joined the search from St. Louis. He also agreed to a genetic test which he expected would definitely reassure his children that they wouldn’t face the same hassle – only to learn that he had inherited the family mutation after all.

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

While Brian inherited the family gene, his sister Karen did not, but she too was in the same study, in the healthy comparison group.


American researchers aren’t the only ones finding answers. In South America, scientists are tracking a huge extended family in Colombia who share a similar variant that causes Alzheimer’s disease. Carriers of this mutated gene begin to exhibit memory problems in their early 40s.

In contrast, one family member – Piedrahita de Villegas – was considered to have “extreme resilience”, with no cognitive symptoms until he was 70 years old. Researchers flew the woman to Quiroz’s lab in Boston for brain scans. And when she died aged 77 from melanoma with only mild signs of dementia, her brain was donated to Colombia’s University of Antioquia for further examination.

His brain was stuffed with amyloid plaques emblematic of Alzheimer’s disease. But the researchers found very little tau – and oddly enough, it wasn’t in the memory center of the brain but in a very different region.

Clearly something affected how and where tau formed. “The thing we don’t know for sure is why,” Quiroz said.

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

This APOE gene comes in different varieties, including a version notorious for increasing the risk of traditional Alzheimer’s disease in older people and another that is linked to a lower risk. Normally, the APOE3 version that Piedrahita de Villegas wore makes no difference for dementia.

But remarkably, both copies of his APOE3 gene were altered by the rare “Christchurch” mutation – and the researchers believe this blocked the toxic tau.

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

“We still have work to do, but we are getting closer to understanding the mechanism,” Quiroz said.

This research already has implications for a field that has long considered fighting amyloid to be the key step in treating Alzheimer’s disease.

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

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

In St. Louis, researchers are checking for another clue: Maybe something special in Whitney’s immune system is protecting her brain.

The results also fuel the search for more escapees to compare. The University of Washington team recently began studying the one unrelated to Whitney. In Colombia, Quiroz said researchers are investigating a few other possible escapees.


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

This includes every two weeks, hooking up to a pump that delivers an experimental anti-amyloid drug. He also undergoes regular brain scans to check for side effects.

Living with uncertainty is difficult and he sometimes has nightmares about Alzheimer’s disease. He tries to follow what he now knows to be his parents’ mantra: “Get the most out of life until you’re 50 and everything after that is a bonus.”

He takes a long time to go fishing and camping with his daughter Emily, now 12, who has yet to be told about the family gene. He hopes there will be answers by the time she is an adult and can consider getting tested.

“When I’m having a bad day and maybe I decide not to continue (the research), I think of her and it all fades away,” he said.


The Associated Press Health and Science Department is supported by the Howard Hughes Medical Institute Science and Education Media Group. The AP is solely responsible for all content.

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