The Forgetting Read online

  Roses had felt ignored after his discovery. No one seemed interested in following up on his breakthrough research. He saw it as a classic case of herd-mentality science. The spectacular popularity of the amyloid hypothesis, he said with his famously unvarnished candor, was simply a matter of “good scientists not being able to look objectively at science, being so subjectively involved in being right and organizing posses to make sure that other people are kept from [getting the grants]—‘hang these guys so they’re not in the way of what we’re doing.’

  “It happens in this field, and I think it has really slowed therapy. The reason I say that is because these guys don’t make drugs. Drug companies make drugs. And when drug companies want to start an Alzheimer’s program, what do they do? They go for what’s popular, for what’s in the press. They say, ‘Oh, here’s something in Nature.’ and if in fact 85 percent of what you see is [amyloid research], well, some drug exec without a scientific background is going to say, ‘I don’t know about this crazy guy Roses, who everybody says is wrong. We’ll invest in amyloid.’ So what happens is that the drug companies’ Alzheimer’s programs are actually amyloid programs, and it feeds upon itself”

  Scientists can vehemently disagree and still be close friends, of course. But not John Hardy and Allen Roses. In 1991, when Hardy was still stationed in Britain, the two got into a transcontinental telephone screaming match over a paper that Hardy was about to publish.

  It was not a small event. Hardy had established a link between a rare, early-onset form of the disease and a mutation on chromosome 21. The paper would be the first genetic linkage to be associated with Alzheimer’s (this was before Roses’s big discovery), and it included some of Roses’s data as part of the proof On the advice of a patent lawyer and because Roses had made it clear that he didn’t really believe in such a link, Hardy had decided not to show the paper to Roses or offer him coauthor credit.

  But then someone leaked the paper to Roses in an anonymous fax from London’s Paddington Station. “I went berserk,” Roses said. The imbroglio that ensued left the Alzheimer’s research community polarized.

  Things had simmered down somewhat since then, but the Hardy-Roses rivalry endured. “John and Allen are civil to each other,” someone close to Hardy told me in Taos, “but there’s no good feeling between the two.” Roses was, in fact, supposed to speak at this conference, but he bowed out at the last minute. In an E-mail correspondence, Roses dismissed the Taos conference. “Most of that is academic rehash that some of our [company] people will filter,” he said. “We are advancing other technologies toward a treatment. Universities do not make drugs. Governments do not make drugs. Pharmaceutical companies make drugs.”

  So here, at ten thousand feet, at ten o’clock at night, Hardy was poking at Roses in his absence. “Diseases are processes” was Hardy’s cagey depiction of their essential disagreement: From Hardy’s point of view, Roses didn’t think of Alzheimer’s as an aggregation of materials and sequence of events so much as a switch turned on by a gene.

  On the third night of the conference, the “tauists” got their chance. This was the stalwart minority of researchers exploring the possibility that tangles, not the plaques, were the real key to understanding Alzheimer’s.

  The tau (tangle) vs. amyloid (plaque) rivalry had become intense over the previous decade. “The battle is raging like the religious wars of medieval times,” observed Zaven Khachaturian. “But it’s good for everyone. I like to sit on the fifty-yard line and cheer.”

  In her talk, Virginia Lee, half of an award-winning husband-wife team from the University of Pennsylvania, playfully jabbed the predominantly amyloid crowd. “I’ll give some background info for those few of you who don’t understand a lot about tau,” she said. Her rivals laughed.

  But it was Lee’s colleague Khalid Iqbal who launched the direct assault. “The amyloid cascade hypothesis has been around for almost ten years,” he said, “and some of the best scientists have been working on it. But this relationship is still not understood.

  “Tonight I will propose to you that we also consider an alternative hypothesis—that Alzheimer’s is fundamentally a metabolic disorder. Like hypertension and coronary heart disease, Alzheimer’s is a metabolic disorder of mid to old age which requires a generic predisposition and one or more environmental factors.”

