The Inheritance

by Niki Kapsambelis

  Her request was emphatic: Let me go.

  Those words would haunt Kate for a long time.

  About two or three years later, Kate began noticing small signs in her mother: She seemed aloof, her recollection of events wasn’t as sharp. Within another couple of years, Maureen was repeating questions and having difficulty processing the answers. The situation worsened when her husband, Dick, died suddenly from a heart attack; he’d been under increasing amounts of stress, including that from watching his wife, who was his best friend, deteriorate.

  Not long after Maureen’s symptoms appeared, her sister Fran also began to decline. Fran was fifth in birth order and considered the family genius; she had a gift for technology and worked for IBM. Despite the eight years between them, she and Julie were particularly close.

  Perhaps it was that bond that allowed Julie Noonan Lawson to become so attuned to changes in her sister’s demeanor, things she would not have noticed in Maureen, who lived in upstate New York; perhaps, because Fran was so intelligent, her small blunders stood out in sharper relief against her everyday brilliance. Despite the family’s theory that the disease would skip their generation, in 1992, Julie began to realize that something was wrong.

  “I recognized her blank stare,” Julie said. “And it was so intuitive that nobody around me agreed with me. Some of it has to do with our connection, and me being five years old and losing my mother.”

  In Fran, she sensed the same emptiness: Even when Fran was looking directly at Julie with her pale blue eyes, nothing seemed really to be reaching the soul behind them. Fran was diagnosed with Alzheimer’s in August 1994, a week before her forty-fifth birthday.

  Though they had had a few fleeting years of respite from the disease, the family realized, they hadn’t escaped. “We all were kind of hellbound on ‘OK, what are we going to do?’ ” Julie recalled. “ ‘We can’t just let this overcome us again.’ ” So when she heard about an Alzheimer’s conference in Boston, designed for health care professionals, she tagged along with a friend who worked in the field and whose mother also had the disease.

  One of the presenters was Trey Sunderland, who explained his protocol of spinal taps, blood draws, and brain imaging. Although everything he discussed was aimed at people who were fifty or older, Julie was immediately impressed. It was the most scientific approach to research that she’d seen yet. Then in her thirties, she strode up to Sunderland and bullied her way into his study.

  “I know I don’t meet your protocol,” she explained, “I know I’m too young. I know my oldest siblings are just barely going to be in the window. But we’ve got it. My mother had it; my sister has it.”

  Julie and Karla DeMoe had a great deal in common, not the least of which was determination. Neither one would take no for an answer. Trey Sunderland gave her his card, and the Noonans began their own family’s journey into the sometimes murky world of Alzheimer’s research.

  • • •

  The Noonan siblings completed memory tests and gave blood samples at Massachusetts General Hospital. But the siblings were looking for more; more answers, more research, more opportunities to contribute. Like the DeMoes, they were determined to do everything they could, but before they would agree to have their body fluids extracted for the NIH study, they wanted a guarantee that the material would be shared with any other researcher who wanted it. Sunderland assured the Noonans that their samples would be available to others.

  One of Sunderland’s studies, which began in 1995, focused on a point in the Alzheimer’s timeline that was on very few scientists’ radars at the time: those years in middle age, well before symptoms typically develop, when amyloid and tau might be silently accumulating in the brain. In those years, nearly a decade before Bill Klunk and Chet Mathis developed their amyloid brain scans, Trey’s protocol checked patients each year with the tools that were available to him at the time—an MRI, clinical and cognitive testing, and spinal fluid samples.

  Marilyn Albert, a cognitive neuroscientist who now leads the Alzheimer’s Disease Research Center at Johns Hopkins University, said Trey’s study was way ahead of its time, particularly in its use of spinal fluid. Several studies now look at amyloid and tau that has spilled into the fluid cushioning the brain and spinal cord, and researchers theorize that the amount of these proteins—when measured along with brain scans and family history—can reasonably predict Alzheimer’s in the general population. If a prevention treatment is to be found, refining various ways to forecast Alzheimer’s will be key in deciding whether a person needs to start taking the medication, and when.

  Beginning in 2000, the Noonan siblings went every year to donate their spinal fluid. They also completed sleep studies and all kinds of seemingly unrelated tests.

  From year to year, their answers to simple questions—Where were you born? What is today’s date?—would reflect the widening cognitive disconnect. Some were simple math problems, such as calculating the number of nickels in a dollar or subtracting backward from twenty in sets of threes. Others were everyday problem-solving questions: If you were visiting a friend in an unfamiliar city and you needed to find out where they lived, how would you do it?

  In an effort to help their doctors better understand their disease, the family provided the NIH with the name of the institution that housed the autopsy results for their mother’s twin sister.

  Just as Maureen had said, both Julia Tatro Noonan and her twin, Agnes, had had Alzheimer’s; although they were identical twins, their age of onset was dramatically different, with Agnes not showing symptoms until 1975, when she was fifty-one years old, more than a decade after her twin. She eventually died from lung cancer ten years later, when she was sixty-one. But an autopsy revealed that Alzheimer’s had ravaged her brain.

