The Man Who Defied Alzheimer’s: Unraveling Doug Whitney’s Remarkable Resilience

Doug Whitney was genetically predestined for early-onset Alzheimer’s, yet he remains cognitively healthy decades past expectations. Scientists are now intensely studying his unique biology, searching for the secrets that could unlock new treatments or even a cure for this devastating disease.

Reported and photographed in St. Louis, Toronto and Port Orchard, Wash.

Before dawn on a March morning, Doug Whitney arrived at a medical center 2,000 miles from his home, ready to participate in an extraordinary scientific investigation. This mild-mannered, bespectacled retiree was about to become a superhuman research subject.

First, a doctor carefully performed a lumbar puncture to extract cerebrospinal fluid—what a research nurse affectionately called “liquid gold” due to its invaluable biological insights. Next, a sample of his skin cells was taken. This was followed by an injection of a radioactive tracer and a 30-minute brain scan, requiring him to lie perfectly still with a thermoplastic mask covering his face. Another tracer injection and another brain scan soon followed.

Over his three-day visit to the Washington University center in St. Louis, Mr. Whitney also underwent comprehensive cognitive assessments, neurological evaluations, and numerous blood draws, yielding multiple tubes for detailed analysis.

For 14 years, Mr. Whitney has been the sole focus of this intensely rigorous scientific inquiry, traveling regularly from his home in Port Orchard, Washington. He isn’t ill; quite the opposite. He was *expected* to be ill.

Mr. Whitney, now 76, is a true scientific rarity, a ‘unicorn’ offering the potential to unlock crucial answers about one of the world’s most devastating diseases. He carries a rare genetic mutation that virtually guaranteed he would develop Alzheimer’s in his late 40s or early 50s, likely leading to his death within a decade.

His mother and nine of her thirteen siblings succumbed to Alzheimer’s in the prime of their lives. His oldest brother also died from the disease, as have other relatives spanning generations. His family holds the somber distinction of being the largest in the United States known to carry an Alzheimer’s-causing mutation.

“Nobody in history had ever dodged that bullet,” Mr. Whitney recounted.

Yet, he has done precisely that. An unknown factor has shielded him from his genetic fate, allowing him to remain free of Alzheimer’s for at least 25 years beyond all medical expectations.

Scientists are now on a quest to uncover the components of his unique biological protection. Its discovery could pave the way for new medications or gene therapies to prevent, treat, or possibly even cure Alzheimer’s—ambitious goals that have eluded researchers for decades.

“This is an extraordinary case,” commented Dr. Kenneth Kosik, a neuroscientist at the University of California, Santa Barbara, who is not directly involved in Mr. Whitney’s research. “The implications are immense, both in the answers it provides and the questions it prompts.”

After years of intensive study, researchers are beginning to unearth critical clues about Mr. Whitney’s remarkable combination of genes, molecules, and environmental influences.

Alzheimer’s disease affects approximately seven million Americans and an estimated 32 million people worldwide. In most instances, the direct cause remains unknown, with symptoms typically appearing after age 65.

However, about one percent of cases are definitively linked to one of three specific genetic mutations. Inheriting one of these mutations almost invariably leads to early-onset Alzheimer’s, which often progresses rapidly.

Because genetic early-onset Alzheimer’s closely mirrors the more common late-onset form, studying these unique families offers invaluable insights.

“Virtually everything we understand about Alzheimer’s today stems from the study of these rare mutations,” Dr. Kosik emphasized.

‘I should have got sick’

Mr. Whitney’s family carries the rarest of these mutations, Presenilin 2. This mutation has been traced back to German immigrants who settled in two villages near Russia’s Volga River in the 18th century. Typically, mutation carriers in Mr. Whitney’s family, whose roots are in Oklahoma farmlands, began showing signs of memory and thinking problems between ages 44 and 53.

When Mr. Whitney reached 50, his wife, Ione, recalls that she and their two children began to watch anxiously for any initial symptoms.

Her apprehension had started in the early 1970s, when Mr. Whitney’s mother suddenly couldn’t recall how to make her cherished pumpkin pie for Thanksgiving. It was then that the couple learned the Alzheimer’s affecting his relatives was hereditary. They were expecting their first child at the time.

“I was just so angry at Doug, at the world, how unfair that was,” she recollected.

Mr. Whitney, whose calm and unruffled demeanor comes from two decades serving in the Navy, responded with characteristic composure. “’We’ve got some choices,’” his wife remembers him saying. “‘You can be angry all your life. Do you want to not have this child? Or do we want to enjoy life and have a family?’”

Her anger subsided as she embraced his perspective. “Doug’s attitude was, ‘We don’t have to worry about this until there’s something to worry about,’” she explained.

When he turned 55, the age at which both his mother and brother had died, his family’s vigilance grew even sharper.

“’How’s Dad doing?’” their son and daughter would inquire every time they called home.

“’I don’t see anything,’” Mrs. Whitney would reply.

“When he turned 60,” she recalled, “it was like, ‘We are good.’”

Then, a cousin, Gary Reiswig, contacted them. He was writing a book about the family, and researchers were looking for more family members with early-onset Alzheimer’s mutations to study.

