The Forgetting Read online

  15 parts ginkgo leaf

  1 part gotu kola herb

  1 part galamus root

  1 part rosemary flowers

  1 part kola nut

  1 part cayenne pepper, the hottest you can get

  One teaspoon of herbs to a cup of tea. Six cups per day.

  Schulze is not alone, of course, in supplying the wishful world with simple explanations and cures for Alzheimer’s. Others have blamed fluoride in the drinking water, amalgam tooth fillings, pasteurized milk, green tea, refined flour, polished rice, gallstones, and tiny parasites in the colon. Among the alleged cures: unrefined sea salt, flaxseed oil, lemonade (in the morning), miso, mistletoe, red grapes, turmeric, essiac tea, chlorela algae, barley grass, shark cartilage, olive leaf extract, acupuncture, electromagnetic pulse therapy, hyperbaric oxygen therapy, ultraviolet blood irradiation, and—another Richard Schulze suggestion—deep, painful massage of the feet.

  A 1995 survey indicated that more than half of Alzheimer’s sufferers have tried at least one of these therapies. Twenty percent have tried three or more of them. The impulse is certainly understandable. A relentless, degenerative disease eats away at a person’s cognition while most well-meaning doctors throw up their hands and declare that there is virtually nothing to be done. Legitimate suspicions arise: These doctors are Western—what about thousands of years of Eastern wisdom? What about substances that the famously slow U.S. Food and Drug Administration hasn’t yet approved? On the Internet, there is excited talk about drugs available only in Europe or Asia. With seemingly little to lose, sufferers and caregivers may grasp for anything that glitters.

  Buyers should beware, though. Conventional science, indeed, does not have all the answers; any serious Alzheimer’s researcher would be the first to acknowledge that. But how do the explanations of others hold up under scrutiny?

  Few of Schulze’s claims are upheld by medically supported fact. Alzheimer’s is a recognizable disease, with a predictable set of symptoms and recognizable pathology. No single case of Alzheimer’s disease has ever been cured by a bowel cleansing, or psychotherapy, or any other treatment. The cause of Alzheimer’s is not yet known, but there is considerable evidence that it is caused by a combination of genetic and environmental factors.

  Schulze’s specific list of environmental culprits—though terrifying to the layman—is not confirmed by any serious scholarship. Reputable studies of fluoride, amalgam tooth fillings, aluminum, and other popularly suspected substances have so far come up empty.

  In the end, though, Schulze’s supreme confidence is the best clue to his illegitimacy; genuine scientists speak in more tentative terms, always careful not to overstep the bounds of what has been proven. Much is known about Alzheimer’s, but the many unanswered questions and its incurability demand humility, not the pretension of certainty.

  As for Schulze’s tea: While heavy doses of gingko have been shown to have some very mild effects in ameliorating some of the symptoms of dementia, the effects always appear to be temporary and do not appear to slow its progress. The final ingredient in Schulze’s dementia tea, moreover, should raise eyebrows. No reputable medical studies show that cayenne powder has a demonstrable effect on the brain, and the quantity he is prescribing will make any beverage fiery hot. Imagine the effect of slipping a copious amount of red-hot pepper into the drink of an unsuspecting patient who is only half-lucid and has no powers of communication left. Now imagine doing that six times a day.

  A year after George Glenner helped explain Alzheimer’s to Ronald Reagan at the White House, he delivered the first major combat victory in Zaven Khachaturian’s war on Alzheimer’s. In 1983, he unlocked the molecular structure of beta-amyloid, the main component of plaques.

  Laboratory science had improved considerably since the day of Alois Alzheimer. In 1906, the forefront of brain research was the ability to view cells and their components at a magnification of several hundred times. Alzheimer could see the outlines of the plaques and tangles; he could draw them, count them, describe them, stand in awe of them. But he could not learn much about them. He could not get inside of them and see what they were made of, or understand how they were altering the surrounding tissue.

