Brian was amenable, so they stopped in and had lunch at the center. A staff member met with them and asked Brian whether he’d be interested in participating in some of their research.
Brian demurred. No, thanks, he said—he was already involved in Dr. Klunk’s study at the University of Pittsburgh. He explained that he couldn’t stay; his sisters were in town, visiting. He had to go back with them.
When the staff pressed him to change his mind, he became increasingly agitated. They offered him some medication; as a man now used to taking pills for his condition, he took it without asking questions.
“I don’t want any problems here,” the center’s employee said quietly to Brian. “I’d sure like you to stay.”
Finally, subdued by the medication, Brian agreed. “I won’t give you any problems,” he said.
But his compliance was short-lived. When he discovered that he wasn’t free to leave, he became enraged at Karla for bringing him there. He demanded to speak with Dr. Klunk.
Karla conferred with Klunk, who agreed to talk with her brother, and suggested that she should also be conferenced in on the call. But when they spoke, Brian tore into Karla, demanding to know why she had dropped him off at the center. Though she thought she had mentally prepared herself to be the bad guy, he was so ferocious that Karla began sobbing; in self-defense, she hung up. Bill Klunk later called her back and apologized; even he hadn’t anticipated how violently Brian would react.
As with Moe, Brian’s mood swings eventually began to mellow out. Within a couple of months, he accepted his new home. When family members came to take him out on day trips, he’d stay out for as long as he could tolerate, then ask to be taken back to the center and his nurses: “I’ve got to go back,” he’d say. “The girls are worried about me.”
Surprisingly, despite the bitter way their marriage had ended, Christy visited him there, too.
“He [was] still part of my life because of my children,” Christy said. The years of anger and hostility didn’t stop her from crying when she saw him. “It hurt to see him in that shape. I wish I could have remembered him in a different way.”
Brian’s comprehension of his living situation seemed to shift by the day. On one visit, a friend left the building to light a cigarette, turned around, and was startled to see that Brian had followed out right on her heels, undetected by the staff. Finally, she handed him a cigarette, and they stood outside the building, smoking and making small talk. They could have been back in Tioga on Gail’s patio; he hardly seemed interested in escaping. They walked back into the building together. But within five minutes, Brian was complaining again about how he was in lockdown and not allowed to leave.
• • •
Brian’s children were grown, but they did stay in touch with him, even if they weren’t particularly close. Kassie had married an aspiring track star, Frankie Rose, whom she met in college; they moved to North Carolina, where she gave birth to a little girl, Brianna. So far, she’d wanted no part of an Alzheimer’s diagnosis; she preferred instead to leave her fate unknown.
“I made a choice to live my life as normally as possible and leave it up to God,” she said. But the question nagged at her every day. If she happened to repeat herself, she wondered: Do I have it?
Her brother, Yancey, was worried, too. He was always misplacing things.
“You know, you’re just carrying that huge weight on your shoulders,” Yancey said. “There’s always little things—like you forget your car keys. I’m pretty forgetful about where I place things. Is this what it’s like? Or am I just having an unorganized day?”
Perhaps influenced by his stepfather’s military career, Yancey had joined the army when he was eighteen. He was Brian’s only son, and he resembled his father closely.
“I’m already at peace with the fact that I probably do have it,” he said. “I noticed a lot more of my dad in me than I see a DeMoe in her,” he added, meaning his sister. “Like the way I sit; my dad used to sit the same way, with my hand up like that. He used to do it all the time. I already think I have it, so it doesn’t make a difference if I find out or not. I’m not going to live my life any differently than this.”
Of course, his physical appearance and his mannerisms had nothing to do with whether he had the disease. But families of Alzheimer’s patients often look for clues to their future, even if they stop shy of obtaining a genetic test.
Yancey was preparing for deployment to Iraq when Brian, increasingly plagued by incontinence and his limited mobility, moved from the memory care facility to a nursing home in Minot. When Yancey came back, he had a few weeks’ leave before heading to Alabama to attend flight school.
When he stopped to see his father, Yancey was rattled; Brian looked so frail, nothing like the man who used to put in hundred-hour weeks in the oil field. He was vacant, feeble; he needed a wheelchair to go outside.
Brian looked up at his son, now a man grown, a man who had been to the other side of the world and seen sights that Brian might only hear about; witnessing destruction that others only talked about; only to come full circle, back home, and see a much different, quieter devastation within the walls of a nondescript Midwestern nursing home.
“Hey,” Brian said. “I know you.”
• • •
When she visited Brian with her husband and daughter, Kassie wanted to believe that her father understood that he was holding his grandchild in his arms. He had pictures of Brianna in his room, and he did seem to know her. She could see it in his eyes.
When Kassie became pregnant with her second baby, she told her father before she told anybody else.
“I kind of knew my secret was safe with him,” she laughed. “It’s sad to say.”
Now, telling him her joyful news, she was shocked when Brian seemed to reach a moment of clarity: “Well, you already have one,” he said.
The baby girl, whom they named Kingston Dakota—after her father’s roots in Jamaica, and her mother’s in North Dakota—would be born in 2010. But Brian would not live to know her.
