Seeking Alzheimer's clues from few who escape genetic fate
Scientists are digging into why a few people escape the rarest form of Alzheimer's, which is inherited and strikes young
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Your support makes all the difference.Doug Whitney inherited the same gene mutation that gave Alzheimerās disease to his mother, brother and generations of other relatives by the unusually young age of 50.
Yet heās 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 familyās similar Alzheimerās destiny for nearly three decades.
To scientists, these rare āescapeesā didnāt just get lucky. They offer an unprecedented opportunity to learn how the body may naturally resist Alzheimerās.
āItās unique individuals oftentimes that really provide us with breakthroughs,ā said Dr. Eric McDade of Washington University in St. Louis, where Whitneyās DNA is being scoured for answers.
The hope: If researchers could uncover and mimic whatever protects these escapees, they might develop better treatments ā even preventive therapies ā not only for families plagued by inherited Alzheimerās but for everyone.
āWe are just learning about this approach to the disease,ā said neuropsychologist Yakeel Quiroz of Massachusetts General Hospital, who helped study the Colombian woman. āOne person can actually change the world -- as in her case, how much we have learned from her.ā
Quirozās team has a pretty good idea what protected Aliria Piedrahita de Villegas -- an additional genetic oddity that apparently countered the damage from her family Alzheimerās mutation. But testing showed Whitney doesnāt have that protective factor so something else must be shielding his brain.
Now scientists are on the lookout for even more Alzheimerās escapees ā people who may have simply assumed they didnāt inherit their familyās mutation because theyāre healthy long after the age their loved ones always get sick.
āThey just think itās kind of luck of the draw and it may in fact be that theyāre resilient,ā said McDade, a researcher with a Washington University network that tracks about 600 members of multiple affected families ā including Whitney, the escapee.
āI guess that made me pretty special. And they started poking and prodding and doing extra testing on me,ā the Port Orchard, Washington, man said. āI told them, you know, Iām here for whatever you need.ā
Answers canāt come quickly enough for Whitneyās son Brian, who also inherited the devastating family gene. He's reached the fateful age of 50 without symptoms but knows thatās no guarantee.
āI liken my genetics to being a murder mystery,ā said Brian Whitney, who volunteers for Washington University studies that include testing an experimental preventive drug. āOur literal bodies of evidence are what they need to crack the case.ā
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More than 6 million Americans, and an estimated 55 million people worldwide, have Alzheimerās. Simply getting older is the main risk -- itās usually a disease of people over age 65.
Less than 1% of Alzheimerās 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 Alzheimerās gene. If they do, theyāre 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 Alzheimerās forms. Itās now clear that silent changes occur in the brain at least two decades before the first symptoms ā 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?
āThatās why Iām here,ā 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. āIt's so important that people in my situation come forward.ā
Whitneyās grandparents had 14 children and 10 of them developed early-onset Alzheimerās. The first red flag for his mother: Thanksgiving 1971, when she forgot the pumpkin pie recipe sheād always made from memory.
āFive years later she was gone,"' Whitney said.
Back then doctors didnāt know much about Alzheimerās. It wasnāt until the 1990s that separate research teams proved three different genes, when mutated, can each cause this uniquely inherited form of the disease. They each speed abnormal amyloid buildup.
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. (Some other siblings later were tested and didn't inherit the gene although two still don't know.)
āWe went through about 10 years when the kids would call home their first question was, āHowās Dad?āā his wife Ione Whitney recalled. āBy the time he turned 60 we kind of went, wow, we beat the coin toss.ā
But not the way heād hoped. In 2010, urged by a cousin, Whitney joined the St. Louis research. He also agreed to a genetic test he'd expected to provide final reassurance that his children wouldnāt face the same worry ā only to learn heād inherited the family mutation after all.
āHe kind of got leveled by that result,ā Brian Whitney said.
While Brian inherited the family gene, his sister Karen didnāt ā but she, too, is part of the same study, in the healthy comparison group.
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U.S. researchers arenāt the only ones on the trail of answers. In South America, scientists are tracking a huge extended family in Colombia that shares a similar Alzheimerās-causing variant. Carriers of this mutated gene start showing memory problems in their early 40s.
In contrast, one family member ā Piedrahita de Villegas ā was deemed to have āextreme resistance,ā with no cognitive symptoms until her 70s. Researchers flew the woman to Quirozās 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 Alzheimerās trademark amyloid plaques. But researchers found very little tau ā 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 donāt know for sure is why,ā 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 peopleās risk of traditional old-age Alzheimerās and another thatās 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 āChristchurchā mutation ā and researchers think that blocked toxic tau.
To start proving it, Quirozās 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.
āWe still have more work to do but weāre getting closer to understanding the mechanism," Quiroz said.
That research already has implications for a field thatās long considered fighting amyloid the key step to treating Alzheimerās.
Instead, maybe āwe just need to block whatās downstream of it,ā said Dr. Richard Hodes, director of the National Institute on Aging.
And since Whitney, the Washington man, doesnāt have that extra mutation, āthere may be multiple pathways for escape,ā Hodes added.
In St. Louis, researchers are checking out another clue: Maybe something special about Whitneyās 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.
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That search for answers isnāt just work for scientists. Whitneyās son Brian estimates he spends about 25 days each year undergoing different health checks and procedures, many of them far from his Manson, Washington, home, as part of Alzheimer's research.
That includes every two weeks, getting hooked up to a pump that administers an experimental amyloid-fighting drug. He also gets regular brain scans to check for side effects.
Living with the uncertainty is tough, and he sometimes has nightmares about Alzheimer's. He tries to follow what he now knows was his parentsā mantra: āMake the best of life till 50 and anything after that is a bonus.ā
He makes lots of time to go fishing and camping with daughter Emily, now 12, who hasnāt yet been told about the family gene. He hopes there will be some answers by the time she's an adult and can consider testing.
āWhen I have a bad day and decide maybe I should not continue (the research), I think of her and then that all vanishes," he said.
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