Mr. Whitney agreed to participate and undergo genetic testing, fully expecting to find that he did not have the mutation. But on his 62nd birthday, he received the shocking news: he did.

“I was speechless,” he recalled. “I mean, 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 equally astonished.

“We tested him three separate times,” he stated. “We simply couldn’t believe the results that he was positive.”

Year after year, researchers grew increasingly perplexed by Mr. Whitney’s continued unimpaired state. He kept his job, meticulously organizing submarine maintenance procedures for a military contractor.

“We were asking, ‘What’s happening here?’” Dr. Bateman said. “He’s still doing fine, still working, still driving around normally.”

Their mission then became to pinpoint precisely what was protecting him.

“We brainstormed all sorts of wild theories,” Dr. Bateman admitted. “We literally started pulling every tool off the shelves and trying anything we could think of.” They conducted countless tests and analyses. They administered surveys covering his childhood, work history, and environmental exposures.

“We basically threw the entire kitchen sink at him,” Dr. Bateman summarized.

Escaping genetic destiny

Researchers refer to Mr. Whitney as an “Alzheimer’s escapee.” So far, only two other individuals worldwide have been conclusively identified as resilient to the early-onset dementia that their mutations should have caused.

Both previous cases involved the Presenilin 1 mutation and were members of a large extended family in Colombia. They remained cognitively unimpaired for at least two decades longer than anticipated, ultimately dying in their 70s from other unrelated illnesses.

Alzheimer’s is fundamentally characterized by the abnormal accumulation of two key proteins in the brain: amyloid, which begins clumping into plaques over 20 years before symptoms manifest, and tau, which forms tangles after amyloid aggregation. Tau pathology is much more strongly linked to cognitive decline.

The brains of both Colombian “escapees” were heavily laden with amyloid, yet exhibited very little tau in the brain regions typically associated with Alzheimer’s, according to Yakeel Quiroz, a neuropsychologist at Boston University.

She and other scientists hypothesize that the Colombian woman was protected by possessing two copies of an exceptionally rare genetic variant known as the Christchurch mutation. They suggest that the Colombian man’s resilience may have stemmed from another variant called RELN-COLBOS.

However, not all Alzheimer’s researchers are entirely convinced that the Christchurch and RELN-COLBOS mutations were definitively responsible for deterring Alzheimer’s in these specific cases.

Dr. Michael Greicius, a neurologist at Stanford University School of Medicine specializing in Alzheimer’s genetics, noted that identifying a single protective mutation in one individual is challenging without comparable cases for rigorous comparison.

“You simply cannot sift through the millions of genetic variants each individual possesses with just one subject and no comparative filter,” Dr. Greicius explained, whose lab is currently analyzing data from the two Colombian cases. Nevertheless, he asserted, “there is immense potential for these rare, protected individuals to offer critical new insights.”

Mr. Whitney’s brain is, in fact, filled with amyloid, likely even more so than other mutation carriers in his family due to his prolonged life, explained Dr. Jorge Llibre-Guerra, a neurologist at Washington University and co-author of a recent study on Mr. Whitney’s case. Crucially, however, he has very little tau.

“He exhibits resistance to tau aggregation and tau spread,” stated Dr. Llibre-Guerra, who also plays a key role in leading DIAN’s clinical trials. “That is precisely where his resilience lies.”

Remarkably, Mr. Whitney only shows tau accumulation in a single brain region: the left occipital lobe. This area is primarily involved in visual-spatial functions and does not typically play a major role in the progression of Alzheimer’s disease, Dr. Llibre-Guerra clarified.

Dr. Quiroz observed that the Colombian woman’s tau also accumulated in the same general brain area. These cases demonstrate that “individuals can indeed develop amyloid pathology without accompanying tau, and that amyloid alone is insufficient to cause cognitive decline,” she emphasized.

Pinpointing how the progression from amyloid buildup to tau accumulation was effectively interrupted could provide an invaluable roadmap for future treatments.

“They have unequivocally demonstrated the decoupling of amyloid from tau tangles, and when that occurs, the result is a remarkable preservation from dementia,” Dr. Kosik, who reviewed the Whitney study for Nature Medicine, commented. “That is the core scientific breakthrough here.”

Clues emerge

Unraveling the intricate puzzle of Mr. Whitney’s resilience has unveiled a complex neurological dance of protective factors.

His DNA, for instance, has been found by researchers to contain several gene variants not present in his afflicted relatives. Dr. Llibre-Guerra points to three mutations of particular interest, potentially involved in neuroinflammation or tau pathology.

Then there is Mr. Whitney’s immune system. “Your inflammatory response is notably lower than that of other mutation carriers,” Dr. Llibre-Guerra explained to him during the March visit, suggesting that his immune system might be protecting him by preventing an overreaction to amyloid deposits.

An especially surprising discovery is Mr. Whitney’s abundance of heat shock proteins. These proteins play a crucial role in preventing other proteins from misfolding, a defect closely associated with numerous neurological disorders.

