The Inheritance

by Niki Kapsambelis

  Gail’s door banged open. Neighbors started showing up with covered dishes, dinners, tempting desserts—enough food to feed a small army, more than the family could ever possibly eat. The town would turn out, in droves, for Moe’s funeral, many of his old friends—who had not seen him since he left Tioga in a police cruiser ten years earlier—expressing shock at how shrunken his body was.

  The DeMoes had not been forgotten. The town did not hate them. It was just that nobody had known what to say.

  • • •

  The autopsy report was dated June 9, 1989, and the consulting psychiatrist was Dr. Leonard Heston from the University of Minnesota, June White’s boss.

  According to the autopsy, before Moe’s brain had been soaked in formaldehyde, it weighed 1,050 grams, or about 2.3 pounds; a normal adult human brain weighs about 3 pounds. Both hemispheres had shrunk, and damage to the frontal cortex—which controls emotions, problem solving, reasoning, planning, and other ingredients in personality—was particularly severe. So, too, was the insula, which is a prune-sized section of the brain that controls cravings, self-awareness, and social emotions such as empathy, guilt, and disgust. All were common patterns of distribution in Alzheimer’s.

  Under a microscope, stained sections of Moe’s brain revealed “enormous numbers” of plaques and tangles. In the sample from his left calcarine cortex, which controls visual perception, there were numerous plaques, frequently with well-developed amyloid cores.

  The report concluded that Moe’s brain showed severe changes “in keeping with the presenile onset of his clinical picture of dementia, which is attributable to Alzheimer’s disease.” At last, the autopsy confirmed what the doctor in Fargo had said years before: Moe’s strange behavior was, indeed, caused by the same disease that had killed his mother.

  • • •

  The search continued for concrete genetic links that bore out the pattern of autosomal dominant inheritance that Robert Feldman and Jean-François Foncin were exploring in Family N. Though Dmitry Goldgaber had discovered the APP mutation on chromosome 21, the initial excitement that followed was short-lived. In families known to carry this inherited form of Alzheimer’s, it turned out that only a tiny percentage tested positive for APP. Family N, for example, did not. So now, a new gene-cloning hunt was under way, searching for other possible autosomal dominant mutations, even when Moe was still withering away in the hospital.

  Peter St. George-Hyslop, the British neurologist and molecular geneticist who had teamed up with Foncin in 1985 to study Family N, had moved from Boston to the University of Toronto. Fortified in part by the access to Family N, he and his team would continue their search for an additional mutation through 1995, adding families as they found them. Other, competing teams backed both by industry and the National Institutes of Health were also after the same prize.

  “It was an exciting project,” Hyslop says. “If you could find the gene, you could understand more about the disease, which at the time was a huge enigma.” Finding the gene meant possibly being able to predict the disease, but it also would allow science to understand the molecular changes that occur as Alzheimer’s unfolds, which in turn would create better drug targets.

  It was difficult work, often riddled with frustration and disappointment. At first, they weren’t even searching in the right neighborhood. Hyslop and his collaborators initially thought chromosome 21—where Goldgaber had identified the APP gene—would also be the hiding place for the Family N mutation.

  One of the teams competing with Hyslop’s was located at the University of Washington, where June White and Leonard Heston’s enormous brain collection, including the DNA donated by the DeMoes, now resided and Heston now worked. The DNA analysis of the brains was in the hands of a bearded biochemist named Jerry Schellenberg.

  Like the others, including Hyslop, Schellenberg’s group had been collecting DNA samples from families who seemed to be inheriting early-onset Alzheimer’s from one parent—either male or female. Each child was born with a fifty-fifty chance of getting the disease in middle age.

  Because autosomal dominant mutations are so rare—occurring in only 1 to 5 percent of all Alzheimer’s patients in the world—those odds work against finding families with the disorder; some of it is luck, and some of it comes from old-fashioned research. Schellenberg, like Hyslop, benefited by connecting with another scientist who had a large collection he was willing to share.

