Alzheimer's Unlocking The Mystery

The fog, as Carl Sandburg said, comes on little cat feet. First you notice that you're always misplacing things, or that common nouns are evading you as stubbornly as the names of new acquaintances. Pretty soon you're forgetting appointments and getting flustered when you drive in traffic. On bad days you find you can't hold numbers in your mind long enough to dial the phone. You try valiantly to conceal your lapses, but they become ever more glaring. You crash your car. You spend whole mornings struggling to dress yourself properly. And even as you lose the ability to read or play the piano, you're painfully aware of what's happening to you. Then the fog thickens. Your own children come to look like strangers, and terrifying delusions migrate freely from your dreams into waking consciousness. Eventually your limbs, bowel and bladder escape your control. You drift into a silent stupor, and after a year or two of bedsores and diaper rash, you stop swallowing food. Death, when it comes, is a formality.

When the German psychiatrist Alois Alzheimer first described this awful disease in 1906, it was mercifully rare. Most people died young enough to avoid it. But life expectancy has risen dramatically since then (from 47 years to 77 years in the United States), and the burden of Alzheimer's has grown accordingly. Some 4 million Americans--one in five of those 75 to 84 and nearly half of those 85 and older--are now afflicted. And if that sounds dire, consider what's in store for our increasingly aged society. By one estimate, the number of U.S. Alzheimer's sufferers will approach 6 million by the end of this decade and could hit 14 million by midcentury.

Countless baby boomers are now confronting the needs of stricken parents, and realizing that their best efforts to stay healthy only raise the odds that they'll survive to meet the same fate. Unlike heart disease, which has well-known risk factors, Alzheimer's is still hard to predict. And today's treatments provide only modest symptomatic relief, if that. But the story is rapidly changing. "We've learned more about Alzheimer's in the past 15 years than in the previous 85," says Dr. Bruce Yankner of Harvard Medical School. In the past year alone, scientists have made several critical discoveries about how Alzheimer's destroys the brain, and their findings have raised tantalizing possibilities for treatment. Drugmakers are now pursuing a half-dozen new remedies, and predicting that one or more will reach the market within seven years. "We've never been at a stage like this," says Dr. Marcelle Morrison-Bogorad of the National Institute on Aging, "where we have so many leads to follow."

For all the recent progress, there is still no foolproof way to diagnose Alzheimer's in a living person. With a patient showing signs of dementia, the physician's main task is to rule out other possible causes, such as strokes, tumors or vitamin deficiencies. When 80-year-old retired architect Morley Madden complained several years ago that he could no longer finish the household projects he started, his family doctor doubted anything was seriously wrong. But when Madden scored badly on a simple cognitive test called the Mini Mental State Exam and an MRI scan showed no signs of a stroke, Alzheimer's became the best name for his problem.

What was actually happening to his mind? At least two things. As Alzheimer discovered from autopsy studies, victims' brains are littered with wads of sticky debris, or plaques, and their neurons contain twisted protein filaments known as tangles. Until recently, scientists could only guess about the significance of these lesions. "No one even knew what they were made of," says Paul Greengard, director of Rockefeller University's Fisher Alzheimer Center. "Now we know what they're made of, and we're beginning to understand what causes their formation."

The first real clue to the mystery came in the late 1980s, when scientists identified a molecule called APP, or amyloid precursor protein. APP is a normal protein produced by healthy neurons. It traverses the cell membrane like a needle stuck through a piece of fabric (chart). After identifying APP, researchers determined that our bodies make at least three enzymes--dubbed alpha, beta and gamma secretase--that can cleave APP into shorter forms. (Beta secretase was positively identified last year.) Unlike alpha secretase, which clips an innocuous protein out of APP, the beta and gamma enzymes work together to produce a shorter, stickier protein called beta amyloid (A-beta). We all produce A-beta, but no one knows exactly what purpose it serves. What's clear is that it can build up in the fluid surrounding neurons to form plaques.

