Do senior moments scare you? Eight years ago Nancy Levitt had one that would unsettle anyone. She was in her mid-40s at the time, and watching her father drift into the late stages of Alzheimer's disease (several aunts and uncles had suffered similar fates). Levitt's son was about to graduate from high school, so she called a mail-order company to order fluorescent-light sticks for him and his friends to wear around their necks at a party. When her package arrived in the next day's mail, the receipt and postmark knocked her flat. She had ordered the same gift a few days earlier--and lost all recollection of it. "I just freaked," she says. Suddenly, every forgotten name, misplaced pencil and misspelled word became a prophecy of doom. Was she getting Alzheimer's herself?
When Levitt sought testing at UCLA, researchers gave her the usual cognitive tests--name some simple objects, repeat a list of words--and assured her she was fine. But the occasional lapses continued, so she returned to the same clinic several years later and enrolled in a study aimed at distinguishing early Alzheimer's from run-of-the-mill forgetfulness. This time the researchers didn't just talk to her. They placed her under a scanner and recorded detailed images of her brain, both at work and at rest. Alzheimer's disease has traditionally been diagnosed by exclusion. If you lagged significantly on a memory test--and your troubles couldn't be blamed on strokes, tumors or drug toxicity--you were given a tentative diagnosis and sent on your way. To find out for sure, you had to die and have your brain dissected by a pathologist. Levitt didn't have to do any of that. By looking at the images on his video screen, Dr. Gary Small was able to give her some reassuring news. She didn't have Alzheimer's disease--and the odds were less than 5 percent that she would develop it any time soon. Levitt calls the images "the most wonderful thing I've ever seen."
Technology is changing all of medicine, but it is positively transforming our understanding of Alzheimer's. Armed with state-of-the-art PET scanners and MRI machines, specialists are learning to spot and track the disease in people who have yet to suffer symptoms. It's one thing to chronicle the brain's disintegration, quite another to stop it, but many experts are predicting success on both fronts. Drugmakers now have two dozen treatments in development. And unlike today's medications, which offer only a brief respite from symptoms, many of the new ones are intended to stall progression of the disease. As Alzheimer's runs its decades-long course, it replaces the brain's exquisite circuitry with mounds of sticky plaque and expanses of dead, twisted neurons. No drug will repair that kind of damage. But if the new treatments work as anticipated, they'll enable us to stop or slow the destruction while our minds are still intact. A decade from now, says Dr. Dennis Selkoe of Harvard Medical School and Boston's Brigham and Women's Hospital, physicians may monitor our brain health as closely as our cholesterol levels--and stave off Alzheimer's with a wave of the prescription pad.
Until we can control this awful illness, early detection may seem a fool's errand. "With diagnostics ahead of therapeutics, there's a lot of potential for harm," says University of Pennsylvania ethicist Arthur Caplan. He worries that entrepreneurs will peddle testing without counseling, leaving patients devastated by the findings. He wonders, too, whether employers and insurers will abandon people whose scans show signs of trouble. Advocates counter that early detection can help patients make the most of today's treatments while giving them time to adjust their plans and expectations. With so many people at risk, they say, anything is better than nothing. Some 4 million Americans have Alzheimer's today, but the number could hit 14 million by 2050 as the elderly population expands.
The diagnostic revolution began during the 1990s, as researchers learned to monitor neurons with an imaging technique called PET, or positron-emission tomography. Unlike an X-ray or CT imaging, PET records brain activity by homing in on the glucose that fuels it. And as Small's team has discovered, it can spot significant pathology in people who are still functioning normally. Instead of glowing with activity, the middle sections of their brains appear dim and torpid. And because Alzheimer's is progressive, abnormal scans tend to become more so with time. In a study published last fall, UCLA researchers scanned 284 people who had suffered only minor memory problems. The images predicted, with 95 percent accuracy, which people would experience dementia within three and a half years.
PET scanning has yet to transform patient care; few clinics have the machines, and Medicare doesn't cover their use. But scientists are now using the technique to see whether drugs already on the market (such as the anti-inflammatory ibuprofen) can slow the brain's decline. And PET is just one of several potential strategies for tracking preclinical Alzheimer's. San Die-go researchers have found that seniors who score inconsistently on different mental tests are at increased risk of dementia--even if their scores are generally high. And in a study published this spring, researchers at the Oregon Health Sciences University hit upon three signs of imminent decline in octogenarians. The 108 participants were all healthy at the start of the study, but nearly half were demented six years later. As it turned out, they had entered the study with certain traits in common. They walked more slowly than their peers, requiring nearly two extra seconds for a 30-foot stroll. They lagged slightly on memory tests. And their MRI scans revealed a slight shrinkage of the hippocampus, a small, seahorse-shaped brain structure that is critical to memory processing. The changes were subtle, says Dr. Jeffrey Kaye, the neurologist who directed the study, but they presaged changes that were catastrophic.
Powerful as they are, today's tests show only that the brain is losing steam. The ideal test would reveal the underlying pathology, letting a specialist determine how much healthy tissue has been replaced by the plaques and tangles of Alzheimer's. It's not hard to fashion a molecule that will highlight the wreckage. Unfortunately, it's almost impossible to get such a probe through the ultrafine screen that separates the brain from the bloodstream. If a probe is complex enough to pick out plaques and tangles, chances are it's too large to pass from the bloodstream into the brain. At UCLA and the University of Pittsburgh, researchers have developed probes that are small enough to get through, yet selective enough to provide at least a rough measure of a person's plaque burden. At Brigham and Women's Hospital, meanwhile, radiologist Ferenc Jolesz is trying to open the barrier to bigger, better probes. His technique employs tiny lipid bubbles that gather at the gateway to the brain when injected into the bloodstream. The bubbles burst when zapped with ultrasound, loosening the mesh of that ultrafine screen and allowing the amyloid probe to enter. Lab tests suggest the screen will repair itself within a day, but no one yet knows whether it's safe to leave it open that long.