  Agnes never participated in research during her life, though in the 1970s, when both women were still alive, Alzheimer’s research had not yet progressed enough to fully explore the rare scenario they presented. As identical twins, they shared the same genome, including their genetic mutation. But because their life spans differed significantly, researchers later theorized the difference in their disease progression may have been epigenetic, caused by outside factors that modify the genome and change the pattern of how genes are expressed without changing the actual DNA sequence. Diet and environmental factors, for example, can create epigenetic changes.

  In 2014, teams from Brigham and Women’s Hospital in Boston and the University of Exeter in England independently found hints of epigenetic changes in Alzheimer’s patients, but emphasized that more research was needed to determine whether the changes accelerated the disease or happened as a result of it.

  Maureen and her family relocated to Oregon. When she died in November 2001 and Julie broke the news to their sister Kathi, who was fighting a painful battle against breast cancer, Kathi simply said, “Good for her.” At least her sister was finally free from the Alzheimer’s curse. Kathi was hours away from death herself, but she considered herself better off than Maureen. She told Julie: “At least I still have my mind.”

  Maureen and Kathi died on the same day; Maureen on the west coast, Kathi on the east. The funerals were spaced far enough apart that Julie flew to each, remembering Kathi’s words.

  • • •

  By June 2003, knowing that a test was available to find the APP gene—the rarer mutation, found on chromosome 21—Julie was ready to learn her own genetic status, which she was convinced might help her regain control over a situation that felt like it was spiraling out of her hands. When she had been hurt as a child, her father used to tell her: “Walk on it; it will get better.” But the losses kept mounting—first her mother, then her sisters—until she staggered under the weight of the burden.

  All she could think was: There had to be some reason for the pain, some end in sight. She struggled to articulate why knowing her mutation status would change that feeling, but her genetic counselor was able to explain:

  “You are in a suspended stat
e of life,” he said. “You can’t hold on to your past and everything you know from your past, because you don’t know your future. Your future is suspended. And my guess is you will feel differently after you know.”

  Julie believes now that some of what he told her was standard operating procedure in genetic counseling; “but when he said it, it was like someone put an oxygen mask on me.”

  On June 19, 2003, her results came back: She was negative.

  • • •

  Of Julia’s ten children, three have died from Alzheimer’s: Maureen, Fran, and Butch. Of the five remaining children, four tested negative for the gene, including Julie. One declined to be tested. Two more children died from other causes: Dennis, the oldest, and Kathi.

  A year after Julie was cleared, in August 2004, four of the DeMoe siblings met with Trey Sunderland at the NIH, and Karla subsequently contacted Julie.

  “I felt like I knew her; I knew who she was,” Karla said. They were kindred spirits, sisters struggling to make sense of a senseless disease that was choking their family trees.

  For Julie, there was the same sense of validation, of comfort: Our family is not alone. We are not freaks. Although the two women have never met, their phone conversations have provided a level of support that nobody else has been able to offer. Like Karla, Julie feels a responsibility to pursue answers; as a survivor, she wants her siblings’ deaths to mean something. Each is the narrator of her family’s tale, keeping track of mounting losses, telling the story again and again in hopes of finding a way out. It is a lonely burden they share.

  • • •

  When Fran was still alive and well enough to speak, she testified before the US Senate’s Special Committee on Aging in June 1995. Two decades after Robert Katzman’s editorial call to arms, Alzheimer’s had gained growing recognition as a major public health crisis. The committee had convened to discuss how increased research funding might pay off in saving long-term health care costs related to Alzheimer’s and other brain diseases.

  Just a week earlier, Jonas Salk had died. In his opening remarks, the committee chairman, Senator William S. Cohen, compared the effort to find effective Alzheimer’s treatments to the fight to prevent polio.

  When it was Fran’s turn to speak, she told the lawmakers how she had once been the family’s memory bank, the one who always knew schedules down to the last detail. Then she started having what she called “brain blips,” when in the middle of a thought or a sentence, she simply went blank.

  “If you have ever lived near the ocean, it’s like when the fog rolls in,” she said. “You can feel the emptiness inside.”

  She knew, even before she was diagnosed, what was coming. It was the worst feeling she’d ever had in her life. She told the senators of her shame when she forgot appointments and details; she didn’t want the people in her life to feel unimportant. She hung dry erase boards throughout her house to help her remember, and she wrote with markers on windows and mirrors. She installed a car phone so her children, then fifteen and thirteen, could reach her if she forgot to pick them up.

  “The only hope that I have is that my children, my family, and millions of others will never have to face this themselves,” she said. “This depends upon continued research funding by this government so that a cure or prevention of this disease can be found. The government is attempting to cut back in all areas. If Capitol Hill cuts back in this area, they will pay much more later for what they could be taking care of now.”

  She had told her children she did not believe they would have to suffer through Alzheimer’s twice, first as a caregiver and then as a patient, as she herself had. As long as the family had participated in research, they’d been given the same forecast: A treatment was coming, but it was probably five to ten years away. The irony was that, as years passed, that prediction never changed.

  After Fran spoke, a research doctor approached her as her son and daughter stood by her side.