  Iqbal pointed out that of all the genetic mutations and environmental factors found to correspond with Alzheimer’s, none are causative—none cause Alzheimer’s every time. It’s also important to note, he said, that the disease can arise outside of the presence of all known risk factors.

  In other words, we don’t know all the causes and may never know them. The causes are so many and so complex that they aren’t even what matter. What matters is the common pathway that the disease takes after it has started. The challenge of researchers is not to stop the train just as all the cars are being assembled and put onto a track. Rather, it is to block that track after the train gets rolling but long before it gets to its destination.

  The likely pathway of this disease that ends in the death of neurons, Iqbal said, is not the formation of beta-amyloid but the hyperphosphorylation of tau—the creation of tangles.

  Then Iqbal delivered the sharpest blow, suggesting that amyloid may not only not be the problem—it may actually be a part of the solution. Amyloid, he said, seems to be not a destructive protein but a repair protein. Amyloid levels, he noted, go up every time there is some harm to the brain.

  This was tantamount to marching into a meeting of the Federal Reserve Board and saying, “Tonight I will propose to you that inflation is not our enemy but our ally.” Iqbal was lobbing grenades here. He had not come to Taos to make new friends. Prusiner, wherever he was in that large dark room, no doubt wore a narrow grin of satisfaction. Here, clearly, was a scientist not following the pack.

  It all came back to Prusiner, then, and his Churchillian taunt: “Men occasionally stumble across the truth, but most of them …”

  Was the amyloid bandwagon a classic example of “herd science,” as Allen Roses and Ruth Itzhaki charged, or was it the legitimate outcome of sober investigation? This, and not any strict question of biology, was the unspoken theme of the conference. The amyloid camp seemed to have infected nearly everyone with optimism. But was that optimism sound?

  The future of Alzheimer’s disease would rest on the answer.

  From a distance, scientific research can seem sterile, all test tubes and assays and peptides and risk factors. The Latin terminology and white lab coats create an impression of scientists as geek technicians, anti-people people who, for reasons of extreme shyness, prefer to wallow in details, crunch numbers, and deal only with objective truth. The stereotype: Scientists are smarter than the rest of us, are uncomfortable in their extreme intelligence, and find it hard to deal with others.

  But close up, the view is entirely different, much more textured and colorful. The better I came to know this elite scientific group of Alzheimer’s researchers, the more I understood how profoundly human their shared endeavor really was. Not far below the surface talk of microtubules and missense mutations was a culture steeped in ambition, loyalty, secrecy, warm companionship, resentment, and greed. There were real, lasting friendships here, and career-threatening antagonisms. Science turns out to be more similar to statehouse or boardroom politics than an outsider would suspect.

  As I was taking it all in, one scientist at the conference quietly reminded me that there was a lot going on beneath the surface of these talks. “An important subtext of these battles,” he whispered in the middle of a presentation, “is that all of these scientists have patents on their discoveries. There’s a lot of money at stake.”

  Not just research money, but Lear Jet and beach house money. A sweeping change in U.S. law in 1980 allowed American universities and researchers to begin applying for their own patents on discoveries made with federal research dollars. Scientists were also permitted to create for-profit
corporations on the side, while maintaining their publicly sponsored university research positions. “An entrepreneurial atmosphere has begun to alter the ethos of science,” is how the Tufts University ethicist Sheldon Krimsky puts it. “Norms of behavior within the academic community are being modified to accommodate closer corporate ties.”

  For this reason, even though the scientists traveled from all around the world to speak to one another, there was also clearly much not being said. While this seemed to be in direct contravention of the historically open-air philosophy of all scientific inquiry, it was also conceivable that market incentives were just what ambitious researchers needed to drive themselves even harder to win this critical race.

