Tariot and Reiman sat through this dialogue with more than twenty companies. One of them was Genentech, a San Francisco–based biotechnology company that was acquired by Roche in 2009. Founded in the mid-1970s, the company was holding among its assets crenezumab, the antibody designed to latch on to—and clear—amyloid in the brain.
• • •
Crenezumab began its life as a molecule invented by scientists at a Swiss biotechnology company, AC Immune. The company was founded in 2003 on a shoestring budget of $3 million by Andrea Pfeifer, a German scientist who hoped to help address unsolved public health issues. AC Immune sold its molecule to Genentech, which developed it into crenezumab.
Months after the sale, Pfeifer learned about the Banner Institute’s plans to conduct Alzheimer’s research in Colombia. She was so touched by the situation that she considered fund-raising for the cause, never knowing that it was her own invention that would be used in the trial. The Banner team selected crenezumab in 2012. When the AC Immune team learned of the connection, it somehow seemed to validate the nine years of work they’d spent developing the molecule. The entire group erupted in celebration.
When asked if she thought crenezumab will work, Andrea Pfeifer spoke with certainty. Even in high doses, crenezumab didn’t carry the side effect that had sidelined other anti-amyloid antibodies—vasogenic edema, an abnormal accumulation of fluid and tiny hemorrhages in the brain. (This complication was also known as ARIA, or amyloid-related imaging abnormalities.) Crenezumab binded to amyloid beta by recognizing when the protein’s composition had changed from healthy to toxic. Certain that the drug would sweep amyloid beta from the body, Pfeifer said the real question was: Is that the root cause of Alzheimer’s disease?
“I have a strong belief that it will do something, yes,” she said. To her, the only variables were related to optimization: What is the best timing? What is the best dose? What is the best schedule?
And just in case amyloid beta wasn’t the only target, AC Immune was also working on the development of an anti-tau molecule.
If her efforts achieved the positive results that had so far eluded other treatments, “honestly speaking, for me, it would be the fulfillment of a dream,” she said. “We do hope that our molecule—any molecule—will change the destination of these people and their families.”
• • •
Because of the potential risk of working in Colombia, the company’s leaders wanted to travel to the country to see the setup for themselves. The team met Lopera, saw the hospital where he worked, examined the satellite locations where participants would travel for their experimental shots. When they returned, they were convinced.
Carole Ho, the neurologist who oversaw Genentech’s early clinical development group, recalled driving through the precarious mountain roads of the Andes, where Lopera once traveled by horseback, and realizing the dedication that had driven him for twenty-five years. As she explained it, Genentech’s motivation came from the belief that science was on its side.
“It’s that deep scientific conviction,” she said. “You should believe in the science, and follow the science.”
Identifying amyloid as a certain target would count as a significant victory, even if Genentech didn’t reap a huge profit, she said. And she was impressed by how homogenous the study subjects were in Colombia.
“It’s in a lot of ways the most controlled clinical trial that you could embark on,” Ho said.
To Tariot, the company’s decision was nothing short of brilliant. Genentech was a latecomer in the market; by the time the company had teamed up with Banner, several competitors were already in late-stage human trials and attracting an enviable amount of publicity.
“Here’s Genentech behind a bunch of big boys in terms of immunization therapies for Alzheimer’s disease. And they say, ‘Well, how could we do better?’ And so they end up with a compound that is more potent, targets more broadly, and is apparently free of this potentially important liability,” Tariot said. “I suppose a subtext to all of this is: Is it good to be first, or not? This might be an example of it being good not to be first.”
• • •
As the pieces for the Colombia clinical trial fell into place, Reiman and Tariot’s plan began to take shape. While they tried to come up with a strategy for winning regulatory approval from the FDA, they sought the advice of Jur Strobos, the former director of the policy research staff in the FDA commissioner’s office. Strobos offered encouragement: Their idea was not impossible, he said. The problem was that most clinical trials for central nervous system disorders just didn’t fit into the FDA’s traditional avenues for approval. But they could find clues for success in other diseases, including HIV, cancer, and heart disease.
What the Banner team should not do, Strobos warned, was to approach the FDA out of the blue with a plan and a drug, begging for approval. Instead, he suggested a compelling rationale for an unorthodox plan that was well designed, with evidence backing up the reasons for each element of the design, and the consensus of the rest of the Alzheimer’s field indicating that this nontraditional approach was the way to go.
Scientists, patient advocacy groups, the NIH, international experts—all had to agree that the trials weren’t some half-baked idea. Check, check, and check. All systems were go; now it was time to see what crenezumab would do. Participants would get two shots under the skin every two weeks for the duration of the study. Because it was a trial aimed at proving a clinical benefit—that the drug would help people think and function better, as observed in their behavior—it was a tall order, and some might have called what Banner planned to do nothing short of grandiose.
It was an adjective Reiman had learned to embrace, even as he acknowledged the uncertainty of what they were about to do.
“We think we have a chance. No guarantee—we think we have a chance,” he said. “Speaking of grandiose, our mission is to end Alzheimer’s without losing a generation.”