  By the time Glenner came to the subject, the view of plaques and tangles through a light microscope was akin to looking at New York City from the Goodyear blimp: a vivid scene, intriguing, but not very enlightening. What interested modern researchers was the street-level view, and the scene behind closed doors—the nearly hidden molecular and chemical processes cooking inside. From the blimp, plaques were large, dense, menacing-looking clouds of foreign matter. Up close, Glenner could see that tiny strips of beta-amyloid, a sticky, insoluble protein fragment, were sticking to one another like wisps of used packing tape torn from a package as it was opened in haste. The tape strips spilled onto the floor, stuck to dust, to hair, to each other. After a while, they started to gum up the whole room.

  Glenner decoded the molecular composition of the starchlike beta-amyloid (from amylum, the Latin word for starch), which in turn enabled other researchers to find its source. This was the foot in the door that many other researchers had been waiting for. “George came along and sequenced the protein,” recalled Zaven Khachaturian, “and, oh my God, it was like the floodgates opened.” The story of how plaques become plaques was finally unraveled.

  Plaques were caused by a chemical accident, the defective breakdown of a benign substance called amyloid precursor protein (APP) that lives throughout the body—in the brain, heart, kidneys, lungs, spleen, and intestines—and has some still-unknown role in cellular function. As a part of routine function, APP regularly gets broken down into much smaller soluble components and washed away with other decomposed tissue and chemicals. But under some mysterious conditions, the breaking-apart doesn’t work right, and out come sticky shards of beta-amyloid. As they stick to each other and attract other detritus—fragments of dead and dying neurons—they slowly form into dense, misshapen clumps: plaques.

  Three years later, in 1986, the tangles were also decoded. Researchers discovered that they were made up of another contaminated protein called tau, which normally serves as railroad ties for a tracklike structure that transports nutrients and other important molecules throughout the cell body of every neuron. The tangled tau had somehow become hyperphosphorylated—corrupted by several extra molecules of phosphorus. Without the railroad ties, the tracks had no integrity. They got bent into a twisted mess.

  Imagine some metal-chewing gremlin working its way down railroad tracks, chewing up the steel ties (the tau). Then, under the weight of the train (the nutrients being transported), the tracks buckle. The damage is compounded as the train continues to speed along, causing a mass of twisted wreckage all along the tracks.

  Inside the neuron, the twisted debris gets worse and worse, as the filaments keep twisting around one another. Communication and cell nourishment are at first compromised, and then drop off to nothing; the neuron cannot sustain itself in any way and begins to wither. The cell membranes collapse, and every part of the neuron—the long axon that is responsible for sending out signals to other neurons, the short, branchlike dendrites responsible for receiving signals from other neurons, and everything else—disintegrates. The thousands of synapses, each representing a fragment of a memory, vanish like a plane flying over the Bermuda Triangle. At the end, there is no trace that the neuron itself ever existed—except for one thing. All that’s left, if a pathologist stains the tissue just right, is a small clump of what neuropathologists call “ghost tangles.” There, a neuron once stood.

  A decade after Khachaturian had gone hunting for new Alzheimer’s researchers, here were the first big payoffs. It was suddenly a very exciting time to be in the field. The modern race to understand Alzheimer’s and defeat it had begun in earnest. But many more hazards lay ahead.

  George Glenner fell mysteriously ill about ten years after his important breakthrough with beta-amyloid. He had shortness
of breath and fatigue, and when doctors started doing tests, none of the obvious possibilities checked out.

  When they finally discovered what it was, the entire Alzheimer’s research community took a shudder: Glenner had somehow contracted a very rare disease called systemic senile amyloidosis—the unexplained proliferation of amyloid proteins throughout the body, clogging up his heart and other organs. It was, in a sense, Alzheimer’s disease of the body.

  “How I got this? We don’t know,” Glenner serenely said to a reporter shortly before he died. “It’s just one of those mysteries.” Whatever the ultimate explanation, it looked like more than a coincidence. It certainly seemed that he was inadvertently sacrificing his own body for the sake of scientific discovery.

  Just before he died in 1995, Glenner was asked if he thought there would be a cure for Alzheimer’s.