  Just before the weekend ended, I caught a telling glimpse of this invisible layer of information. One of the last to speak was Ivan Lieberburg, not a director of a university lab but head of research and development for Elan Pharmaceuticals, based in San Francisco. Universities do not make drugs … pharmaceutical companies make drugs. Lieberburg discussed, in very general terms, all the possible treatment possibilities, and then hinted at a few areas that his company is now focusing on. He apologized to the group for having to restrict his talk; for proprietary reasons, he said, there was much he could not say. But he did drop a few hints. “We’re really on the threshold of a new age,” he said. “I think we’re coming very close to the goal line now, thanks to what many of you have done.” The tone was beyond hopeful—it was celebratory.

  Afterwards, as he packed up his slides, Lieberburg turned to me and said, “This was one of the most frustrating experiences I’ve ever had in my life, to speak to a group like this and not tell them what I know.” Stay tuned, he said. Something big is coming this summer. Something very big.

  Mom hasn’t been feeling good the last couple days, I wonder if her medication has something to do with it. She takes:

  Propulsid 20 milligrams, twice a day

  K-Dur 20meq SA TAB, once a day

  Synthroid 0.025 milligrams, once a day

  Imdur 30 milligrams, once a day

  Procardia XL 60 milligrams, once a day

  Prilosec 20 milligrams, once a day

  Aspirin 325 milligrams, once a day

  Betagan eye drops, two drops for each eye, twice a day

  Trinsicon/Ferocon, once a day

  Paxil 30 milligrams, once a day

  Neurontin 100 milligrams, once a day

  Nizoral (cream), once a day

  Ditropan/Oxybutynin chloride 5 milligrams, twice a day

  Extra-Strength Tylenol, once a day

  After sleeping for just a little bit last night, she woke up crying. She wanted us to take her to the hank. We told her it was the middle of the night—the bank was closed. She threw a fit. We told her we have cash here in the house in case she needs it. It was futile. Everything we said made no sense to her, and she made no sense to us. She went back to bed and cried. We let her cry herself to sleep.

  This morning when I went to wake her for breakfast I found her pajama bottoms “hung up to dry” and she had no Depends on. It could he that she needs a change in mood medications.

  —C.J.

  Toledo, Ohio

  Chapter 11

  A WORLD OF STRULDBRUGGS

  Alois Alzheimer did not get to pursue his namesake disease for very long. In 1912, just a year after publishing his first substantial paper on Alzheimer’s disease and only two years after it was named for him, he accepted a new job as head of psychiatry at the University of Breslau. On the train to assume his new post, he collapsed; a case of infectious tonsillitis had developed into rheumatic fever, spreading to the kidneys, joints, and the lining of the heart. He was taken directly from the Breslau train station to the hospital. Though he eventually gained enough strength to leave the hospital, he never fully recovered. “At the conference of German Psychiatrists in 1913 I saw him,” Kraepelin later recalled. “Although outwardly he appeared sprightly/active, his mood was dejected and depressed; he looked into the future with bleak foreboding.… In the effort to complete his duties to the full, Alzheimer did not understand how to protect himself.”

  Alzheimer grew weaker and weaker and finally died in 1915. He was fifty-one—the same age that his famous patient Auguste D. had been when she first experienced symptoms of forgetfulness.

  For someone born in the mid-nineteenth century, fifty-one years was not brief: Life expectancy for Alzheimer’s generation in Germany was somewhere in the low forties. Alois Alzheimer’s boss in Frankfurt, Emil Sioli, lived to be seventy; the legendary cellular pathologist Rudolf Virchow lived to be eighty-one; but these were the exceptions. “Although historical records indicate that older people have always existed in human societies,” says University of Chicago epidemiologist S. Jay Olshansky, “survival beyond age fifty for most members of a population was a rare event until the twentieth century.”

  Today, endurance is the norm. One in eight Americans is over sixty-five. Ninety percent of all babies born today in the developed world will live past sixty-five.

  Such a dramatic expansion of life’s quantity begs the question: Can we hope to match it with comparable gains in quality?

