The Inheritance

by Niki Kapsambelis

  Moreover, wasted time would most greatly impact the volunteers, who could not afford to age beyond the point where the drugs would be able to help them.

  “There’s no chance that they would escape the disease if they have the gene,” Bateman said. “It’s quite a desperate situation for them.”

  • • •

  In Oklahoma, forty-two-year-old Sherry DeMoe Pickard, Jerry and Sharon’s oldest daughter, prepared to travel to St. Louis for the clinical trials associated with the DIAN study. She decided against genetic testing, but her family supported her decision to move forward with the drug trials. Her six daughters were all still at home—the oldest twenty, the youngest seven.

  The testing was moot anyway; Sherry’s memory was starting to fail. The woman who had once planned to become a teacher could easily recall some details—such as the new curriculum she was using to homeschool her children, and the color of the Volkswagen bug her father had refurbished for her sixteenth birthday—but had trouble with others, such as how many years she had been married, how many sisters her husband had, or how old she was now.

  When she went to Washington University for her baseline visit in 2013, she was pleased to be able to contribute to Alzheimer’s research, even though the testing, poking, and prodding exhausted her. Less than a year later, she could not remember how long she had been there, or whether the doctors had taken her blood or conducted a spinal tap. Her family encouraged her not to worry too much about it, and she did her best to comply.

  But while she did not dwell too much on the disease, or the uncertainty of her own fate, she did believe it was important to contribute to knowledge that might benefit the next generation.

  “I have a lot of daughters,” she said. “By doing all of this, it’ll help for their future, doing what I’m doing.”

  Her mother, Sharon, accompanied her to St. Louis to serve as her study partner.

  “There’s times when I think, ‘I can’t do this again,’ ” said Sharon. “But I know I can. And I will.

  “God has purposes for everything. We don’t always know what and why. And sometimes we find out, and sometimes we don’t.”

  She thought back to when Jerry was sick—a time when she was so distraught that she contemplated suicide. She lived through it, and now she knew why.

  “I think the purpose is for me to be here for them, for her. I think that was the main purpose. We got through all the other, and I can’t say this is going to be bigger; I don’t know . . . I don’t know how this is going to be with a child.”

  Part

  FOUR

  Few will have the greatness to bend history itself, but each

  of us can work to change a small portion of events, and

  in the total of all those acts will be written the history

  of this generation. It is from numberless diverse acts of

  courage and belief that human history is shaped.

  —Robert Kennedy, June 6, 1966

  Twenty-Three

  THE SILVER TSUNAMI

  AS BATEMAN’S TEAM prepared to begin its drug trials, other scientists were simultaneously working on the bigger picture: how to prevent Alzheimer’s in the general public. By marrying the science of the two populations together—those genetically stricken and those who spontaneously developed Alzheimer’s without a mutation—the doctors hoped to solve what was shaping up to be a massive health care crisis.

  Paul Aisen, the Baptist believer who headed the Alzheimer’s Therapeutic Research Institute for the University of Southern California, was instrumental in that effort, along with his longtime collaborator, Harvard professor Reisa Sperling, who served as the study’s principal investigator.

  Their study attempted to answer this critical question: How would older people from the general population, not mutation carriers, respond to anti-amyloid drugs before their memories began to fail?

  The two had met through the Alzheimer’s Disease Cooperative Study, a consortium of eighty different clinical sites in the United States and Canada that formed in 1991 as part of a partnership with the National Institute on Aging. Aisen, veteran of many ADCS efforts, led the cooperative from 2007 through 2015.

  When scientists want to research Alzheimer’s treatments, particularly those that don’t interest the pharmaceutical industry, the ADCS helps drive those studies. For example, it successfully debunked the myth that ginkgo biloba, one of the top-selling herbal remedies in the United States, improved memory for Alzheimer’s patients.

  The DIAN study was testing whether the Lilly drug solanezumab, which flopped in people with more advanced Alzheimer’s, worked better in people who either had no symptoms or were mildly impaired. DIAN would target people with all the known mutations: PS1, PS2, and APP.

  Solanezumab carried enough safety data to convince Reisa Sperling that it was viable for use in the study she and Aisen were planning. Even if it wasn’t a perfect solution, she thought it would likely answer some questions that she had been dying to ask, such as: What true risk of impairment does amyloid represent? After all, some people carried amyloid in their brains yet functioned normally, which researchers now knew from imaging amyloid in a living brain with PiB.

  Studies in older people had the potential to relate more directly to the garden-variety Alzheimer’s that had started to close its grip on the world’s population. As baby boomers aged, society was becoming increasingly worried about the potential consequences if no means of prevention could be found.

  Several reports about those concerns labeled baby boomers “the silver tsunami” because of the possible devastation their health demands could wreak on an already burdened system. In 2013, a study published in the New England Journal of Medicine predicted that the $109 billion cost of caring for Alzheimer’s patients in 2010—not counting informal care costs, such as services provided by family members to take care of the person—would more than double by 2040. Sperling and Aisen had their work cut out for them.