  “I just want you to know, you do not need to worry about your kids,” the doctor reassured her. “We will have a cure for this.”

  Eighteen years later, with Fran gone, and the prediction still “five to ten years,” Julie reflected on that moment: “I’m glad she went down thinking that way.”

  But Fran’s children, now grown, still live in a world with no cure.

  Twelve

  MALDICIÓN

  “Incredible things are happening in the world. . . . Right there across the river there are all kinds of magical instruments while we keep on living like donkeys.”

  —Gabriel García Márquez, One Hundred Years of Solitude

  THE CONNECTION BETWEEN Karla DeMoe and Julie Noonan through Trey Sunderland’s NIH study offered comfort to two families who had previously been isolated by what seemed like a personal plague. What they did not know was that three thousand miles south of Tioga’s flat plains, in the rural mountains of Colombia, lived a cluster of people who shared their fate. If science could find a way to merge them in research, they would have an ideal group for testing possible drug therapies.

  • • •

  Dr. Francisco Lopera has taken a long, complicated odyssey through the world of Alzheimer’s, persevering against much greater odds than most of his American-based colleagues in his quest to find a treatment for his people. In many ways, Alzheimer’s is like the guerrillas who populate his native Colombia: Sometimes it lies in wait, and sometimes it hides in plain sight, but it is always deadly, always calculating, and nobody is sacred. When as a young doctor Lopera met his very first Alzheimer’s patient, he had no way of knowing that his efforts would hold the key to uniting global efforts to find a treatment.

  In pursuit of his enemy, Lopera has trudged along winding one-lane dirt paths in the rural outposts of Colombia, as treacherous a terrain as it is beautiful, where kidnapping is so commonplace he has matter-of-factly asked colleagues to bring toothbrushes when they accompany him—just in case. As a young doctor, Lopera had himself been kidnapped and taken deep into the forest to treat a wounded guerilla soldier, then returned to his hospital. Though he had grown indifferent to the danger, the volatility of his country would significantly hamper his efforts to collaborate with other Alzheimer’s researchers.

  • • •

  A childhood fascination with flying saucers originally drove Lopera toward astronomy. But after reading a newspaper article that said flying saucers existed only in the mind, he thought, “If that is correct, it is better to study the mind.” At university, he started off in psychology, then switched to neurology because it was a stronger program. If he studied the brain, he reasoned, the mind would soon follow.

  After serving an initial residency in the rural outposts of Choco, Lopera moved to Medellín, where he was completing a residency as a clinical neurologist, with a special interest in the relationship between language and the brain.

  One day in 1984, relatives brought to the clinic a forty-seven-year-old man suffering from almost total memory loss, rendering him unable to work. He had been experiencing his symptoms for four years, his family reported; now he had deteriorated to the point where he simply stared into space or burst into maniacal laughter.

  “I was shocked by that, because he was very young, and because his father and his grandfather had the same history,” Lopera said.

  While Lopera was gaining new insight into the possible heritability of the disease, back in the United States, George Glenner was floating the idea that a specific defective gene was triggering Alzheimer’s, though it would be another three years before Dmitry Goldgaber would discover APP. Karla DeMoe was a new mother, and her father, Moe, was just reaching the point where he had forgotten his own children’s names.

  Lopera followed the afflicted man to his town, Belmira, and talked to other relatives, some of whom blamed the illness on an ancestral curse, known as la maldición. With their help, he reconstructed the history of other cases of dementia among their relatives, and he created the first pedigree for that group. La b
obera, they called it: the foolishness. Some said a village priest had caused the epidemic by casting a spell on parishioners who stole from the collection box. Some said people lost their minds if they touched the bark of a particular tree.

  In the United States, members of families that were similarly affected by Alzheimer’s also invented rationalizations for the disease. Some thought it affected women more than it did men (this is supported by statstics: almost two-thirds of Americans with Alzheimer’s are women, partially owing to the fact that they generally live longer). Some thought you were more likely to get it if you physically resembled a relative who had it, and Brian DeMoe’s lookalike son, Yancey, was one of them. Some tried to decipher patterns of inheritance, willing the disease to skip a generation, just as the Noonans once did.

  Lopera summarized his findings in a paper and published it three years later in a Colombian medical journal. From that point forward, his career would be devoted to solving the mysteries of autosomal dominant Alzheimer’s disease.

  The obstacles Lopera faced were formidable. Lucía Madrigal, a veteran member of his research team at the University of Antioquia, was cast from the same mold as hard-boiled battlefield nurses everywhere. At times during her career, she has had to make her rounds by horse or on foot; as roads became safer, she was able to reach some families by car, as June White had been doing since the 1980s.

  On one trip, while collecting blood samples in Angostura, Lucía was kidnapped by a drug cartel and held for eight days. She ordered them to take care of the samples, regardless of what they did to her. Surprisingly, the drug lords obliged, keeping the vials cold in a river until she was released. A few months later, she returned; one of her kidnappers, a guerrilla boss, asked her to help with his mother, who was stricken with Alzheimer’s. She agreed.

  “We had a period very, very dangerous for us,” admitted Lopera. But he was quick to add: “The violence is better now.”