  “Of course,” he said.

  I have really struggled with the honesty issue. What do you say to someone who sits on her bed and says that she has never stayed out overnight without letting her parents know where she is? What do you say to someone who thinks she is a teacher and if she doesn’t get home and into her classroom there will be a whole class of children left unattended? What do you say to someone who thinks she has no money to pay bills and will lose everything she owns if she doesn’t get home to a job that you know she has been retired from for years? I couldn’t find any reason for telling her over and over that she has a horrible terrible degenerating disease that was making her feel the way she does.

  I found that she became less anxious if I just listened to what she was saying and feeling. Sometimes saying nothing was better than anything I could say. Telling her that I would take care of some of these things put her a bit more at ease. It may feel better for me to verbalize the facts, but what she needs is comfort and security—not the truth. The truth won’t change anything.

  —N.B.

  Merrimack, New Hampshire

  Chapter 10

  TEN THOUSAND FEET, AT TEN O’CLOCK AT NIGHT

  Taos

  Dusk settled in on the first night of the Molecular Mechanisms conference. Two hundred scientists, weary from travel but rejuvenated by the cold, pure mountain air, fell into their chairs to listen to Stanley Prusiner’s keynote address. Perhaps he couldn’t compete with Monica Lewinsky’s pitiful tale, but he had prepared some drama of his own.

  Prusiner had swept-back white hair, and an arched brow that conveyed authority when he spoke. He also had a surprisingly bitter tone in his voice, as though someone had taken something from him that he knew he would never get back. Though he was world-famous for his discovery of “prions”—the previously unknown infectious proteins that cause Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy (a.k.a. “mad cow disease”) in cows—the accomplishment seemed to have left an emotional scar.

  For many years Prusiner had been a pariah in the scientific community, openly ridiculed for a theory many regarded as off the wall. It seemed preposterous that mere proteins could be infectious, since they weren’t really alive.

  Gradually, though, the evidence accrued and Prusiner was vindicated. The prion notion was so distinct from the rest of science that the distinguished American physician Lewis Thomas called it “the strangest thing in all biology.” In contrast to a virus, which injects its own DNA into the host’s nucleus, using the cell machinery to make copies, infectious prions require no genetic manipulation to spread. These oddly shaped proteins destabilize other nearby proteins simply by rubbing up against them, converting the neighbors into the same malignant shape. One prion transforms the next which transforms the next, creating a chain reaction that leads to what Prusiner calls a “sticky sheet” of clumpy protein. As the immune system responds by attempting to remove all the unwelcome particles, the host brain becomes a spongy mass.

  As far as anyone could tell, Alzheimer’s is not an infectious prion disease (though George Glenner’s death from amyloidosis had caused concern). But there were enough common elements to interest Prusiner. He also seemed interested in being here in a moral capacity, as a successful fellow researcher from a nearby disease who perhaps had some lessons to share with his research cousins.

  The message was embedded in his tone of resentment. As he delivered a detailed overview of his work on an overhead projector, Prusiner also retaliated against his past tormenters. He repeatedly displayed a cartoon image of a younger Stanley Prusiner (with dark hair) being squashed by a giant thumb. The thumb represented mainstream science, which kept him down because of his unconventional ideas. Prusiner finished his talk with an acrid quote from Winston Churchill:

  Men occasionally stumble across the truth, but most of them pick themselves up and hurry off as if nothing had happened.

  A fitting statement from a man of politics and war, perhaps, but not a very uplifting note from a champion of scientific inquiry. Prusiner was a sore winner; it was not very becoming. But he was a winner, nonetheless, and his tale of triumph over adversity conveyed the intended message to these elite researchers: Don’t be afraid to buck the conventional wisdom; that’s how scientific progress is made.

  Seventy-two of the world’s most coveted ski runs were about a ten-minute drive away from the conference. Free shuttle buses waited out front on Civic Plaza Drive, with their doors wide open; eleven hundred skiable acres under a sun that famously shines 323 days a year. But with the high stakes in mind, almost everyone quietly declined, on account of what they would have had to miss; sessions were running from 8:00 A.M. to 10:00 P.M. each day, with breaks for coffee and meals.

