“There’s other ways to have children,” Robin said. “How many kids out there need a parent?”
Where her sister Dawn cried chronically, Robin’s disease presented a different, more haunting symptom: She would laugh to fill empty spaces in conversation, almost indiscriminately: Ha ha ha ha ha ha ha, like one of the kuru victims that Dmitry Goldgaber’s old boss, Nobel Laureate Carleton Gajdusek, once studied. When she talked about her worries over one of her younger daughters, who had largely stopped speaking since Mike’s death, she’d laugh uproariously: Ha ha ha ha ha ha ha. When a psychiatrist at the Alzheimer’s Disease Research Center asked her what her days were like when her kids weren’t home, she giggled.
The psychiatrist asked Robin: Did she ever contemplate suicide?
“Oh, no,” she insisted firmly. “I’m trying to live as long as I can.”
Her two children from her first marriage were now grown; of the three she’d had with Mike, one was nearly finished with high school, and she believed Mike’s brothers would take care of the other two when she no longer could. But it was painfully apparent that she had nobody like Karla to keep an eye on her. She had become so easily disoriented that the Pittsburgh staff monitored her with an electronic tag so she didn’t accidentally leave the building and get lost; yet when she returned to Wisconsin, she would resume driving.
“It is what it is; what are you gonna do? Make the best of it while you can. It’s a sad situation. And I want to make the kids feel safe and [I’ll] try to be here. I’m sure I’ll still be OK until they graduate,” she said, sitting in a conference room at the Alzheimer’s center and adding her chilling punctuation: Ha ha ha ha ha ha ha.
“Things happen for a reason, or people come into your life for a reason. And I feel so lucky that I get to be here. Because coming here makes me feel like someone’s watching over me.”
• • •
Dawn and Robin’s youngest sister, Colleen, had always been the black sheep of the family. Her personality was an odd mashup of sharp contrasts: intelligent, but flighty; gregarious, but irritable; ambitious, but chronically rebellious. Growing up, she liked to compare herself to her cousin Dean, because they were both rule breakers; but unlike Dean, Colleen had never outgrown that trait, never settled down.
In her prime, she had owned a successful beauty shop, two cars, a snowmobile, and a house with an impressively large yard, all the product of her innate gumption and creativity. But by the time she was in her midforties, it was all gone; the business was closed, her equipment was in storage, and she was well on her way to becoming the crazy cat lady of Brule, Wisconsin.
“She’s got the kindest heart, and you can wound her deeply with anything cruel,” said Becky Vork, who grew up next door to the three Miller sisters and was Colleen’s closest friend. “She has a really kind, kind side, but she comes off abrasive to other people if you don’t really know her.”
Becky would prove to be the rarest of friends, one who was truly there, even in the depths of the disease. Many of the DeMoes experienced the isolation of friends who disappeared when they developed symptoms, from Gail and Moe to Steve and Lori McIntyre. People promised to help, offered support, and then scattered. It was just too hard, seeing a middle-aged person in diapers, stuttering over the simplest words, exploding in anger over invisible slights.
But Becky was different. She was sterling, and she would do anything for Colleen, whom she considered a sister. When business began to taper off at Colleen’s beauty salon, it was Becky who confronted her. Customers she’d had for more than a decade complained that Colleen was becoming inconsistent, irresponsible. She fell behind in her rent; she fell behind in her taxes.
“Be honest,” Becky said to her friend. “What the hell’s going on? Where’s the girl that was kind of like my hero, running her own business, having her own house?”
Colleen was evasive. She blamed the drop-off in her business on the slumping economy that followed the attacks of September 11, 2001.
“Come on!” Becky said. “The world stopped getting haircuts? That’s ridiculous. And I get that the economy plays into your business, but mostly it was people being driven away by her behavior.”
After a one-night stand with an old boyfriend over Labor Day weekend in 2004, Colleen became pregnant. Though it was unexpected, Colleen welcomed motherhood, giving birth to a daughter in 2005.
