When David Shenk set out to write his intelligent and unusually circumspect book The Forgetting, he had, he said, two ambitions: to write a “biography” of Alzheimer’s disease, and to chronicle the race for its cure. A biography of a disease is a strange nomenclature. It suggests, at the start, that Alzheimer’s has a life of its own, one that is distinct from its victims’. Alzheimer’s doesn’t have its own life, except in this: it is animated by fear. A nationwide poll conducted this spring for the Alzheimer’s Association by Peter D. Hart Research Associates found 95 percent of all respondents saying that Alzheimer’s was a “serious problem facing the nation,” and well more than half—64 percent—of those between 35 and 49 years of age reporting that they were concerned about getting the disease themselves. Four million Americans already have Alzheimer’s, a number that is expected to grow to fourteen million by midcentury. As Gary Small, the director of UCLA’s Center on Aging, says in his bullish manual for beating the odds, The Memory Bible: An Innovative Strategy for Keeping Your Brain Young, “we are all one day closer to Alzheimer’s disease.”
By the same logic, then, we are all one day closer to the cure for Alzheimer’s, too. “Ten years to a cure,” a Japanese researcher said to David Shenk in March 1999 at the biannual “Molecular Mechanisms in Alzheimer’s Disease” conference. He, like other researchers Shenk encountered there, was “giddy” at the prospect. Giddiest of all, it seems, was Ivan Lieberburg, the head of research and development for Elan Pharmaceuticals. “We’re really on the threshold of a new age,” Shenk reports him saying. “I think we’re coming very close to the goal line now….”
When Lieberburg said this, it had been nearly a century since a German physician, Alois Alzheimer, first admitted a disoriented, volatile, yet seemingly healthy, fifty-one-year-old woman to his clinic. Unable to remember her own name, she nonetheless accurately described her condition. “I have lost myself,” she told the doctor.
Over the next four and a half years the woman continued to decline, losing the ability to speak, to feed herself, to walk, or to know her own incapacity. Alzheimer was at a loss to diagnose her condition, which did not fit any known model. It was only when she died, and he was able to view slides of her brain, that the doctor found what appeared to be the cause of her premature senility. As Shenk describes it,
…At a magnification of several hundred times, he finally saw her disease.
It looked like measles, or chicken pox, of the brain. The cortex was speckled with crusty brown clumps—plaques—too many to count. They varied in size, shape, and texture and seemed to be a hodgepodge of granules and short, crooked threads, as if they were sticky magnets for microscopic trash.
And that wasn’t all:
In the second and third layers of the cortex, nearly a third of the neurons had been obliterated internally, overrun with what Alzheimer called “a tangled bundle of fibrils”—weedy, menacing strands of rope bundled densely together.
Plaques and tangles—these have, ever since, defined the disease that bears Alzheimer’s name. They are a prominent feature of an Alzheimer’s brain. Still, it remains unknown which phenomenon—if either—causes the neurons to die and the brain to shrink and the body to revert to an autonomic state, and then to die. It is not known, in other words, if plaques or tangles or both cause Alzheimer’s or if they are merely the disease’s signature, left behind in the neural detritus.
Like the majority of Alzheimer’s researchers, the scientists at Elan Pharmaceuticals were guessing the answer was plaques. One of them, Dale Schenk—no relation to David Shenk—had a novel, and many said “simplistic,” idea: vaccinate against them. Since the main component of plaque is a protein called beta-amyloid, which is foreign to the human body, Dale Schenk reasoned that injecting patients with a small amount of it might produce enough antibodies to tag and remove the beta-amyloid in the brain, in the same way that injecting a small amount of a weakened live virus like, say, polio stimulates the immune system to make antibodies to that virus. Schenk further reasoned that since the brain’s natural defense system, the barrier that keeps blood from flooding the brain, was not perfect, and a small number of unwanted particles were always crossing the threshold, injecting beta-amyloid into the bloodstream would result, eventually, in a certain number of beta-amyloid antibodies entering the brain. As David Shenk writes, “[Dale] Schenk’s epiphany was that a body constantly manufacturing its own supply of beta-amyloid antibody would produce so much of it that three parts per thousand would be plenty” to breach the barrier.
In 2000, not long after he baldly hinted that the game was almost over, Ivan Lieberburg went public with the news that Dale Schenk’s hunch had been right. Beta-amyloid antibodies had successfully removed plaques in mice. These were no ordinary mice; ordinary mice do not get plaques and tangles. Ordinary mice do not get Alzheimer’s. Instead, these were transgenic mice that had been genetically altered to grow plaques. What Schenk’s experiments showed was that after vaccination, those plaques cleared up. According to David Shenk,
The injected beta-amyloid was prompting the immune systems to produce targeted antibodies, a small portion of which were crossing the blood-brain barrier and binding directly with beta-amyloid in the brain. Then the offending substances were effortlessly being cleared away as cellular trash.