  There was so much ground to cover, including the entire human genome, with its 30,000 genes and three billion nucleotide base pairs. In the early 1990s, much of the work had shifted to molecular genetics, as researchers began to uncover genetic links to Alzheimer’s all over the human genome: Chromosomes 1, 14, 19, and 21, they discovered, each have genes that can help cause Alzheimer’s.

  They learned that only 5 percent of Alzheimer’s cases—most of them involving onset in middle age—are caused directly by a single gene. In this small minority, the disease is inherited as simply as detached earlobes or brown eyes, from just one parent’s dominant gene. Anyone carrying this gene will get the disease, if they live long enough; statistically, the victims will pass the gene and the disease on to 50 percent of their children.

  The cause or causes of the other 95 percent of cases were not so clear. Much emerging evidence supported a theory that the disease is “multifactorial”—caused by an unfortunate accumulation of genes and environmental factors. According to this analysis, initiating Alzheimer’s disease is like pushing a school bus over a small hill: No single individual can possibly do it alone, but the right group of players coming together at the right time can make it look easy.

  Making sense of such a complex landscape required an unprecedented amount of cooperation. Scientific discovery has always depended on an ever-growing scaffold of ideas and observations. But this brand of sped-up science, where data can be retrieved, analyzed quickly, and shared instantly over the Internet, required an unimaginably intricate network. The presentations in Taos—e.g., “… working from data on presenilin mutations published by Karen Duff in New York and Gerard Schellenberg in Seattle, and using transgenic mice supplied by Karen Hsiao in Minneapolis, we set out to …”—conjured up a histopathological ballet. Teams of researchers scattered around the world, constantly aware of and reacting to the movements of everyone else, were creating an improvisational dance with a startling number of graceful interchanges.

  But there was also awkwardness, and discord. At the end of the first complete day, devoted almost exclusively to understanding the building blocks of the amyloid plaques, and to whether it is not the plaques but perhaps the free-floating beta-amyloid that actually does the damage, the Mayo Clinic’s John Hardy, a warm and irreverent Brit with droopy eyes and an easy smile, rose to speak. He emphasized from the outset that he wasn’t promising
much. “Just sort of a potpourri, bits and bobs to finish off the evening.

  “I’ve always wanted to give a talk at ten thousand feet at ten o’clock at night with four gin-and-tonics in me,” he quipped to the tired group. “We’ll see how it goes.”

  Before he got into the meat of his talk, though, he couldn’t resist a poke at an absent rival. “Allen Roses isn’t here, in case you haven’t noticed,” he said with a grin, “so I thought I’d show this slide.”

  The slide, entitled “Diseases Are Processes,” was a wry allusion to a long-standing dispute. For several years, Hardy had been one of the leading proponents of the “amyloid cascade hypothesis,” which suggested that plaques are closer to the root of Alzheimer’s than tangles. According to this theory, the disease is preceded by a buildup over time of beta-amyloid, which eventually reaches a critical mass and triggers other unwanted events, including the formation of tangles. Most Alzheimer’s researchers—probably some 80 percent—had come to embrace this line of thinking and had dedicated their research to some aspect of it.

  Roses, director of genetics research at the pharmaceutical giant Glaxo Wellcome, dissented. He dismissed plaques as “tombstones” and “scar tissue” that are largely irrelevant to the underlying mechanisms of the disease. The “amyloid establishment,” he complained, was drawing far more resources than it merited. Roses’s research had led him to believe that tau—tangles—are closer to the root of the problem. In 1992, as director of the Alzheimer’s program at Duke, he had made probably the most important genetic discovery to date: a variant of a gene called ApoE, located on chromosome 19 (a human cell has 46 chromosomes), that appeared to increase the risk of developing Alzheimer’s by a factor of twenty. Seven years later, it was still the only verified genetic discovery related to the more common form of the disease.