“The levels you possess are significantly higher than what we would typically expect,” Dr. Llibre-Guerra informed him. “It’s possible that these proteins are actively preventing misfolded proteins, especially tau, from disseminating throughout your brain.”

Researchers propose that Mr. Whitney’s extensive service in the Navy—specifically, a decade spent working in the engine room of a steam-propelled ship—might have contributed to this accumulation of heat shock proteins.

“The heat down there, you could expect temperatures of 110 degrees for four hours at a stretch,” Mr. Whitney recounted. “We did a lot of sweating.”

It was so intensely hot that he occasionally needed to be hosed down just to cool off.

All these factors, potentially alongside other as-yet-undiscovered elements, may be working in concert to safeguard him, researchers hypothesize.

His case is so profoundly complex that Dr. Bateman described his team’s recent published study as nothing less than “a call to arms.” Its aim is “to draw attention from other researchers, to say, ‘Hey, here’s an incredibly important person, a truly significant case, and we desperately need your help to unravel this mystery.’”

A generational puzzle

Researchers are also keenly interested in the Whitneys’ son, Brian, who inherited the same mutation from his father.

At 53, Brian Whitney, who works at a flooring store and volunteers as a firefighter in Manson, Washington, remains cognitively healthy. Researchers note that he does not possess any of the potentially protective gene variants identified in his father, nor did he experience the same prolonged exposure to high heat.

It’s conceivable that he has benefited from anti-amyloid drugs he received as part of a clinical trial led by DIAN, Dr. Bateman suggested. Researchers recently reported that among 73 trial participants, the 22 who received anti-amyloid drugs for the longest duration—an average of eight years—experienced half the risk of developing cognitive problems compared to those who did not receive the drugs. While researchers cannot disclose if Brian was among those 22 who received an active drug rather than a placebo in the trial’s early phase, he has since received an anti-amyloid drug in later phases and currently receives infusions of another.

“Why am I still asymptomatic?” Brian pondered. “Is it because I’m like my dad? Or is it because of the drug therapies?”

Brian is acutely aware that a cousin his age developed Alzheimer’s at 50, necessitating a move in with relatives and accommodations at his manufacturing job.

To keep his mind sharp, Brian engages in word games and Sudoku. “Sometimes I’ve had a bad day and forgotten a couple of people’s names and sort of got a little concerned,” he admitted. Then, he’ll challenge himself to recall the names, and “usually, I’ll come back around and go, ‘Oh, that was so and so.’”

Generally, however, “I don’t really feel like I dwell on it every single day,” he said. “Early on, I certainly did, but perhaps I’ve reached a point where I accept it for what it is.”

This resilient approach seems to have been adopted by Brian’s 15-year-old daughter. While Brian and his wife have not heavily emphasized the family’s Alzheimer’s history, their daughter has observed nurses giving him drug infusions at home and has accompanied him to St. Louis. She has expressed to her parents that she is not afraid to be tested for the mutation once she turns 18, and if she has it, she is committed to participating in studies.

“We’re simply grateful to be a part of any and all research related to Alzheimer’s,” Brian affirmed.

Some relatives, however, are less forthcoming about the disease. “There are members of the family who prefer not to discuss it,” Ione Whitney noted. “It’s genuinely difficult to share your medical information publicly, because everyone seems to have a theory—like, if you just ate right, this wouldn’t happen to you.”

Yet, she firmly believes, “Someone has to speak out about this, because we’re making no progress with everyone silently coping in their own homes or within their immediate families.”

Their dedication runs deep; Mrs. Whitney, 75, even crafted a quilt that now hangs prominently in the researchers’ offices.

“It’s an opportunity to contribute something valuable to humanity,” Brian remarked. “Getting involved in research can be intimidating,” he acknowledged. But “it has almost felt liberating, because I can confront this challenge within a community of others who are experiencing similar struggles.”

During Doug Whitney’s most recent battery of tests in St. Louis, he informed Dr. Llibre-Guerra that he wasn’t encountering any significant difficulties, apart from an occasional lapse in recalling names and recent events.

He accurately answered all questions during a cognitive assessment. When asked to differentiate between a lie and a mistake, he thoughtfully responded, “a mistake is generally unintentional; a lie is generally intentional.”

Later, Dr. Llibre-Guerra confirmed that, compared to his scores four years prior, Mr. Whitney’s cognitive performance showed no substantial decline, only a slight overall dip likely attributed to his age. In fact, he scored better on some tests, a fluctuation that Dr. Llibre-Guerra noted is common.

The only area where his scores have consistently worsened is in visual-spatial function, which Dr. Llibre-Guerra believes could be linked to the tau accumulation observed in the specific brain region responsible for such skills.

His performance vastly surpasses that of his relatives who carry the same mutation, most of whom are considerably younger. When they typically reach the age of impairment in the family, Dr. Llibre-Guerra stated, “you invariably begin to see a decline, and it’s usually very consistent.”

Scientists have yet to pinpoint Mr. Whitney’s “missing needle in the haystack” and declare a “eureka!” moment, Dr. Bateman acknowledged. However, they are relentless in their pursuit. The profound mystery that protects Doug Whitney is far too valuable to remain unsolved.