Dale Schenk and others were able to replicate these results with guinea pigs, rabbits, and monkeys. Further confirmation came from researchers at the University of South Florida. Their mice not only got better, they apparently got “smarter.” Rid of plaque, they were able to negotiate mazes that had stumped them before. “They were normal now, apparently,” Shenk writes in The Forgetting. “For these humanized mice, at least, Alzheimer’s disease was now preventable.”
When Elan Pharmaceuticals announced the preliminary success of the Alzheimer’s vaccine, it was, understandably, big news. The wire services picked it up and sent it around the world; CNN, the BBC, and Time, among others, followed suit. Their reports noted not only that Schenk’s experiment had shown success in the animal models, but that in further trials the beta-amyloid vaccine had proved safe for humans. This did not mean it worked, only that the vaccine was safe enough to test it further to determine its efficacy.
It is at this hopeful moment in the Alzheimer’s story that The Forgetting ends, with the race still on but close enough to being over for David Shenk to reflect, somewhat wistfully, on the meaning of the disease, and what he has come to see as its essential capacity to humanize us:
Through the Alzheimer’s prism, we can experience life’s constituent parts and understand better its resonances and quirks. And as the disease relentlessly progresses toward the final dimming of the sufferer, it forces us to experience death in a way it is rarely otherwise experienced. What is usually a quick flicker we see in super slow motion, over years. It is more painful than many people can even imagine, but it is also perhaps the most poignant of all reminders of why and how human life is so extraordinary. It is our best lens on the meaning of loss.
If that was true then, it remains true. This January, two years after the promise of the beta-amyloid vaccine was broadcast worldwide, and less than six months after The Forgetting was published, Elan Pharmaceuticals had another announcement to make. This one was offered quietly, without fanfare, on its Web site: inexplicably, and without warning, four people participating in the Phase II efficacy trials had developed encephalitis. No one could say why. A month later, in February 2002, eleven more participants out of about three hundred were stricken by a similar brain inflammation. “We never saw a hint of this,” Ivan Lieberburg told a reporter from The Washington Post. “It came as a total shock to Elan.” In March the company permanently halted its trials of the beta-amyloid vaccine.1
In the face of drug failures like Elan’s, as well as the dearth of reliable medical interventions, and in the light of life spans that are challenging the accuracy of actuarial charts, and a generation that can expect to see increasing numbers of its fellows fall victim to Alzheimer’s—see them, pay for them, become them—a literature on popular neurology is burgeoning. These are books written for the affected, a readership that includes—because this disease moves so slowly and insidiously—the potentially affected, which is to say, many of us. They are cultural markers, not only of a particular moment in medical history, but of a growing collective dis-ease.
Typically, and perhaps inevitably, an anxious didacticism connects these books to one another; they consciously play to fear by trading on hope. Even Lawrence Whalley’s straightforward and mostly uninflected dissertation, The Aging Brain, is implicated. A readable academic volume that synthesizes current research to map the changing physiology of the human brain as it gets older, The Aging Brain is offered not only on intellectual terms, but as a palliative. “…This book draws on the startling advances in molecular biological research and computer technology to counter the widespread pessimism about what the future holds in store for us,” Whalley writes in the preface. “These new ideas hold out the possibility of transforming life in old age by preventing or even reversing the damage to brain cells implicated in mental decline.”
In reality, the text of The Aging Brain is more guarded than that. Whalley, who was part of the team that, in the 1980s, discovered a connection between chromosome 21 and early-onset Alzheimer’s disease, is more prone to pose questions than to draw conclusions from the research he reviews. And he is unwilling to interpret the research prescriptively. A discussion on the effect on neurodegeneration of free radicals—extremely reactive chemical compounds, which are naturally produced by the body and have been linked to Alzheimer’s as well as cancer and heart disease—does not lead to the suggestion that readers start swallowing high doses of vitamin E and other antioxidants, but rather to a measured consideration of whether oxidation is a cause or an effect of neuronal damage, and to the suggestion that beta-amyloids themselves may be the culprit, causing free radicals to develop in the bloodstream. “Further study of the neurotoxic activity of beta-amyloid may point to therapeutic strategies (such as vitamin E supplementation of the diet) aimed at…reducing the neurotoxic effects” is as far as he’ll take it.
In another section, Whalley’s consideration of the brain’s essential “plasticity”—its ability to make new pathways and redirect itself, which may be crucial to overcoming certain kinds of brain damage—leads him to this restrained reflection:
The company continues to pursue an immunological approach to treating Alzheimer's, and has other Alzheimer's drugs in its pipeline.↩
The company continues to pursue an immunological approach to treating Alzheimer’s, and has other Alzheimer’s drugs in its pipeline.↩