Part
THREE
You’ve been paid for by people who never even saw
your face. Your mother’s mother, your father’s father.
And so it behooves you to prepare yourself so you can
pay for someone else yet to come. Whose name you’ll
never know. You just keep the good thing going.
—Maya Angelou
Sixteen
THE BAPTISTS AND THE TAUISTS
FOR DECADES, SQUABBLING within the Alzheimer’s research field has persisted over whether amyloid or tau is the key driver in the disease.
The nicknames for the two camps, Baptists (plaques) and tauists (tangles), echo the near-religious adherence each has to their particular dogma, though there is much crosstalk between them, with each school of thought acknowledging that the other plays at least some role in the disease. It is a classic chicken-and-egg debate.
Since the 1980s, the Baptists have been in the majority. The human body produces the amyloid precursor protein (APP) in several organs, although not much is known about its function in a healthy person. Some studies suggest that in the brain, it helps direct the movement of nerve cells during early development. In a normally functioning body, enzymes cut the protein to create smaller fragments called peptides. One of those fragments is amyloid beta, which is thought to be involved in plasticity, or the ability of neurons to change and adapt over time.
In Alzheimer’s patients, something goes awry in the process, the protein does not break down correctly, and the sticky pieces of beta-amyloid cling together like wads of chewing gum, along with pieces of dead neurons; they go on to form plaques, which interrupt brain function.
• • •
In the amyloid-versus-tau debate, Paul Aisen, head of the University of Southern California’s Alzheimer’s Therapeutic Research Institute and former director of the Alzheimer’s Disease Cooperative Study, was an unapologetic Baptist
.
In his eyes, the theory explained so much: Why a mutation that triggers the overproduction of amyloid results in Alzheimer’s. Why 75 percent of people with Down syndrome—which is caused by an extra copy of chromosome 21, the same gene where amyloid precursors live—develop Alzheimer’s.
He acknowledged that the disease includes other processes—such as the mangling of tau proteins inside neurons, disrupting the cell’s ability to transport nutrients and ultimately killing it—and that those might be fine targets for other therapeutics. But he believed the best way to arrest the development of Alzheimer’s before it destroyed memory was some combination of drugs targeting amyloid in various forms: Hit it in the bloodstream and hit it in the brain.
Simply put, “If your goal is to shut off the engine behind neurodegeneration, attack amyloid,” Aisen said.
For years, he was fascinated with the earliest stages of Alzheimer’s: What subtle brain changes foretold the devastation to come? How early could science detect those changes? And could doctors stave off future damage by treating those early symptoms before the memory began to crumble?
The majority of Alzheimer’s research is dedicated to the premise that if scientists can somehow prevent beta-amyloid from clumping into plaques, they will successfully interrupt the disease.
But the tauists remain a vocal minority in the field, arguing that failed attempts to find an effective treatment can be explained by the fact that science is focusing on the wrong target—amyloid—when it should be focusing on tau.
The debate has turned bitter at times, with tauists arguing that Baptists are sucking up all the publicity—and ensuing research money—to the detriment of the greater, collective cause. Allen Roses of Duke University, who was famous for his 1992 discovery of apolipoprotein (ApoE) gene variants that heighten the risk of Alzheimer’s in the general population, was dismissive of the amyloid hypothesis: “I can go into any cemetery and find a tombstone over a dead person. The tombstone didn’t kill him.”
Located on chromosome 19, ApoE is a gene that codes a protein that carries cholesterol in the blood. Since the early 1990s, Roses argued that ApoE’s variations, or alleles—known as ApoE2, ApoE3, and ApoE4—hold the real key to Alzheimer’s. The theory says E2 and E3 bind to tau and stabilize it so it doesn’t twist into the tangles that pepper the brain in Alzheimer’s disease. But the E4 allele does not cling to tau, and Roses said that’s why people with that variant have a higher risk of developing the disease.
Baptists agree that ApoE4 is important, they just think it’s for a different reason: In addition to not stabilizing tau, they say it also appears to promote the buildup of beta-amyloid. Tauists say the amyloid buildup is simply a side effect of the true problem, or the “tombstones” that Roses described.
• • •
One man who counted Roses as a friend was Eric Reiman, a tall, well-heeled man with salt-and-pepper hair and a gravelly voice that moves rapid-fire through the most complex of explanations. Reiman is now the executive director of the Banner Alzheimer’s Institute, an important outpost in the world of Alzheimer’s research housed in a freshly minted building a stone’s throw from its parent medical complex in Phoenix.
Reiman frames the amyloid-versus-tau debate with a colorful analogy: “Think of Alzheimer’s as: it starts with some kindling (amyloid) to ignite the fire (tau). By the time you have the fire, does it really matter if now you’ve addressed the kindling?”
Educated at Duke, Eric Reiman was on the faculty at Washington University when Bill Klunk trained there, before Klunk went on to the University of Pittsburgh and created the PiB brain-imaging agent. The two men stayed in touch as professional colleagues, and Reiman deeply admired Klunk’s dedication. Reiman was fascinated with the way different parts of the brain work in concert to orchestrate normal behavior, and conversely how they conspire to produce psychiatric disorders, but he did not work directly on Alzheimer’s disease.