Three years later, she was diagnosed with the mutation.
• • •
As Colleen’s memory declined, she began taking first Aricept, then Exelon, a skin patch that was another form of cholinesterase inhibitor, preventing the body from breaking down the neurotransmitter acetylcholine—a temporary and not always reliable fix for Alzheimer’s symptoms. But she kept that information to herself for a while; she didn’t want people to think badly of her. A social worker friend helped her figure out how to pay her bills and negotiate some of the complexities of daily living; at home, she also relied on her little daughter to help her with small tasks and remember where she had misplaced things.
When she visited Pittsburgh for the DIAN research, Becky came with her, using vacation days she had carefully hoarded from her job. She packed extra clothes for Colleen, knowing her friend was too disoriented by Alzheimer’s to bring what she needed. She monitored Colleen’s bank account, replenishing it in $100 increments, checking her debit card for accidental purchases. She answered questions for the research staff about Colleen’s history and current state of mind.
Colleen wanted Becky to assume guardianship of her daughter when the time came. Becky, who was entering her fifties and whose own son was grown, believed the little girl would be better off with someone younger, a biological relative. The child’s father was not an option; he was unemployed and had been known to struggle with drugs. But a paternal aunt with children of a similar age was eager to step up. Becky helped design the plan to make that transition and checked in with Colleen’s doctor and social worker to monitor the situation.
Like Karla, Becky sometimes had to be the bad guy with Colleen, the person who told her things she didn’t want to hear—like the fact that her daughter would be better off with an aunt, whom Colleen disliked but Becky trusted.
“I will do anything I need to do for that kid and for Colleen,” Becky said. “All I say to my husband is: I’m just trying to do what’s right, every day.”
Sometimes, she thought about their childhood: inseparable girls who lay on the Millers’ kitchen floor, eating cookie dough and calling the local radio station, begging the deejay to play their favorite song: Fleetwood Mac’s “Landslide.”
She couldn’t have imagined, then, how hard things would get: First Pat, then all three of Pat’s girls. Better not to think about it, she thought. Better instead to focus on what Colleen was giving back to science than on what the disease was taking away.
“If I think about it too much, I’ll die,” she said.
Twenty-Two
SOMETHING TO SHOOT FOR
DEVELOPING A DRUG, any drug, for eventual use in human beings is a mind-bogglingly expensive proposition fraught with risk for the company involved. Some sources peg the median cost of creating a new pharmaceutical at roughly $350 million, but that figure rises into the billions if the company has brought multiple medicines to market in a decade, because for every success, there are many more failures, and the business has to carry the weight of each failure on its books. Part of the risk inherent to investment in drugs is that so many of them fail.
Of course, the payoff for success is equally large. When Alzheimer’s researchers begin to lose faith, they look for inspiration to one of the most famous stories in recent pharmaceutical research: the discovery of Lipitor, the trade name for Pfizer’s wildly successful statin.
In the early 1980s, drugmaker Parke-Davis spent eight years developing Lipitor to reduce cholesterol levels and prevent heart disease. At the time, nobody was sure if the right target was LDL (now called “bad” cholesterol), HDL (“good
” cholesterol), or triglycerides (fats associated with buildup in artery walls)—just as nobody in the Alzheimer’s field is sure if amyloid or tau is the right target, or if it’s both.
At first, Lipitor didn’t generate a lot of enthusiasm at Parke-Davis. Then known as CI-981, it functioned about as well as its competitors when used in animal models, but one rival drug was already on the market, and three others were already in large-scale human studies.
Given those circumstances, the company was reluctant to pay for expensive human trials but finally agreed to move forward because the patent on one of its top-selling drugs was about to expire, and the market for statins was expected to be so big that even a small share would make money—just as the market for Alzheimer’s drugs is expected to be huge. With little else in the pipeline, Parke-Davis threw a Hail Mary on CI-981.