  In 1991, Schellenberg naturally had no genome map to use as a reference guide. So instead, he worked to identify the mutated gene by comparing pieces of DNA from afflicted families—known as “markers”—to markers that other scientists were associating with Alzheimer’s disease, looking for a match that would point to the chromosome with the faulty gene.

  “We were literally plucking markers out of the air,” he recalled.

  It was like finding yourself in New York City without a map and looking for a specific address. If you went down every street in the city, and were systematic about the way you did it, you’d eventually find what you were looking for; it was only a matter of time.

  “The first time you do this, you’re really excited,” Schellenberg explained; it was like buying a lottery ticket. The world seems full of possibility, the odds of winning huge. But after hundreds of failed attempts, the anticipation of a scientific eureka fades.

  Schellenberg’s job was to align the lab work that one group on the team had completed with the statistical analysis of another. They’d tried something in the neighborhood of 150 genetic markers, focusing on chromosome 21 and more recently branching out to chromosome 14. Each failure represented weeks’ worth of work by about 140 people; messy, tedious work that had to be scored, analyzed, and categorized by family before revealing itself to be worthless.

  In June 1992, eighteen months into the gene testing, Schellenberg was waiting for a printout of the numbers associated with a genetic marker on chromosome 14, expecting the usual negative numbers. But when he looked down, positive numbers were spewing out of his printer.

  “I thought the key that hits the minus sign must have been broken or something,” he recalled. Instead, he had struck pay dirt: He now knew he was looking in the right neighborhood, making his search much, much narrower—more like searching a city block for the right address instead of the entire metropolis.

  The marker matched the DNA of so many of his Alzheimer’s families that Schellenberg was certain he’d find, somewhere on chromosome 14’s sequence, the mutation responsible for the vast majority of inherited cases. Unlike APP, which only matched a small percentage of affected families, this one would explain Family N and many more, including the DeMoes.

  Before the paper with the Schellenberg team’s findings could be published, an international meeting of Alzheimer’s researchers was scheduled in Italy. Worried that his team might get scooped before its discovery appeared in print, Schellenberg went to the meeting with a slide that had their results on it. If someone else tried to present the same information, he wanted to be sure he could prove that they were at least tied for first.

  As soon as he realized the discovery was still theirs alone, he went home early. The next goal: finding the specific mutation on chromosome 14—that mystery address he’d been hunting—that was the source of the matching marker.

  • • •

  Three years after Moe’s death, Karla received a note on University of Minnesota letterhead:

  Oct. 20, 1992

  Dear Ms. Hornstein:

  In the October 23rd issue of Science magazine, an article will appear reporting the definite linkage of a gene causing Alzheimer’s disease to a small segment of human chromosome 14 in some families.

  There are no immediate consequences of this to you and your family. However, the two molecular genetics laboratories involved in the study (at the Universities of Minnesota and Washington) are continuing to work toward the specific location of the gene and no doubt other laboratories will soon join them. This means that it m
ay soon be possible to predict on the basis of a blood test very early in life who will and who will not get the disease. Not everyone will want this information but it is time to start thinking through the choices that may soon be presented to you.

  In the longer run, this is a most important breakthrough. After the gene is isolated, the goal will be to discover what it does or fails to do that results in Alzheimer’s disease. Then ways to compensate for this error will be sought—a drug perhaps, or maybe only an adjustment of diet. It may even become possible to replace the faulty gene. The bottom line is that knowing the structure of the gene will provide rational bases for preventing the disease.

  I realize that you have waited for this very good news through long trials of fire and heartbreak. Thank you for your wonderful cooperation. It has made a great advance possible.

  Sincerely,

  Leonard L. Heston, M.D.

  June A. White

  The letter came with a copy of the Science article, authored by Schellenberg. Coauthors included Leonard Heston and June White. An accompanying article said the team had been studying DNA sequences in nine families with a hereditary pattern of early-onset Alzheimer’s, though it did not specify—and Schellenberg could not say for certain—whether the DeMoes were one of them. All seemed to carry a similar genetic marker on chromosome 14.

