Searching for evidence of Alzheimer’s from the few who escape genetic fate

Doug Whitney inherited the same gene mutation that caused Alzheimer’s disease in his mother, brother and generations of other relatives until the unusually young age of 50.

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

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

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

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

The hope: If researchers could uncover and mimic whatever protects these escapees, they could develop better treatments — even preventative treatments — not just for families plagued by inherited Alzheimer’s but for everyone.

“We’re just learning about this approach to the 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, how much we’ve learned from her.”

Quiroz’s team has a pretty good idea of ​​what was protecting Aliria Piedrahita de Villegas — an extra genetic quirk that apparently countered the damage from her family’s Alzheimer’s mutation. But the test showed that Whitney lacks this 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 just assume they didn’t inherit their family’s mutation because they’re healthy long after their loved ones always get sick.

“They just think he’s lucky in the lottery, and they might actually be resilient,” said McDade, a researcher at a University of Washington network that tracks about 600 members of several affected families — including Whitney, the runaway.

“I guess that made me very special. And they started pushing and doing extra tests on me,” said the Port Orchard, Washington, man. “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’s made it to the fatal age of 50 without symptoms, but he knows that’s no guarantee.

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


More than 6 million Americans, and about 55 million people worldwide, have Alzheimer’s. Getting older is 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 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 certain to get sick around the same age as their parent.

This near certainty allows scientists to study these families and learn critical information about how Alzheimer’s forms. It is now clear that silent changes occur in the brain at least two decades before the first symptoms—a potential window for intervention. Among the culprits, sticky amyloid starts to build up, followed by tau tangles that kill neurons.

What happens instead in the brains of the resistant?

“That’s why I’m here,” said Doug Whitney, who for years has given blood and spinal fluid samples and undergone brain scans and cognitive tests in the hunt 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 disease. First red flag for his mother: Thanksgiving 1971, when she forgot the pumpkin pie recipe she always made from memory.

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

Doctors didn’t know much about Alzheimer’s back then. It was not until the 1990s that separate research groups demonstrated that three different genes, when mutated, can each cause this uniquely 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 had started showing symptoms at 48. (Several other siblings were later tested and did not inherit the gene, though two more don’t know.)

“We’ve had about 10 years of kids calling home and their first question being, ‘How’s daddy?’ his wife Ione Whitney recalls. “When he turned 60, we kind of went, wow, we flipped the coin.”

But not as he hoped. In 2010, at the urging of a cousin, Whitney joined the St. Louis. He also agreed to a genetic test that he expected would provide final assurance that his children would not suffer from the same concern – only to learn that he had ultimately inherited the family mutation.

“It’s leveled with this result,” Brian Whitney said.

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


American researchers are not the only ones on the trail of 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 experience memory problems in their early 40s.

In contrast, one family member – Piedrahita de Villegas – was considered to have “extreme resistance”, with no cognitive symptoms until her 70s. Investigators flew 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 examination.

Her brain was riddled with amyloid plaques, a hallmark of Alzheimer’s. But the researchers found very little tau—and curiously, it wasn’t in the brain’s memory center but in a very different area.

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

DNA offered a suspect: An extremely rare mutation in an unrelated gene.

This APOE gene comes in different varieties, including one version that is notorious for increasing the risk of traditional Alzheimer’s during old age and another that is associated with a lower risk. Normally the APOE3 variant that Piedrahita de Villegas carried makes no difference to dementia.

But remarkably, both copies of the APOE3 gene were altered by the rare ‘Christchurch’ mutation – and researchers believe it blocks toxic tau.

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

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

This research is already having implications in a field that has long believed that fighting amyloid is the key step in treating Alzheimer’s.

Instead, maybe “we 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 could be multiple escape routes,” Hodes added.

In St. Louis, researchers are looking at another clue: Maybe something special about Whitney’s immune system is protecting his brain.

The findings also fuel the search for more escapees to compare. The University of Washington team recently began studying someone unrelated to Whitney. In Colombia, Quiroz said investigators are looking for a few more possible escapees.


This search for answers is not just a job for scientists. Whitney’s son Brian estimates he spends about 25 days each year getting different health checks and procedures, many of them away from his home in Manson, Washington, as part of Alzheimer’s research.

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

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

He spends a lot of time going fishing and camping with daughter Emily, now 12, who has yet to be told about the family gene. She hopes there will be some answers by the time she’s an adult and can consider getting tested.

“When I’m having a bad day and I decide maybe I shouldn’t continue (the research), I think about it 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 Education Media Group. AP is solely responsible for all content.

Leave a Comment