For 14 years now, American retiree Doug Whitney has been the one-person focus of exceptionally detailed scientific investigation. It is not because he is ill. It is because he was supposed to be ill.
The New York Times reports that during his three-day regular visits to Washington University School of Medicine in St Louis, he has cognitive assessments, neurological evaluations and blood draws that extracted multiple tubes for analysis.
Whitney (76), is a scientific unicorn with potential to provide answers about one of the world’s most devastating diseases. He has a rare genetic mutation that essentially guaranteed he would develop Alzheimer’s disease in his late 40s or early 50s and probably die within a decade.
His mother and nine of her 13 siblings developed Alzheimer’s and died in the prime of their lives. So did his oldest brother, and other relatives going back generations. It is the largest family in the United States known to have an Alzheimer’s-causing mutation.
“Nobody in history had ever dodged that bullet,” Whitney said.
But somehow, he has done just that. Something has shielded him from his genetic destiny, allowing him to escape Alzheimer’s for at least 25 years longer than anyone expected.
Scientists are searching for the recipe for his biological secret sauce. Its discovery could potentially lead to medications or gene therapies to prevent, treat or possibly even cure Alzheimer’s, goals that continue to frustrate researchers despite decades of efforts.
Now, after years of studying Whitney, researchers are unearthing clues about his magic combination of genes, molecules and environmental influences.
Alzheimer’s afflicts about 32m people worldwide. In most cases, the direct cause is unknown and symptoms begin after 65.
About 1% of cases, however, are known to be caused by one of three genetic mutations. Inheriting one of those almost always causes early-onset Alzheimer’s, which often progresses quickly toward death.
Because genetic early-onset Alzheimer’s closely resembles typical late-onset Alzheimer’s, studying these families can yield important insights.
“Almost everything we know about Alzheimer’s today comes from these rare mutations,” Dr Kenneth Kosik, a neuroscientist at the University of California-Santa Barbara, who is not part of Whitney’s research team, said.
‘I should have got sick’
Whitney’s family has the rarest mutation, Presenilin 2. The mutation has been traced to German immigrants who settled in two villages near the Volga River in Russia in the 18th century. Mutation carriers in Whitney’s family usually began exhibiting memory and thinking problems between 44 and 53.
When Whitney turned 50, his wife, Ione (75), said, she and their two children began watching for signs.
She had been bracing herself since the early 1970s, when his mother suddenly forgot how to make her beloved pumpkin pie for Thanksgiving, and the couple learned that doctors had determined that the Alzheimer’s afflicting his relatives was hereditary. They were expecting their first child at the time.
When he reached 55, the age his mother and brother died, his family’s antennae became even more attuned. They were delighted when he turned 60, with no signs at all of the disease.
Then, a cousin, Gary Reiswig, contacted them saying that he was writing a book about the family and that researchers were seeking more members of families with early-onset Alzheimer’s mutations to study.
Whitney agreed to participate and to undergo genetic testing, assuming he did not have the mutation. But on his 62nd birthday, he learned that he did.
“I was speechless,” he said. “I found I was at least 10 or 12 years past when I should have got sick.”
Dr Randall Bateman, a neurologist who directs the Dominantly Inherited Alzheimer Network (DIAN), at Washington University, was stunned, too.
“We tested him three times,” he said. “We didn’t believe the results that he was positive.”
Year after year, researchers became increasingly perplexed that Whitney remained unimpaired. They set out to determine what was protecting him.
“We had a bunch of crazy ideas,” Bateman said. “We started pulling everything off the shelves and anything that we thought we could have him do.” They tested and analysed. They gave him surveys about his childhood, work history and environmental exposures.
Escaping genetic destiny
Researchers call Whitney an Alzheimer’s escapee. Scientists have so far conclusively identified two others in the world who were resilient to the early-onset dementia their mutations should have caused.
Both had another mutation, Presenilin 1, and belonged to a large extended family in Colombia. They remained cognitively unimpaired for at least two decades longer than expected and died in their 70s from other illness.
Alzheimer’s is characterised by abnormal accumulations of two proteins in the brain: amyloid, which starts clumping into plaques at least 20 years before symptoms emerge, and tau, which forms tangles after amyloid accumulate. Tau is much more correlated with cognitive decline.
The brains of both Colombian “escapees” were laden with amyloid but had little tau in regions associated with Alzheimer’s, said Yakeel Quiroz, a neuropsychologist at Boston University.
She and other scientists believe the Colombian woman was protected by having two copies of an extremely rare genetic variant called the Christchurch mutation. They say the Colombian man’s resilience might have come from another variant called RELN-COLBOS.
Not all Alzheimer’s researchers are convinced that Christchurch and RELN-COLBOS mutations helped deter Alzheimer’s in those cases.