  Also working in the older population were Pierre Tariot and Eric Reiman of the Banner Institute, in an effort separate from their research into the Colombian paisa. They shared information with Aisen and Sperling, as well as the DIAN group and, for a time, Allen Roses, the tauist from Duke who first identified variants of the ApoE gene on chromosome 19 that heighten the risk of Alzheimer’s disease in the general population. (Roses died in 2016.) The scientists in each study compared notes: What’s working? How do we standardize what we’re collecting so we can compare results? How are we measuring cognitive function? How do we disclose any of our findings to the public? The combined efforts created important momentum, with each study contributing a different perspective to the field’s knowledge base, helping to move any future prevention studies forward.

  • • •

  The two trials focusing on older people were, like the mutation studies, driven by genetic predictors. The Banner Institute’s trial sought to treat 650 people between the ages of sixty and seventy-five, most from the United States. Instead of an autosomal dominant mutation, they carried two copies of the ApoE4 gene variant identified by Roses. Though not as rare as the mutations that plagued the Colombians, the DeMoes, and the Noonans, the condition—which affects about 2 percent of the general population—was still potentially lethal. Researchers initially believed carrying two copies of ApoE4 represented a 90 percent chance of developing Alzheimer’s; but subsequent risk estimates have lowered that number to 58 to 68 percent, or about the same risk that women with the BRCA1 gene mutation—including actress Angelina Jolie—have for breast cancer.

  People who only carry one copy of ApoE4 have a lower risk of getting Alzheimer’s—roughly 30 to 45 percent—but there are more of them. About 25 to 30 percent of the general population carries one copy of ApoE4. Reisa Sperling and Paul Aisen widened the parameters of their research in the general population to include these people as well, ranging in age from sixty-five to eighty-five years old. They named their study Anti-Amyloid Treatment in Asympto
matic Alzheimer’s, or A4 for short.

  The A4 study hoped to enroll a thousand people. Sperling and Aisen started by recruiting their subjects, whose cognitive function was completely normal at the beginning of the study, but in whose brains amyloid plaques were accumulating. At fifty-six different sites across the United States—plus four in Canada and one in Australia—about half would receive a placebo, and half would be dosed with solanezumab. An additional five hundred people with no amyloid plaques would serve as a second control group so Sperling and Aisen could compare their results to the normal aging process, a step that would help them better understand the role amyloid played.

  It was a huge undertaking, one that defied FDA tradition. To approve a medication for use in Alzheimer’s patients, the agency had always required drug trials to include two criteria for success. The first was an effect on some measure of cognitive performance, such as a memory test. But sometimes, test scores are deceptive; a patient can ace a test but still stumble over daily tasks that the results didn’t capture.

  So the FDA also required drug trials to measure “clinical meaningfulness,” or a sense of improvement as judged by the patient, a caregiver, or a doctor. Aricept and other drugs that doctors routinely prescribed for Alzheimer’s had won FDA approval by showing some benefit in both these measurements—cognition and clinical meaningfulness—even though the drugs didn’t delay the disease, or even slow it down.

  The problem was that these measurements seemed impossible to achieve when testing drugs on people in the “preclinical” stages. Someone who appears normal won’t struggle with memory or daily tasks, so how can researchers measure an improvement?

  But a surprising answer came out of the University of California, San Francisco. Its study analyzed about four hundred people diagnosed with mild cognitive impairment, two hundred with mild Alzheimer’s, and two hundred who were considered completely normal.

  What they found was startling: About a third of the “normal” group’s members were actually spilling brain amyloid peptides into their spinal fluid—something that science would expect to see in an Alzheimer’s patient, as did Trey Sunderland and Susan Molchan, but not a healthy person—and PET scans revealed small signs of brain degeneration. Aisen took those results as yet another sign that “amyloid is not just an innocent bystander.”

  But the study also suggested, as many had long believed, that the Alzheimer’s brain was subtly changing years before anyone would notice a problem. Some brain scans did show degeneration—specifically in the hippocampus, a sea horse–shaped region nestled in the middle of the brain, responsible for forming long-term memories, similar to a computer’s hard drive.

  However, Aisen realized there was already a much simpler tool, one he’d previously dismissed as too primitive to be useful in patients whose symptoms were virtually invisible.

  The Mini Mental State Examination, known to clinicians as the MMSE, is the most commonly used test for people experiencing memory problems. Scored on a thirty-point scale, it takes about ten minutes to complete and asks simple questions, such as the time and date, repeating back a list of words, or basic math calculations, such as counting backward from one hundred by sevens.

  Since its introduction in 1975, little about the MMSE has changed. A score of 27 to 30 indicates that the person is normal, while the scores of Alzheimer’s patients generally range from zero to 24. The first person ever dosed with PiB scored 25.

  People with mild cognitive impairment, that gray area between normal and full-blown Alzheimer’s, usually score between 24 and 30. But the MMSE is so imperfect that even people with dementia can sometimes score a perfect 30.

  Julie Noonan Lawson thought the test, which she referred to as “their mini-mental thing,” was silly. She recalled how her afflicted siblings—particularly Fran, the family brainiac—used to memorize the MMSE so they could outsmart it. One brother, asked to remember a grocery list, would categorize it and spit it right back out.