  Karla wasn’t really sure what any of it meant, except that maybe it might be a way to find out if someone would get the disease earlier in life. She had taken an administrative job at a small college, so she went to the library at work and tried to look up more information, but the article was too technical to make much sense to her. It was the last time she ever heard from June White, who retired three years later.

  In hindsight, the letter should have served as a warning bell for what was to come. Karla would save the letter and the article, but another decade would pass before she would read it again with any sense of urgency.

  Despite Schellenberg’s triumph, it was Hyslop and his team who finally identified the mutation in 1995. He named it PS1, or presenilin 1. It was the most common mutation found in this rare autosomal dominant form of Alzheimer’s; it affected the DeMoes, Family N, even Auguste Deter, the original patient identified by Alois Alzheimer.

  Of the many teams competing for the mutation’s discovery, some backed by financial resources such as the NIH, Hyslop’s was decidedly the underdog. He and his partners, Foncin and an Italian, Amalia Bruni, were working with the research equivalent of pocket change—a little more than $100,000 per year. Bruni, in fact, was pursuing Family N as a volunteer in her spare time.

  Yet Hyslop thought their lack of financial resources might have had an unexpected benefit. Without the luxury of funding, they couldn’t afford to chase potentially fruitless avenues. “Sometimes, when you don’t have enough money, you have to think out very carefully what you’re going to do, and conduct the right experiment,” he said.

  And luck, he added: It helps to have a little of that, too.

  • • •

  A few family members the group had studied remained in contact with Hyslop. One in particular, a pathologist, called monthly, offering to help and asking for updates on the progress the team had made. He had been so worried about passing the disease along to a new generation that he had deliberately avoided having children, and had set a life goal of convincing someone to find a solution.

  About six months before they found the gene with the mutation, he stopped calling; he’d fallen ill.

  Hyslop waited until he was absolutely certain they’d identified the gene; then he called the man to report the news. Although he couldn’t come to the phone, the man’s wife relayed the news. “He is intensely grateful,” she told Hyslop in that call. “It’s something that he’s been waiting for for a long time.”

  Later that night, he died from a malady unrelated to Alzheimer’s disease. He hadn’t been a carrier.

  Seven

  UNTAMED HEARTS

  NOW THAT MOE was gone, fifty-four-year-old Gail was single for the first time, really, since she was twelve years old. All her children were essentially grown; even Jamie had turned eighteen. It was time to move on with her life.

  In the aftermath of Moe’s 1989 funeral, the town’s judgment had softened. There was no shortage of gentleman callers for Gail DeMoe, known throughout the town as Grandma Gail, who believed in living life to the fullest and practiced what she preached. “Grandma had her own secrets,” Karla says. “Mother was quite the partier in her day.”

  When they were out in public, if she saw a man close to her age, Gail would joke with her kids: “That could be your new daddy!”

  Her message was simple: Do not waste the present by dwelling on the past. But she never forgot Moe. He would always be her husband.

  • • •

  Of Moe and Gail’s six children, only half—Brian, Doug, and later, Jamie—lingered in Tioga to devote the better part of their working years to the oil fields. Although Brian ventured briefly elsewhere—he remained “Toby Tyler, King of the Oil Patch,” unrepentant pot smoker and respected veteran of the local bar scene.

  Doug, the next oldest boy, stayed rooted in their hometown his entire life. His comfort zone extended about as far as the town limits, and sometimes not even that far. Doug worked for the same oil company from as far back as anyone can remember, even when competing firms came to town. He worked only one job—latching pipes on drilling rigs. Everyone in the oil patch has a nickname: Toby Tyler, Chrome Dome, Belt Buckle, Weiner. Doug’s was Doug Latch. Even his children called him that on occasion.

  As they grew into adulthood, Doug and Dean no longer spent as much time together. Doug’s closest high-school friend, Gary Anderson, had also moved away, so Doug often found himself at loose ends.

  Without Dean, he seemed incomplete. He filled the void left by his brother’s absence with the companionship of the women he dated, becoming dependent on them, and—increasingly—on Gail.