On December 23, 2013, the Banner Alzheimer’s Institute announced that the team had officially administered the first doses of crenezumab to participants in Colombia. For Francisco Lopera, it was a moment he had waited more than three decades to witness.
The clinical trial in the paisa families will be formally completed in 2020, the point at which the results can be considered truly definitive, says Ken Kosik, Lopera’s longtime research partner. In a context where seven years may see the death of several of the study’s subjects with no further answers, that thought gives both Kosik and Lopera pause; they have walked, quite literally, down so many crumbling roads just to reach this point, largely without recognition, often facing hostility from the world outside their science.
“We don’t have time to do all the research we can do,” Lopera said ruefully. “We will not have time. Because we are using all our lives studying these families, and now we are starting.”
Kosik agreed: “We are now old, and this project is just beginning.”
Twenty-Six
LIKE FATHER, LIKE SON
OVER THE YEARS, oil companies moved Dean’s best friend, Monte Olsen, around the country; such was the nature of the job. One summer, he was asked to consider Dubai. After consulting with Dean and another friend, he turned it down. But then the company came back and offered him Australia.
At first, Monte declined again; his youngest son was just about to graduate from high school, and he didn’t want to uproot the boy. The next time he was asked, he accepted. But Dean was very much on his mind. In the first year and a half he was in Australia, Monte came back to the United States to attend five funerals. Despite his best attempts to ignore Dean’s fate, he was acutely aware of how little time he might have left with the man he considered his brother. And like Becky Vork, who was so devoted to Dean’s Wisconsin cousin, Colleen, Monte’s true friendship was a blessing.
They struck a bargain: When the time came where he could not live on his own, Dean would move in with Monte, who would hire caregivers. It’s a
promise that husbands, wives, children, siblings, and friends have made to thousands of Alzheimer’s patients over the years. It was, in fact, the promise that Sharon DeMoe made to Jerry. The reality of keeping that promise is something most people can’t anticipate: The hallucinations. The fear. The wandering. The repetition. It means mopping up accidents, hiding valuables, hiding weapons—or objects that can be used as weapons. When the patient is only middle-aged, it means physically restraining the sudden violence of someone who is still strong, who has no boundaries—who might strike out at children, at old people, at women, even if that would have been unthinkable before the disease. In fact, Alzheimer’s patients are often most violent toward the people they love best, as Gail had learned.
Monte, veteran of the decline of Brian and Doug—as well as ill health in members of his own family—knew better than most what he was promising to do. His plan did not change.
He never thought it was a good idea for Dean to learn his genetic status, believing somehow that the knowledge would create the reality. If he never found out, he never needed to believe he had it. But since Dean went ahead and did it anyway, Monte promised to remain loyal.
“I don’t want to accept it, and Dean knows that,” he said. Still, Dean talked to him about it. He told him about the research he was doing in Pittsburgh. He talked about his hope of helping someone else. He became, in Monte’s eyes, a hero.
“This gene will kick in when it decides to kick in,” Monte said. “I hope something doesn’t happen to him before it happens to me.”
• • •
Living in Tioga during the workweek meant that Dean had ample opportunity to spend time with Doug. But while other family members made time to go to the nursing home, or to take him on outings, Dean became increasingly distant. Watching his brother struggle was just another reminder of what he was up against. He visited, but only every so often; and when he did, it ruined his day.
The marked difference between Doug’s decline and Dean’s relative stability illustrated another puzzle that Alzheimer’s research had long sought to explain: what caused such a wide gap in the timing of symptoms among family members? Doug and Dean were only one example; there were also Pat and her oldest daughter, Dawn, both of whom had been in nursing homes at the same time; and Julia Tatro Noonan and her identical twin sister, Agnes, whose symptoms—and deaths—happened about a decade apart.
In Santa Barbara, California, Ken Kosik’s university research team thought it might have one answer. Matthew Lalli, a postdoctoral student working in Kosik’s lab, sequenced the genomes of one hundred members of the paisa family. In people whose onset was delayed, they found a gene variant preventing the accumulation of a protein called eotaxin, the levels of which rise as people age. The team theorized that eotaxin levels might affect the age of onset in Alzheimer’s, especially since aging is the single highest risk factor for developing the disease among the general population. Unlike epigenetic changes—which do not change the DNA sequence, but do modify DNA in other ways—the eotaxin variant actually changes a nucleotide in the person’s DNA.
Kosik’s group partnered with another University of California team in San Francisco to measure eotaxin in 150 people with Alzheimer’s or dementia. People with the same gene variant suppressing that protein that had been found in the paisa also had a modest delay in the onset of their Alzheimer’s disease.
Kosik said the variant occurs in about 30 percent of the general population, and could potentially be a therapeutic target to delay Alzheimer’s. But he cautioned that more research needed to be done in larger studies to evaluate the team’s findings.
• • •
While Dean’s family was also reluctant to accept his fate, they were fully supportive of his efforts to combat the disease. His son, Tyler DeMoe, made his first trip to Pittsburgh when he turned twenty-two, and he was eager to participate in the research for which his father and extended family had been a mainstay.