In 1988, he joined the local Alzheimer’s Association chapter in Phoenix, Arizona, just to set an example for his children, who were then eight and three years old. At the time, he wanted to show them the importance of performing community service in an area separate from his professional life.
A few years later, in 1993, he read a story in the Wall Street Journal about the discovery of the ApoE connection by his friend, Roses, back at his alma mater, Duke. Reiman, whose expertise was in brain imaging, thought he might have stumbled across a way to hasten prevention trials in Alzheimer’s patients.
Reiman theorized that if he began studying people at three different risk levels for Alzheimer’s—low-risk, with no copies of the E4 allele Roses had noted; higher risk, with one copy; and highest risk, with two copies—he could start tracking their brains in middle age and see how they changed. In those days before Bill Klunk and Chet Mathis created PiB to image amyloid deposits, Reiman planned to look at other biomarkers that were considered predictors of the disease.
In Alzheimer’s, it could be the way the brain metabolizes glucose, which doctors can view by injecting a person with radioactive glucose and visually tracing its path via brain scans. Glucose, the main sugar in the blood, is the primary fuel that the brain uses for energy. As far back as the 1980s, science has known that portions of an Alzheimer’s-riddled brain do not metabolize glucose well—typically the parts of the brain responsible for memory retrieval, as well as planning for the future and daydreaming. Screening for diminished glucose metabolism could predict Alzheimer’s well before symptoms appear. What was not known was what role this dysfunction played in the disease, although some researchers believed impaired glucose uptake helped to form the tau tangles. Another Alzheimer’s biomarker was brain shrinkage, which doctors measured with an MRI.
Instead of studying fifty thousand people across twenty years, as a traditional prevention study might do, Reiman thought he could look at a couple of hundred E4 carriers over two years. His team would try a different prevention therapy every two years—an admittedly aggressive course of action—and report on the outcome. And while they were at it, Reiman thought perhaps they could also work toward developing a new standard of care for patients and their families. He was beginning to realize the magnitude of the disease’s ripple effect, the way it ravaged even the strongest family bonds and crushed the health of overwhelmed relatives, just as it had contributed to Gail DeMoe’s nervous breakdowns when Moe was still alive, and Sharon’s struggles as she sought help for Jerry.
“Over half of family caregivers become clinically depressed; they’re often frustrated, physically exhausted, feeling helpless and uncertain,” he said. And the limitations of the health care system’s reimbursement model—which often does not fully cover the cost of patient care—meant there was no money available to help them, he added.
“There’s not even adequate reimbursement to do a full medical evaluation—certainly not enough incentive for people to learn how to help patients and family caregivers navigate the course of their illness and address the range of everyday questions they have, if they even knew to ask,” Reiman said. “What are the financial issues, or the legal issues we need to address? Is there an elder law attorney that I might use? How do I get my loved one bathed? How do I get some sleep at night, or get a break without worrying?”
Pierre Tariot, who would become one of Reiman’s closest collaborators, coined a phrase for the system’s blasé attitude toward Alzheimer’s: “Diagnose and adios.”
Once again, Reiman knew the field could do better.
A few years later, the Banner Alzheimer’s Institute was born, with Reiman serving as its executive director. Working as part of a consortium within Arizona, Reiman started by studying the effects of lowering cholesterol, publishing results in 2001. ApoE proteins transport cholesterol in the blood and central nervous system, and both the generation and clearance of beta-amyloid are regulated by cholesterol. But pharmaceutical companies, always conscious of their bottom line, were unimpressed.
Eve
n if the consortium could prove that one of their drugs shifted a biomarker of Alzheimer’s disease, such as glucose metabolism, they still wouldn’t win FDA approval solely on that basis. The government had simply been burned too many times with other medical disorders. Recent medical history was littered with examples of treatments that offered spectacular results in changing the biomarkers of a disease but completely failed to produce any clinical benefit: There were cholesterol-lowering medications that didn’t lower mortality rates; treatments that increased bone density but didn’t decrease fractures in osteoporosis patients.
The FDA has a system in place that prioritizes its approval of new drugs to treat serious diseases for which current treatments are nonexistent or inadequate. Among these is its “accelerated approval” designation, established in 1992. These regulations say the FDA can approve drugs filling an unmet clinical need based on a surrogate end point, which is a marker—a physical sign or other measurement—that is believed to predict a clinical benefit. This is largely a judgment call by the FDA based on scientific support for the end point, and winning accelerated approval is a significant shortcut that can save valuable time in getting a drug to people who need it.
But achieving accelerated approval isn’t easy. At a meeting with the FDA in the mid-2000s, a statistician stood up and made a chilling pronouncement. He said he would not consider a biomarker a viable way to predict a drug’s clinical benefit unless he also saw eight clinically proven treatments in which the treatment’s biomarker effects accurately predicted a benefit. In other words, in order to prove that treating a symptom was beneficial, he wanted to see eight versions of a cure.
A British colleague sitting next to Reiman leaned over and muttered, “Eric, I thought this was the greatest country on earth. If we had eight clinically proven treatments, what would we need a biomarker for?”
The Inheritance Page 18