  Yet the test was actually more useful than it seemed. Aisen realized that a series of MMSE scores separated by time changed consistently in people with brain amyloid who were otherwise normal. The changes were tiny, fractional, and still in the normal range. But they persisted.

  Over a two-year period, someone with preclinical Alzheimer’s would drop about a half point on the test, a difference too small to be important in one person; but when it happened in two hundred otherwise normal people, it was significant. Aisen and Sperling added this measurement to their arsenal.

  • • •

  The FDA also agreed to make its rules more flexible, thanks in large part to the efforts of Russell “Rusty” Katz, who worked for the FDA’s Center for Drug Evaluation Research. It was Katz who had created the definition of “clinical meaningfulness” in the early 1990s. He realized that researchers needed more leeway if they wanted to test a drug in patients who were still apparently normal.

  Before he retired in the summer of 2013, Katz wrote of his support for looser guidelines relaxing the clinical meaningfulness requirement. As soon as the proposed new policy appeared in the New England Journal of Medicine, it received support from pharmaceutical companies, whose funding was critical for such research. When the requirement was relaxed, drugs that treated people before they became symptomatic stood a much greater chance of winning FDA approval.

  Although the FDA was willing to allow drugs to go to market without demonstrating that they improved a person’s daily function, follow-up studies would have to show a benefit as time progressed.

  Aisen believed this new model of collaboration among government regulators, academic researchers, and pharmaceutical companies was key to achieving any kind of breakthrough.

  “It’s too big a problem for anyone to tackle alone,” he said. “What is striking is: Despite the fact that this field has utterly failed for over a decade, everyone is very optimistic.”

  Reisa Sperling wasn’t expecting a home run from A4, but she was hoping for a glimmer of success. Maybe the trial would show a tipping point for amyloid—a level of accumulation after which people begin to lose their memories. If so, doctors might know when they needed to intervene.

  And then there was the question of tau, the protein that made up tangles—not just in the brains of Alzheimer’s patients, but also in people with sustained head trauma, such as football players and other athletes who played high-impact sports.

  “I’m just amazed that we are still fighting about whether it’s amyloid or tau, because it’s so clearly both,” Sperling said. Her husband, Keith Johnson—a radiologist and neurologist who also taught at Harvard Medical School—coined a phrase: “Amyloid pulls the trigger, but tau is the bullet.”

  To Sperling, the debate was better framed as a chicken-and-egg question: Which comes first, the amyloid or the tau? Does one beget the other, or are they both separate streams of the disease process?

  Even though Aisen firmly believed that amyloid drove the disease, he pointed out that once it hits a certain point, its levels plateau, even as the brain becomes progressively more damaged. Tau, on the other hand, did increase quite a bit as the brain lost substance and function. He, like Sperling, wanted to know more.

  To help answer those questions, they added yet another resource to their study: T807, a radiotracer that did for tau what Bill Klunk and Chet Mathis’s Pittsburgh Compound B did for amyloid; it allowed doctors to see tau in the living brain through PET scans. Johnson, Sperling’s husband, was an early advocate of T807. He traveled to conferences to speak about what he found in patients who were scanned using the compound.

  For example, in November 2013, he told colleagues at the Clinical Trials in Alzheimer’s Disease meeting in San Diego that in patients where T807 showed accumulation of tau in the brain, memory was impaired. But the patients could still retrieve words and perform the brain’s so-called executive functions, such as keeping track of time, making plans, or evaluating ideas.

  Increasingly, scientists began loo
king at the likelihood that salvation lay in treating both plaques and tangles. Sperling compared a brain overwhelmed by Alzheimer’s to an overflowing bathtub: To fix the problem, you have to first turn off the spigot (amyloid), then empty the basin (tau).

  Her hope was that her study, combined with the work of others, would help pinpoint which proteins were responsible for which symptoms. About half the participants would be scanned for the presence of abnormal tau under Johnson’s leadership. Already, Sperling was thinking ahead to the possibility of combination therapies, one attacking amyloid, the other attacking tau.

  “That’s my holy grail,” she said.

  Perhaps it would be the combination that could deflect the silver tsunami, although Reisa Sperling found that particular metaphor wholly inadequate.

  “A tsunami is a single wave. We’re talking about wave, after wave, after wave of people developing risks for Alzheimer’s,” she argued.

  Without meaningful intervention, it was a crisis powerful enough to overwhelm the country’s health care system, to cripple the infrastructure of American society. It was a thought powerful enough to drive her relentlessly through the emotionally draining prospect of disappointment. From the moment she launched one clinical trial, she thought about the next step forward, and the next, and the next.

  Even then, with every volley, she worried that she was going to fail. When Sperling was in medical school three decades earlier, her grandfather had developed Alzheimer’s, inspiring her to find a cure before the disease could claim her father. She was too late; her father, a college chemistry professor, was diagnosed with Alzheimer’s in 2014.

  “Sometimes I feel like we’re ahead of ourselves, and sometimes I feel like we’re terribly behind,” she said. “I’m worried that I’m losing the battle.”