Twenty-four employee volunteers served as the drug’s guinea pigs, and their results would make medical history: Despite the drug’s lackluster performance in animal models, it was extremely potent in humans. Eighty milligrams of CI-981, the recommended dose for patients with very high cholesterol, beat any other statin by a 40 percent margin.
Even with such impressive results, Parke-Davis’s wonder drug wasn’t a lock for success. To convince the FDA to fast-track its approval for CI-981, now renamed Lipitor, its developers would have to demonstrate that the drug filled an unmet medical need. And since competitors were already available on the market, that argument was a tough sell.
The company found its answer in a group of South African children with a rare genetic disorder that hindered the body’s ability to clear cholesterol. The disease left signature lumps of waxy deposits under the skin on their fingers. With levels topping three times that of a normal adult’s cholesterol, the children were dying from heart attacks at an average age of fourteen. Other statins had failed to budge the condition.
But Lipitor did. Though it didn’t cure all the stricken children, it packed enough of an impact to persuade the FDA to prioritize the drug. And it worked on the rest of the population, too, not just those who were genetically stricken. By 1997, Lipitor had been cleared for sale. For Pfizer, which acquired Parke-Davis, it was a true blockbuster, with annual sales topping $11 billion before its patent expired in 2011, allowing a cheaper generic version to enter the market. Lipitor became the best-selling drug in pharmaceutical history.
Now pharmaceutical companies large and small were looking for the next Lipitor. And it seemed as though Alzheimer’s might be the right disease for just such a discovery.
All the pieces seemed to be in place: PiB allowed scientists a new window on the brain with images that would illustrate how the disease changed it, at least in terms of amyloid accumulation. No effective treatments existed, so when research suggested solutions that seemed like long shots, the government—driven by the pending health care crisis of aging baby boomers—was willing to listen. And in Alzheimer’s, as with heart disease, pharmaceutical companies recognized a market of vast potential, one that might even surpass Lipitor.
The research field, as well as pharmaceutical companies, focused heavily on amyloid as a target. But as additional studies began to back up the tau theory, suggesting it was the primary driver, drug development was following suit, as was the push to image tau proteins the way PiB imaged amyloid. Some scientists, including Eric Reiman, believed that a successful Alzheimer’s treatment might well be a combination of drugs targeting both amyloid and tau, just as combination therapies helped HIV patients.
Drugs were the key protagonists in human clinical trials; if they succeeded in showing a clinical benefit in Alzheimer’s patients, researchers could apply for FDA approval. Several were in various stages of development, despite discouraging statistics. From 1998 to 2011, a whopping 101 Alzheimer’s treatments had failed to reach patients. During that same time frame, three medicines won approval to treat symptoms of the disease, but their benefits were only temporary. With a record of three lukewarm wins and 101 losses, the smart investment play would have been to look for other, more promising diseases to treat. Still, the industry soldiered on: Another ninety-three new medicines for Alzheimer’s and other dementias remained in development. A drug that completely prevented the disease was the holy grail, but one that delayed onset by even five years would be considered a major victory, not only because it would buy valuable time for the patient, but also because it would signal that science was on the right track in targeting the disease’s elusive underlying pathology.
There were signs that the history of repeated failures was taking its toll. A 2015 report compiled by the Dementia Forum of the World Innovation Summit for Health (WISH) warned that donors and big pharma had developed a case of “funding fatigue.” Between 2009 and 2014, major drug companies cut the number of research programs into central nervous system disorders by half. As Eric Reiman warned, the field was not going to allow many more shots on goal; they had to get these drug trials right, or as right as they possibly could, because others might not follow. Drug companies were businesses, and they would invest in treatments that paid off.