How does that happen? Overproduction is not usually the problem. A typical Alzheimer's sufferer makes A-beta at the same rate as a healthy person, says Dr. Dennis Selkoe of Harvard Medical School and Boston's Brigham and Women's Hospital. The problem is one of disposal. A-beta normally dissolves after it drifts away from the cell, but it sometimes folds into insoluble forms called fibrils, which stick together to create plaques. We all generate some plaques as we age. The real trouble seems to begin when they trigger an inflammatory response. The brain generates toxic agents called free radicals when fighting off infections, and fibrils trigger the same reaction. "If fibrils are sustaining the inflammation," says Harvard geneticist Rudy Tanzi, "neurons will die by friendly fire."

As they've learned more about plaque formation, researchers have also gotten a clearer picture of how tangles come about, and how they exterminate brain cells. As the accompanying diagram shows, a healthy neuron looks vaguely like an octopus. Its spherical body is covered with long, slender appendages called neurites, which branch out to form connections with other cells. These appendages are built around internal structures called microtubules, which give the neuron its shape and serve as its circulatory system, transporting nutrients and chemical messengers. The glue that holds this whole system together is a protein called tau. Tau molecules bind tightly to the sides of the microtubules, reinforcing them like the crosspieces on a railroad track. But when Alzheimer's strikes, the tau molecules detach and tie themselves in knots. As that happens, the microtubules disintegrate and neurons die, taking names, dates and faces with them.

What makes tau tangle? Some scientists now suspect that the process begins when amyloid plaques press up against the outer surfaces of neurons, setting off a cascade of chemical changes within. The plaque connection is still in doubt, but the cascade of changes is not. In a study published last month, a team of Harvard researchers showed that tangles are the work of an enzyme called cdk5, which escapes normal restraints and tears tau loose from its bearings. Scientists have yet to handcuff this enzyme, but they now have another perpetrator to chase.

As the pathology of Alzheimer's comes into focus, a broader question arises. Why are some people stricken in their 50s while others stay lucid into their 90s? Heredity is part of the answer. During the past decade, researchers have identified three genes that, when mutated, cause our cells to overproduce A-beta. These mutations run in families, and virtually everyone who inherits one develops Alzheimer's by the age of 60. Familial, early-onset Alzheimer's is rare, accounting for only 3 to 5 percent of all cases. But the common form of the illness also has a large genetic component. Studies suggest that Alzheimer's incidence is three times higher among people with one affected parent than in people whose parents were both spared. And folks with two affected parents experience a fivefold increase in risk. "Most of these people do not have genes that are directly causative," says Tanzi. "Their genetic makeup makes them more susceptible to environmental triggers."

Those environmental triggers are still something of a mystery, but we know they're out there. And as Sally Luxon and Diane Schuller's experience makes clear, they're powerful. As identical twins, Sally and Diane share the same set of genes. Growing up in Ohio, they dressed alike, slept in the same bed and flashed the same crooked teeth whenever they grinned. Diane still looks younger than her 63 years. She enjoys traveling with her husband and keeping up with her kids, her grandchildren and her 86-year-old mother. Sally, who suffers from advanced Alzheimer's, hasn't spoken since 1993 or walked since '94. She shows no sign of recognizing her daughters--or even her twin. "You just hold her hand," Diane says, "and hope that when you give her a hug and kiss, somewhere deep down she knows you're there."

Both sisters are part of a Duke University study of Alzheimer's disease in twins. Their disparate fates are hard to explain, but researchers have identified several nongenetic factors that may affect people's odds. Head injury is probably the best documented. Researchers know from autopsy studies that head trauma can cause an acute buildup of amyloid plaque, and epidemiological surveys suggest those sudden deposits can have long-term con-sequences. In a five-year study involving 2,000 elderly New Yorkers, Dr. Richard Mayeux of Columbia University found that those who'd been knocked unconscious as adults developed Alzheimer's at three times the rate of those who hadn't. But because head trauma is so rare, Mayeux doubts it accounts for more than 1 percent of cases.

Just as trauma can leave the brain vulnerable, so can a lack of stimulation. Whether they track people in Shanghai, Bordeaux or East Boston, researchers find that those with the least education suffer the highest rates of Alzheimer's. In one recent survey, scientists at Indiana University looked at 2,200 African-Americans older than 65. Those with rural backgrounds and less than seven years of schooling suffered 6.5 times more Alzheimer's than educated city dwellers. It's possible that low education is simply a marker for other forms of childhood deprivation. A study appearing in the journal Neurology this week supports that possibility, showing that people who grow up with more than five siblings are at higher risk than people from smaller (and presumably more nurturing) families. In either case, the bottom line is that well-nurtured brains are more resilient. "They have more capacity," says Yankner, the Harvard neurologist, "so they can withstand more damage before showing signs of disease."