When the DIAN study’s doctor told him how important his contribution to research could be, Tyler thanked him for the opportunity.
“I am extremely humbled to be a part of these studies, and very excited to think that I may be able to contribute to a breakthrough,” the doctor said.
“Yeah, I feel the same,” said Tyler. And he meant it.
By the time Tyler sat down that Monday morning to answer questions, he’d already been in Pittsburgh for two days—enough time for him to have a few adventures. The study’s protocol required him to bring a partner who could separately answer questions about his cognitive abilities. For patients like his father, or like Sherry DeMoe or his aunt Lori, the study partner offered an objective point of view: whether the patient was struggling more with memory or becoming more agitated, for example. People with Alzheimer’s often don’t perceive even obvious changes in themselves.
But for Tyler, who had no symptoms and didn’t even know whether he carried the gene, the study partner was merely a formality. He chose his friend Zack Brorby, whom he’d known since grade school. They were neighbors, and now they were students together at the University of North Dakota.
The day they landed, the boys headed down to the city’s South Side to find a sports bar so they could watch some college basketball. They settled on a place called Mario’s and began talking to other patrons at the bar, who asked where they were from.
“North Dakota,” Tyler answered.
“What brings you to Pittsburgh?”
“It’s a long story,” he said at first. After a few beers, he switched his answer to: “I’m participating in some research.”
“You’re going to be a doctor?”
“No, I’m gonna get studied,” he said.
Some people were genuinely interested; one guy shook Tyler’s hand. People were intrigued when he said the research was for Alzheimer’s disease; he barely looked old enough to be allowed in the bar.
Tyler was used to it. Most of his friends knew about his family’s history, but they didn’t necessarily understand the full implications. For example, a lot of them didn’t know Alzheimer’s was fatal, and he had to explain it to them.
“I’m like, ‘Yeah, man.’ It’s intense when you talk about it,” he said. But he refused to let it scare him. He was thoughtful about the disease, but it didn’t consume him. He believed in living life as fully as possible. Tyler was ever his father’s son.
He moved through the battery of tests at Pittsburgh like a pro. Every morning he woke up, and he and Zack left the hotel, passing the same bum hanging out in front of a gas station across the street; Tyler gave him a cigarette every day. He charmed everyone on the staff at the Alzheimer’s center, answering all the screening questions with endearing honesty. When a social worker asked him if he abused alcohol, remembering Mario’s, he said, “Well, I might have abused it the first night I was here.”
The MRI, which had spooked his aunt Karla and driven other family members crazy with its loud noise, lulled him right to sleep. He was fascinated by the PiB that was created down the hall. Even the PET scan, which required him to have a soft plastic mask molded to his face to keep his head still while the scanner operated, didn’t faze him; he asked if he could keep the mask afterward as a souvenir.
“I might wear this out tonight,” he said.
After talking to a genetic counselor, he decided that, at least for now, he didn’t want to learn his genetic status. There would be plenty of time for that in the future, if he needed to know.
Twenty-Seven
ALL THE CARDS ARE ON THE TABLE
THE SAME SUMMER that Tyler visited the University of Pittsburgh for the first time, his aunt Lori McIntyre came back for her annual trip.
Seated at a conference table, surrounded by an elite team of researchers, Lori was as relaxed as she’d ever been. She showed off her new T-shirt, which bore the ironic motto Where am I? The staff who hadn’t met her on previous visits smiled nervously at her joke, not knowing her well enough to understand her sens
e of humor.
She and Steve had traveled the previous day from Wyoming, where they had moved in 2010. In Idaho, when Lori’s memory started to falter, they decided their gypsy days were done. Steve requested a job transfer to a location where his wife could be among their closest friends.
“I threw my hardship card on the table and wrote a letter to the [Union Pacific] officials in Omaha. They all knew about Lori’s disease,” Steve recalled. “Wrote ’em a letter and said if a job opening ever comes up in southeast Wyoming, western Nebraska, I’d like to be considered. Five days later, they called me and said, ‘You’re going to Wyoming.’ ”
They settled once again in Laramie, in a house that looked out toward the majestic peaks of the Snowy Range, just a few miles from their youngest daughter, Chelsey, and their only grandchild, Claire.
When they went to Pittsburgh for the research, they were accompanied by Lori’s friend from Nebraska, Robin Tjosvold, the nurse who had helped with Chelsey’s birth. Ironically, though many people considered Lori one of their closest friends, very few stuck around when her disease began to show. Of the three women who had vowed to serve as surrogate mothers to Lori’s daughters, only Robin had lived up to her word. The others made the occasional effort with a phone call or a letter. They’d been sidelined by their own lives, their own health concerns, their own grandbabies. It was Robin who drove out to visit Steve and Lori, who danced with her, comforted her, still laughed with her, still made her feel human.
On Mother’s Day, Lori’s three daughters gave Robin a card, too: Its cover showed two old ladies dancing, with the caption They dance like they’re the only two who can hear the music. It suited them perfectly.
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