• • •
The committee charged with selecting drugs for the DIAN clinical trials had to choose from fifteen different candidates nominated by drug companies. Committee members evaluated each based on the drug’s safety, the mechanism by which it worked, its potency, and its stage of development. From 2010 through 2012, they categorized and prioritized the drugs until they whittled their original list down to two:
Eli Lilly and Company’s solanezumab, nicknamed “sola,” an antibody which bound itself to soluble forms of amyloid carried in the bloodstream before the body deposited it into plaques, and Roche’s gantenerumab, which bound to amyloid in the clumping stage.
Solanezumab had already been tested in people with full-blown Alzheimer’s disease, with disappointing results. But data analysis from those trials suggested that it slowed cognitive decline in patients with the mildest forms of the disease, indicating its potential as a preventative drug.
The trial’s success would be measured incrementally. Of course, the ultimate goal was to stop Alzheimer’s for all time, but that was a high bar; even if investigators found a wonder drug, they estimated it would take twenty years to show that presymptomatic patients did not develop the disease after taking the compound; it would take forty years to eradicate the disease. At a minimum, the trial hoped to show that the drugs conferred at least some subtle cognitive benefit that budged biomarkers.
“That’s possible. That’s something we can shoot for,” said Randy Bateman, the DIAN trial’s principal investigator.
To participate, volunteers had to be at least eighteen years old and anywhere from fifteen years younger to ten years older than their parent was when they first started showing signs of Alzheimer’s disease. In cases like Dawn’s daughters, Alayna and Leah, determining their mother’s age of onset was difficult, since Dawn’s strange behavior began in her thirties—a possible side effect of the antidepressants she was taking—but she was not formally diagnosed with Alzheimer’s until years later. In cases such as theirs, doctors asked questions during the screening process to tease out a probable age of the disease onset in the parent. But since women participating in the study had to agree not to have children while they were taking the drugs, both Leah and Alayna opted out. They wanted children. Leah was already married with one child at the time she first participated in research.
The study’s volunteer range also included people who were classified with mild cognitive impairment but were still healthy enough to potentially reap some benefits. Worried that Dean was close to missing his window of opportunity, Karla urged him to join before his symptoms progressed any further. Already, it was too late for Lori and Doug. Though Dean hoped to complete his drug tests in Pittsburgh, where he was comfortable with the staff and the setting was familiar, he agreed to go to St. Louis instead, because Washington University was set up to accept trial participants several mo
nths before Pittsburgh. The trial enrolled a total of two hundred people.
Participants brought either a family member or a friend to their visits to provide an outsider’s perspective about the real-world impact the drugs were having on their daily lives. The study also included a placebo group, meaning some participants wouldn’t get a real drug at all; a computer randomly assigned the placebo to volunteers, although people who did not carry the mutation would not get the drugs, whether or not they knew their status. Because DIAN was testing two drugs at the same time, participants who were mutation carriers had a 75 percent chance of getting an active drug instead of a placebo.
After the initial screening visit at one of the DIAN sites, once a month a team of visiting nurses would administer the drugs to volunteers in their homes, either by injection or IV line. Every three months, participants underwent an MRI scan as a safety screen, designed to detect any brain swelling, a possible side effect; every six months, they completed cognitive testing on computer tablets. And once a year for three years, they went back to a DIAN site—such as Washington University or the University of Pittsburgh—for a physical, blood samples, brain scans, a spinal tap, additional cognitive testing, and more drug dosing.
Even in the early days of DIAN, Bateman and John Morris coordinated efforts with Eric Reiman and Pierre Tariot’s Banner Institute, which was working to launch a drug trial of its own in the Colombian population championed by Francisco Lopera and his American partner, Ken Kosik. Their cooperation wasn’t just the product of professional courtesy; it was a necessity. Competing against one another would only cause failure in all the trials, Bateman predicted. There were simply too few mutation carriers to go around, and each failure would dampen an already skittish market. Pharmaceutical companies were not going to invest indefinitely.
“We’re only really going to get this time to do this,” he said. “There’s a place for competition, but there’s a time when competition hurts.”
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