Seeking Alzheimer’s clues from ‘escapees’
ST. LOUIS — Doug Whitney inherited the same gene mutation that gave Alzheimer’s disease to his mother, brother and generations of other relatives by the unusually young age of 50.
Yet he’s a healthy 73, his mind still sharp. Somehow, the Washington man escaped his genetic fate.
So did a woman in Colombia who dodged her own family’s similar Alzheimer’s destiny for nearly three decades.
To scientists, these rare “escapees” didn’t just get lucky. They offer an unprecedented opportunity to learn how the body may naturally resist Alzheimer’s.
“It’s unique individuals oftentimes that really provide us with breakthroughs,” said Dr. Eric Mcdade of Washington University in St. Louis, where Whitney’s DNA is being scoured for answers.
The hope: If researchers could uncover and mimic whatever protects these escapees, they might develop better treatments — even preventive therapies — not only for families plagued by inherited Alzheimer’s, but for everyone.
“We are 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 actually change the world as in her case, how much we have learned from her.”
Quiroz’s team has a pretty good idea what protected Aliria Piedrahita de Villegas, an additional genetic oddity that apparently countered the damage from her family Alzheimer’s mutation. But testing 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 may have simply assumed they didn’t inherit their family’s mutation because they’re healthy long after the age their loved ones always get sick.
More than 6 million Americans, and an estimated 55 million people worldwide, have Alzheimer’s. Simply getting older is the main risk — it’s usually a disease of people over age 65.
Less than 1 percent 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 family Alzheimer’s gene. If they do, they’re almost guaranteed to get sick at about the same age as their parent did.
That near certainty allows scientists to study these families and learn critical information about how Alzheimer’s forms. It’s now clear that silent changes occur in the brain at least two decades before the first symptoms — a potential window to intervene. Among the culprits, sticky amyloid starts building up, followed by neuron-killing tau tangles.
What happens instead in the brains of the resilient?
“That’s why I’m here,” said Doug Whitney, who for years has given samples of blood and spinal fluid and undergone brain scans and cognitive exams, in the hunt for clues. “It’s so important that people in my situation come forward.”
U.S. researchers aren’t the only ones on the trail of 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 start showing memory problems in their early 40s.
In contrast, one family member — Piedrahita de Villegas — was deemed to have “extreme resistance,” with no cognitive symptoms until her 70s. Researchers 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 Colombia’s University of Antioquia for closer examination.
Her brain was jampacked with Alzheimer’s trademark amyloid plaques. But researchers found very little tau — and weirdly, it wasn’t in the brain’s memory hub but in a very different region.
Clearly something affected how tau formed
and where. “The thing that we don’t know for sure is why,” Quiroz said.
DNA offered a suspect: An ultra-rare mutation on an unrelated gene.
That APOE gene comes in different varieties, including a version notorious for raising people’s risk of traditional old-age Alzheimer’s and another that’s linked to lower risk. Normally the APOE3 version that Piedrahita de Villegas carried makes no difference for dementia.
But remarkably, both copies of her APOE3 gene were altered by the rare “Christchurch” mutation — and researchers think that blocked toxic tau.
To start proving it, Quiroz’s team used preserved cells from Piedrahita de Villegas and another Colombian patient to grow some cerebral tissue in lab dishes. Cells given the Christchurch mutation developed less tau.
“We still have more work to do but we’re getting closer to understanding the mechanism,” Quiroz said.
That research already has implications for a field that’s long considered fighting amyloid the key step to treating Alzheimer’s.
Instead, maybe “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 Washington man, doesn’t have that extra mutation, “there may be multiple pathways for escape,” Hodes added.
In St. Louis, researchers are checking out another clue: Maybe something special about Whitney’s immune system is protecting his brain.
The findings also are fueling a search for more escapees to compare. The Washington University team recently began studying one who’s unrelated to Whitney. In Colombia, Quiroz said researchers are looking into a few more possible escapees.