Recent studies have identified several substances that may help us minimize that damage as we age. In test-tube experiments, vitamin E helps quell the toxic free radicals associated with A-beta. Epidemiological studies suggest that regular users of ibuprofen and other anti-inflammatory drugs may reduce their Alzheimer's risk by as much as 60 percent. And estrogen, which inhibits the formation of A-beta, offers another possible shield. In a 1996 survey of 1,300 elderly women, Mayeux found that those who'd taken the hormone after menopause reduced their Alzheimer's risk by half--regardless of family history. Researchers are now running clinical trials to test these findings.

Treating Alzheimer's is still a crude art. Cognex and Aricept, the two drugs currently on the market, can ease the symptoms by boosting the action of a brain chemical called acetylcholine. But even when these drugs work--and some patients don't respond at all--they usually work for only six to nine months. William Van Zandt of Middletown, N.J., was two years into Alzheimer's disease when he started taking Aricept in 1997. "Within a week, there was such a noticeable difference," his son Billy recalls. "He went from being completely uncommunicative to forming whole sentences. My brother and sister called up in tears, saying, 'We've got the cure'." But Van Zandt resumed his decline eight weeks later, and after six months the family dropped the drug. Eight weeks' relief is of course better than nothing. But as Dr. Peter Rabins of Johns Hopkins observes, we've made only "a little dent."

We may soon make a bigger one. Armed with a more detailed understanding of the disease, researchers are pursuing treatments that aim not just to ease symptoms but to stop the destruction of neurons. The potential market is enormous, and an array of drug companies--from small biotech firms to giants like Bristol Myers Squibb--are racing to tap it. And because there are so many leads to follow, they're running in several different directions. One approach is simply to stall the production of A-beta, the protein that forms amyloid plaques. Until last year, no one knew exactly how A-beta got clipped out of the longer APP molecule. Now that scientists have identified at least one and possibly both of the responsible enzymes, a half-dozen firms are working on drug molecules to control them. If the effort succeeds, it could open a new era in care.

Another approach is to vaccinate people against the A-beta peptide, and count on their immune systems to gobble up plaque as it forms. Scientists at Elan Pharmaceuticals knew that was a long shot when they started testing the approach three years ago. In a now famous experiment, they mixed A-beta with a substance known to trigger a strong immune response, then injected it into plaque-prone laboratory mice. To their astonishment, it worked. In one seven-month test, untreated animals showed a 17-fold increase in plaque, while those who got the shots showed a substantial decrease. Elan is now launching a small safety study in early-Alzheimer's patients. The risk is that it will simply cause more brain inflammation, but that hasn't happened in animals.

The possibilities don't end there. Other researchers are pursuing treatments that, if successful, would prevent the formation of tangles by keeping the tau protein anchored to microtubules. Still others are hoping to treat patients with protective genes. Unfortunately, none of these treatments will restore life to dead neurons. Success will require that we spot the disease before it causes serious symptoms. Dr. Gary Small of UCLA is now pursuing an imaging technique that would enable doctors to detect plaques and tangles in early-stage patients. And several teams are studying the value of testing people's blood for high levels of A-beta? "The day may come when we test healthy old people for excessive A-beta, then use a drug to control it," says Dr. Steve Younkin of the Mayo Clinic in Jacksonville, Fla. "People may know their readings the way they know their cholesterol levels." That is the dream: to make Alzheimer's as manageable in the future as cardiovascular disease is today. The future is bearing down fast, as 76 million baby boomers speed toward old age. We can only hope that our recent discoveries pay off in time to make a difference.

14 million

Americans will have Alzheimer's by the middle of this century unless we learn to prevent or cure it


of people 75 to 84 have Alzheimer's, and the disease affects nearly half of those 85 or older

People with one afflicted parent are

3 times

more likely to develop Alzheimer's than those with no family history

Estrogen-replacement therapy may reduce a woman's risk of Alzheimer's by


regardless of her family history