  Shortly before Karla and Matt got married, Doug became engaged to his then girlfriend, a woman named Lola. It was a tumultuous relationship, and Doug was needy and nervous. She broke off the engagement and returned the ring. The DeMoe siblings chipped in to buy it from Doug, then gave it to Matt for Karla.

  Eventually, Doug and Lola reunited and married when Lola got pregnant with their daughter, Jennifer. The marriage ended when Jennifer was three, and for the next decade, Jennifer saw her father only on holidays or over the summer. Even so, she always thought of them as close. She had a little half brother, Brady Thompson, but never felt as close to Brady as she did to their dad.

  At thirteen, around the time Brady was born, Jennifer went to live with Doug at Grandma Gail’s house, but he hadn’t had much practice as a parent. Though she grew into a pretty woman with a husky voice and a booming, hearty laugh, Jennifer was a chubby teenager, and Doug’s strategy for addressing the issue was to lock up food.

  Jennifer lived in Minot for a while, and traveled to Montana sometimes with her boyfriend. But her father stayed behind. He didn’t take vacations; he didn’t have hobbies; he didn’t know how to use a computer. His only real interest was his love of new vehicles: trucks, motorcycles, power boats—anything with a motor.

  “His life was this town. He had no need to see what else was out there,” Jennifer said. “It’s always been a safety blanket.

  “Brian, my dad: They’re very simple men,” she observed.

  • • •

  At the opposite end of the spectrum was Lori. Of the DeMoe siblings who left Tioga, Lori was easily the most widely traveled. In the nearly four decades Steve McIntyre spent working on the railroad, he traveled to every state west of the Mississippi, from New Orleans to Seattle, Chicago to Los Angeles. For a significant chunk of that time, Lori was with him—first in their travel trailer, moving from one city to the next while the crew worked on the tracks. When it was time to move to the next location, they simply tied their refrigerator and cupboard doors shut, moved
loose objects to the floor, and jumped behind the wheel. The gypsy lifestyle suited Lori’s restless spirit perfectly; on the road, and in Steve, she found a contentment she had never known.

  One weekend in 1979, Lori told Steve she was pregnant. Their wedding plans abruptly shot to the top of their priority list.

  Even “when I was young, I knew that I didn’t want a big wedding,” Lori said. “I always knew that. We had a redneck wedding,” she added, laughing.

  Their first daughter arrived on August 3, 1980, and a second baby girl followed three years later. For about a year, the young family lived in the twenty-eight feet of space afforded by the travel trailer. Then they upgraded and moved into a bunk car, which was like a trailer house on wheels, equipped with a dining nook, a bedroom area, a bathroom, and a shower.

  Lori and Steve would be married five years before they moved into their first house, in Kimball, Nebraska. They loved their wandering life, never knowing where they’d wind up next. They were about as far from the monotony of Tioga as they could get.

  One fellow railroad wife remembers Lori cheerfully hauling clothes to the Laundromat, baby in tow; she was always working on a craft, usually an afghan or a baby blanket for one of her friends. She was busy, capable, unsinkable.

  Though he was traveling during the week, Steve’s heart remained with his family, and his admiration for the masterful job Lori did was apparent even when he was frustrated with her. “She raised those girls,” he would say. As they grew, the girls became small reflections of their mother: plucky, fiercely independent, creative, and fearless.

  Steve and Lori’s third daughter was born the year they moved to Kimball; one of her nurses, Robin Tjosvold, would become one of Lori’s closest friends for the rest of her life.

  During those years, Lori’s independence served her well. With Steve home only one day a week, she never missed a beat; her seemingly limitless energy was enough to raise three active girls and take care of other people’s children, too, in a de facto backyard day care. Every birthday cake the girls ever had was home-baked and decorated by their mother, and they were the best cakes in town. She sewed all their Halloween costumes and a lot of their clothes, as well as clothes for their dolls. She was always deeply involved with them—coaching a competitive jump-roping team, taking them camping, dancing, listening to their triumphs and heartbreaks.