  Because there were relatively few elderly at the time, it would have been impossible for Alzheimer to imagine the implications of his work. He had identified a disease that would become a serious epidemiological problem only as human populations achieved much longer life spans. Neither he nor any of the extraordinary minds in his circle could have foreseen that “this Alzheimer’s disease” would in the next century emerge as the central public health epidemic of the industrialized world.

  Perhaps it is not so bad that they couldn’t see clearly into the future. If doctors in 1910 could somehow have envisioned the appalling side effects of medical progress, the agony of neurodegeneration and other diseases of deterioration experienced mostly by people who live into their seventies and beyond, they would have found this very difficult to reconcile with their work. “Modern health care permits growing numbers of people to live to advanced age under circumstances that call into question the meaning of survival,” concludes Hunter College’s Harry Moody.

  Olshansky echoes this sentiment. “Our society is experiencing unprecedented rates of survival into older ages,” he writes, “but this success has also been accompanied by a rise in frailty and disability in the general population. This is a consequence that neither the medical community nor society was prepared for.”

  A 1997 “State of World Health” report by the World Health Organization began this way: “Dramatic increases in life expectancy, combined with profound changes in lifestyles, will lead to global epidemics of cancer and other chronic diseases in the next two decades. The main result will be a huge increase in human suffering and disability.”

  Epidemiologists call this extension of frailty time a “prolongation of morbidity.” It is the paradox that the extension of life inevitably yields new suffering. Alzheimer’s is perhaps the perfectly poignant emblem of this medical quandary: As we defeat disease, we also create disease. Any particular illness may be conquered, but mortality is unavoidable.

  Evolutionary biologists are also fascinated by the rapid increase in longevity and its unintended consequences. From their perspective, the central concept here is one of hidden diseases—disorders that have always existed for human beings in a potential state, but that have never been fully realized until recently.

  Hidden diseases only emerge after inordinate wear and tear. A serious cyclist buying a state-of-the-art touring bicycle, for example, can expect to repair and replace many parts on a fairly predictable schedule: tires, inner tubes, and brake pads will all wear down; the bike’s chain and ball bearings in the wheels’ hubs will require constant lubrication, and even then they will seriously fatigue after several thousand miles. For these parts and others, replacement is common, expected, necessary.

  It will take some extreme use, though—imagine crisscrossing the United States several hun
dred times—to wear out a set of handlebars or the bicycle’s frame. There are weaknesses hidden somewhere in those durable parts that are impossible to predict and not even relevant until an extremely advanced age of use.

  The long-term frailties are there somewhere, but they cannot be seen. For some fifty thousand years, as the vast majority of human beings died under the age of fifty, disorders like hearing loss, prostate cancer, osteoarthritis, breast cancer, colon cancer, amyotrophic lateral sclerosis, and Alzheimer’s disease were mere diseases-in-waiting. Only in the last fifty to one hundred years have they started to come into view.

  Given this, perhaps the most remarkable thing about the history of senile dementia is that it has been so conspicuous. In practical terms, it was a hidden disease with very few victims before the twentieth century, and yet references to senility are strangely ubiquitous throughout recorded history—not just in medical records, but also in legal, political, and cultural texts. Sometime around 500 B.C. the Greek legislator Solon mentioned that impaired thinking due to old age could invalidate a last will and testament. A reference to dotage is included in the “Story of the Larrikin and the Cook,” one of the tales from the fifteenth-century The Thousand and One Nights. The Florentine Codex, a history of Aztec culture in Mesoamerica compiled by the Franciscan monk Bernardino de Sahagún in the sixteenth century, mentions the “childish” grandfather and other “foolish” old people. Other earlier chroniclers of senility include Euripides, Chaucer, Montaigne, Chekhov, Balzac, Carlyle, Hugo, Trollope, Conan Doyle, Bernard Shaw, Joyce, Melville, Conrad, Tocqueville, Wharton, Darwin, Cooper, Poe, Hawthorne, Sinclair Lewis, O. Henry, Sir Walter Scott, Dickens, and Thoreau. In War and Peace, Tolstoy wrote: