Seeking Alzheimer’s clues 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.

Yet he is a healthy 73-year-old, his mind still sharp. Somehow, the Washington man escaped his genetic fate.

So did a woman in Colombia who avoided her family’s Alzheimer’s-like fate for nearly three decades.

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

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

The hope: If researchers could discover and mimic what protects these fugitives, they could develop better treatments — even preventative therapies — not just for families afflicted with hereditary Alzheimer’s but for everyone.

“We’re just learning about this approach to disease,” said neuropsychologist Yakeel Quiroz of Massachusetts General Hospital, who helped study the Colombian woman. “A person can really change the world, as is the case with her, how much we have learned from her.”

The Quiroz team has a good idea of ​​what protected Aliria Piedrahita de Villegas, another genetic quirk that apparently countered the damage of her family’s Alzheimer’s mutation. But tests have shown that Whitney doesn’t have that protective factor, so something else must be protecting her brain.

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

“They just think it’s kind of luck and in fact it could be that they’re resilient,” said McDade, a researcher with a Washington University network that follows about 600 members of multiple affected families, including Whitney, the fugitive.

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

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

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

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More than 6 million Americans and approximately 55 million people worldwide have Alzheimer’s. 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 is caused by inheriting a single copy of a particular mutated gene. Children of an affected parent have a 50% chance of inheriting the family gene for Alzheimer’s. If they do, it’s almost guaranteed that they’ll get sick around the same age as their parents.

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

What happens instead in the brain of resilient people?

“That’s why I’m here,” said Doug Whitney, who has for years provided blood and spinal fluid samples and undergone brain scans and cognitive exams, hunting 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-onset Alzheimer’s. Her first red flag for her mom: Thanksgiving 1971, when she forgot the pumpkin pie recipe she always made from memory of her.

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

Doctors didn’t know much about Alzheimer’s back then. It wasn’t until the 1990s that separate research groups showed that three different genes, when mutated, can each cause this uniquely inherited form of the disease. Each 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 had started showing symptoms at age 48. (A few other siblings were later tested and didn’t inherit the gene, though two still don’t know.)

“We spent about 10 years where the kids would call home and their first question was, ‘How is Daddy?’” recalls his wife Ione Whitney. “When he turned 60, we went, wow, we beat the coin toss.”

But not as he had hoped. In 2010, at the urging of a cousin, Whitney joined the St. Louis search. She also agreed to a genetic test that she expected would provide the final reassurance that her children would not face the same concern, only to discover that she did inherit the familial mutation after all.

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

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.

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US researchers aren’t the only ones in the wake of the answers. In South America, scientists are tracking a huge extended family in Colombia who share a similar variant that causes Alzheimer’s. Carriers of this mutated gene begin to show memory problems around the age of 40.

In contrast, one family member – Piedrahita de Villegas – was found to have “extreme endurance,” with no cognitive symptoms until his 70s. Researchers took the woman to Quiroz’s lab in Boston for brain scans. And when she died at 77 of melanoma with only mild signs of dementia, her brain was donated to the University of Antioquia in Colombia for closer scrutiny.

His brain was chock full of amyloid plaques typical of Alzheimer’s. But the researchers found very little tau, and strangely, it wasn’t in the brain’s memory center, but in a very different region.

Something clearly influenced how and where tau was formed. “The thing we don’t know for sure is why,” Quiroz said.

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

That APOE gene comes in several varieties, including one version known to increase people’s risk of getting traditional Alzheimer’s in later life and another that’s linked to a lower risk. Normally the APOE3 version that Piedrahita de Villegas carried makes no difference for dementia.

But surprisingly, both copies of its APOE3 gene were altered by the rare “Christchurch” mutation, and researchers think it blocked toxic tau.

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

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

That research already has implications for a field that has long seen tackling amyloid as the key step to treating Alzheimer’s.

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

And since Whitney, the man from Washington, doesn’t have that extra mutation, “there may be more ways out,” Hodes added.

In St. Louis, researchers are testing for another lead: Maybe something special about Whitney’s immune system is protecting her brain.

The findings are also fueling the search for other fugitives to compare. The Washington University team recently began studying one who is not related to Whitney. In Colombia, Quiroz said researchers are looking into a few more possible escapees.

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That search for answers isn’t 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, Washington, as part of Alzheimer’s research.

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

Living with uncertainty is difficult and sometimes he has nightmares about Alzheimer’s. She tries to follow what she now knows is her parental mantra: “Make the most of life until you’re 50 and anything after that is a bonus.”

He finds plenty of time to go fishing and camping with his daughter Emily, now 12, who hasn’t yet been told about the family gene. She hopes there will be some answers when she is an adult and can consider testing.

“When I have a bad day and decide maybe I shouldn’t continue (the research), I think about her and then it all fades away,” she said.

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

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