One way or another, many of us now seem destined to learn we have Alzheimer's disease while we're still of sound mind. The question is whether we'll be able to do anything more constructive than setting our affairs in order and taking a drug like Aricept to ease the early symptoms. Fortunately the possibilities for therapy are changing almost as fast as the diagnostic arts. Experts now think of Alzheimer's not as a sudden calamity but as a decades-long process involving at least a half-dozen steps--each of which provides a target for intervention. Slowing the disease may require four or five drugs rather than one. But as AIDS specialists have shown, the right combination can sometimes turn a killer into a mere menace.
Though experts still quarrel about the ultimate cause of Alzheimer's, many agree that the trouble starts with a scrap of junk protein called amyloid beta (A-beta for short). Each of us produces the stuff, and small amounts are harmless. But as A-beta builds up in the brain, it sets off a destructive cascade, replacing healthy tissue with the plaques seen in Alzheimer's sufferers. No one knew where this pesky filament came from until 1987, when researchers discovered it was part of a larger molecule they dubbed the amyloid-precursor protein (APP). Thanks to more recent discoveries, they now know exactly how the parent molecule spawns its malevolent offspring.
APP is a normal protein that hangs from a neuron's outer membrane like a worm with its head in an apple. While performing its duties in and around the cell, it gets chopped up by enzymes called secretases, leaving residues that dissolve in the brain's watery recesses. Occasionally, however, a pair of enzymes called beta and gamma secretase cleave APP in just the wrong places, leaving behind an insoluble A-beta fragment. Some people produce these junk proteins faster than others, but after seven or eight decades of service, even the healthiest brain carries an amyloid burden. When it reaches a certain threshold, the brain can no longer function. That's why Alzheimer's dementia is so rampant among the elderly. Given enough time, anyone would develop it.
The ideal Alzheimer's remedy would simply slow the production of A-beta--by disabling the enzymes that fabricate it. Elan Corp. was the first drugmaker to try this tack. During the mid-'90s its scientists developed several gamma-secretase blockers and tested them in animals--only to find that they sometimes derailed normal cell development, damaging bone marrow and digestive tissues. A few companies are still pursuing gamma blockers, but beta secretase now looks like a safer target for therapy. More than a half-dozen drugmakers are now working on beta inhibitors. "In the industry," says Dr. Ivan Lieberburg of Elan, "we're hoping that the beta-secretase inhibitors will have as much therapeutic potential as the statins." Those, of course, are the cholesterol-lowering medicines for which 35 million Americans are now candidates.
Secretase inhibitors may be our best hope of warding off Alzheimer's, but they're not the only hope. As scientists learn more about the behavior of A-beta, they're seeing opportunities to disarm it before it causes harm. One thing that makes A-beta fragments dangerous is their tendency to bind with one another to form tough, stringy fibrils, which then stick together to create still larger masses. Three companies are now testing compounds designed to keep A-beta from forming fibrils--and at least two other firms are working to keep fibrils from aggregating to create plaque. All of their experimental drugs have helped reduce amyloid buildup in plaque-prone mice, suggesting they might help people as well. But human studies are just now getting underway.
Suppose for a moment that all these strategies fail, and that amyloid buildup is simply part of the human condition. As Selkoe likes to say, there's more than one way to keep a bathtub from overflowing. If you can't turn down the faucet, you can always try opening the drain. Recognizing that most of the people now threatened by Alzheimer's have already spent their lives under open amyloid faucets, researchers are pursuing several strategies for clearing deposits from the brain. One elegant idea is to mobilize the immune system. Three years ago Elan wowed the world by showing that animals given an anti-amyloid vaccine mounted fierce attacks on their plaques. Vaccinated mice reduced their amyloid burdens by an astounding 96 percent in just three months. The vaccine proved toxic in people, triggering attacks on normal tissue as well as plaque, but the dream isn't dead. Both Elan and Eli Lilly are now developing ready-made antibodies that, if successful, will target amyloid for removal from the brain without triggering broader attacks by the immune system.
Even later interventions may be possible. As a person's amyloid burden rises, so does the concentration of glutamate in the brain. This neurotransmitter helps lock in memories when it's released in short bursts, but it kills neurons when chronically elevated. At least two teams are now betting they can rescue cells surrounded by amyloid, simply by shielding them from glutamate. One possible life jacket is a drug called Memantine, which is already approved in Europe. It covers a receptor that lets glutamate flow freely into neurons, but without blocking the glutamate bursts needed for learning and memory. New York's Forest Laboratories is now launching an American trial of the drug, and hoping for approval by next year.
If even half these treatments fulfill their promise, old age may prove more pleasant than today's projections suggest. For now, the best we can expect is an early warning and perhaps a year or two of symptomatic relief. That may seem a paltry offering, but it's a far cry from nothing. As Small argues in a forthcoming book called "The Memory Bible," people at early stages of Alzheimer's can do a lot to improve their lives, but few of them get the chance. Three out of four are already past the "moderate" stage by the time their conditions are recognized. Some may find solace in ignorance. But the case for vigilance is getting stronger every day.