Dr Michael Greicius, a neurologist at Stanford University School of Medicine who studies the genetics of Alzheimer’s, said identifying a mutation that protects one person is difficult without analogous cases for comparison.
“You just can’t winnow down the millions of variants that every individual has with one subject and nobody to filter against,” said Greicius, whose lab is analysing data on the two Colombians.
“There’s incredible potential for these rare, protected individuals to provide critical new insights.”
Whitney’s brain is full of amyloid, probably even more than other mutation carriers in his family because he has lived so long, said Dr Jorge Llibre-Guerra, a neurologist at Washington University who co-authored a recent study on Whitney’s case. But he has very little tau.
“He’s resistant to tau aggregation and tau spread,” said Llibre-Guerra, who helps lead DIAN’s clinical trials. “That’s where his resilience is.”
Whitney has tau accumulation in only one brain region, the left occipital lobe. That area is involved in visual-spatial functions and does not play a major role in Alzheimer’s, Llibre-Guerra said.
Quiroz said the Colombian woman’s tau accumulated in the same general area. The cases show that “people can actually have amyloid pathology without the tau, and that amyloid is not enough to actually create a decline”, she said.
Determining how progression from amyloid build-up to tau accumulation was interrupted could provide a treatment guide.
“They have now shown the decoupling of amyloid from tau tangles and, when that happens, the sparing of dementia,” said Kosik, who reviewed the Whitney study for Nature Medicine. “That’s where the science lies.”
Clues emerge
Unravelling the riddle of Whitney’s resilience has revealed an intricate neurological ballet.
There is his DNA, found to include several gene variants his afflicted relatives don’t have. Most interesting are three mutations possibly involved in neuro-inflamamation or tau pathology, Llibre-Guerra said.
There is Whitney’s immune system. His inflammatory response is lower than other mutation carriers, meaning his immune system may be shielding him by not over-reacting to amyloid.
And there is an especially surprising discovery: Whitney has an excess of heat shock proteins, which help keep other proteins from folding incorrectly, a defect associated with many neurological disorders.
“His are significantly higher than what you would expect,” Llibre-Guerra said. “Those proteins may be preventing the misfolded proteins, especially tau, from spreading throughout the brain.”
Whitney’s Navy role – working for about a decade in the engine room of a steam-propelled ship – might have driven his accumulation of heat shock proteins, researchers said.
“The heat down there… temperatures of 110 degrees for four hours at a time,” Whitney recalled. “We’d do a lot of sweating.”
All of those factors, possibly with others that remain undiscovered, may be acting in combination to protect him, researchers said.
Researchers wonder if Whitney's accumulation of heat shock proteins, perhaps acquired from those Navy years in the engine room of a steam-propelled ship, might be helping to protect him from Alzheimer's.
A generational puzzle
Researchers are also interested in the Whitneys’ son, who inherited the mutation from his father.
At 53, Brian Whitney, who works for a flooring store and is a volunteer firefighter in Washington, remains cognitively healthy. He does not have any of the possibly protective gene variants identified in his father. And he didn’t have the same years-long exposure to high heat.
It is possible he has benefited from anti-amyloid drugs he received in a clinical trial led by DIAN, Bateman said. Researchers recently reported that out of 73 trial participants, the 22 who received anti-amyloid drugs the longest – eight years on average – had half the risk of developing cognitive problems as people who didn’t receive the drugs.
Researchers cannot disclose if Brian was among those 22 who received a drug and not a placebo in the trial’s early phase. But in later phases, he received an anti-amyloid drug, and he currently gets infusions of another one.
Brian is acutely aware that a cousin his age developed Alzheimer’s at 50, and had to move in with relatives.
Brian plays word games and Sudoku to keep his mind sharp.
“Sometimes I’ve had a bad day and forgotten a couple people’s names and sort of got a little concerned,” he said. Then, he’ll test himself on the names, and “usually, I’ll come back around and go, ‘Oh that was so and so.’”
Generally, though, he doesn’t dwell on it every single day. “Early on, I did, but maybe I’ve got to the point where this is what it is.”
During Doug Whitney’s recent testing in St Louis, he told Llibre-Guerra he wasn’t experiencing difficulties, except for sometimes forgetting names and recent events.
He accurately answered questions during a cognitive assessment. Later, Llibre-Guerra said that compared with four years ago, his cognitive scores showed no significant decline, only a slight overall drop, probably attributable to his age.
On some tests, he actually scored better, the doctor said, noting that scores can fluctuate.
The one test on which his scores have steadily worsened involves visual-spatial function, which could reflect the tau accumulation in the brain area linked to such skills, Llibre-Guerra said.
His performance far exceeds that of relatives with the mutation, most of them much younger.
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