Looking for Alzheimer’s clues from the few who escape genetic fate

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

Although he is a healthy 73 years old, his mind is still sharp. Somehow, the Washington man escaped his genetic fate.

So did a Colombian woman who for nearly three decades avoided the same Alzheimer’s fate as her family.

Scientists, these rare “runaways” were just not lucky. They offer an unprecedented opportunity to understand how the body can naturally resist Alzheimer’s.

“Often it’s the unique individuals that really give us the breakthroughs,” said Dr. Eric McDade of Washington University in St. Louis, where Whitney’s DNA is being sought. for answers.

The hope: If researchers can discover and mimic what protects these escapees, they might develop better treatments – even preventive therapy – not just for families with hereditary Alzheimer’s disease, but for everyone.

“We’re just learning about this approach to disease,” said neuropsychologist Jakeel Quiroz of Massachusetts General Hospital, who helped study the Colombian woman. “One person can really change the world – as in his case, how much we learned from him.”

Quiroz’s team has a pretty good idea of ​​what was protecting Aliria Piedrahita de Villegas—an additional genetic quirk that apparently conflicted with her family’s Alzheimer’s mutation. But testing has shown that Whitney lacks this protective factor, so something else must be protecting her brain.

Now scientists are looking for even more Alzheimer’s escapees — people who may have simply thought they didn’t inherit the family mutation because they’re healthy past the age when their loved ones always get sick.

“They just think it’s the luck of the draw, and maybe they’re actually resilient,” said McDade, a researcher at the University of Washington. network which controls 600 members of several affected families – including the fugitive Whitney.

“I think that made me pretty special. And they started fighting and fighting and doing additional testing on me,” said Port Orchard, Washington. “I told them, you know, I’m here, whatever you need.”

For Whitney’s son Brian, who also inherited the destructive family gene, the answers can’t come fast enough. He’s reached the fatal age of 50 without symptoms, but knows that’s no guarantee.

“I liken my genetics to a murder mystery,” said Brian Whitney, who volunteers at the University of Washington in research involving an experimental preventive drug trial. “Our factual evidence is what they need to solve the case.”

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More than 6 million Americans and about 55 million people worldwide have Alzheimer’s. It’s just aging that’s the main risk – it’s usually a disease of people over 65.

Less than 1% of Alzheimer’s is caused by inheriting a single copy of a specific mutated gene. Children of an affected parent have a 50-50 chance of inheriting the family’s Alzheimer’s gene. If they are, they are almost guaranteed to get the disease around the same age as their parent.

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

What happens instead in the endurance brain?

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

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

“Five years later, he’s gone,” Whitney said.

Back then, doctors didn’t know much about Alzheimer’s. It was not until the 1990s that separate research teams proved that three different genes, when mutated, could each cause this unique inherited form of the disease. Each of these accelerates the abnormal accumulation of amyloid.

Doug Whitney’s family could only watch and worry as his 50th birthday came and went. His older brother developed symptoms at age 48. (Some other siblings were later tested and did not get the gene, although two still don’t know.)

“About 10 years in, when the kids would call home, their first question would be, ‘How’s Daddy?'” his wife, Ione Whitney, recalled. “When he turned 60, we went, wow, we flipped a coin.”

But not in the way he expected. In 2010, at her cousin’s request, Whitney joined the St. Louis study. She also agreed to a genetic test that she hoped would give her final assurance that her children would not suffer from the same concerns — only to learn that she had inherited the family mutation.

“He kind of evened it up with that score,” Brian Whitney said.

Although Brian inherited the family gene, his sister Karen did not – but she is also part of the same study, in a healthy comparison group.

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American researchers are not alone in their search for 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 in their early 40s.

In contrast, one family member — Piedrahita de Villegas — was considered “extremely resistant,” with no cognitive symptoms until age 70. The researchers took the woman to Quiroz’s lab in Boston for a brain scan. And when he died at age 77 of melanoma with only mild signs of dementia, his brain was donated to Columbia’s Antioch University for further study.

His brain was riddled with Alzheimer’s trademark amyloid plaques. But the researchers found very little tau — and strangely, it wasn’t in the memory center of the brain, but in a completely different region.

Obviously something affected how the Tau formed and where. “What we don’t know exactly is why,” Quiroz said.

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

This APOE gene comes in different varieties, including a version known to increase the risk of traditional age-related Alzheimer’s disease in humans and another associated with a lower risk. Normally, the version of APOE3 that Piedrahita de Villegas carried has no bearing on dementia.

But amazingly, both copies of his APOE3 gene were replaced by a rare ‘Christchurch’ mutation – and researchers think this blocked the toxic tau.

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

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

This research is already having implications for a field that has long considered fighting amyloid as a key step in Alzheimer’s treatment.

Instead, “we just have to block what’s underneath it,” said Dr. Richard Hodes, director of the National Institute on Aging.

And since Whitney, Washington, D.C., does not have this additional mutation, “there could be many ways to escape,” Hodes added.

Researchers in St. Louis are testing another clue: Maybe something special in Whitney’s immune system is protecting her brain.

The findings also fuel the search for more fugitives for comparison. A team at the University of Washington recently began studying one unrelated to Whitney. In Colombia, Quiroz said researchers are looking for several more possible escapees.

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

This involves attaching a pump every two weeks that delivers an experimental amyloid-fighting drug. He also gets regular brain scans to check for side effects.

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

He spends a lot of time going fishing and camping with his daughter Emily, now 12, who hasn’t yet been told about the family gene. He hopes to have some answers before he’s an adult and can consider testing.

“When I have a bad day and I decide not to continue (research), I think about it and then it all goes away,” he said.

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