•  Audio: Geoffrey Cowley and Dr. Ali Rezai on Next Frontiers I: Hi-Tech Rx •  Audio: Listen to the complete weekly On Air show

       
DEAD, TWISTED NEURONS
       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.

Video Gallery •  View video clips from "Next Frontiers: Health and Technology," presented by Discovery Health Channel and Newsweek

       
DETECTING DAMAGE
       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 The ideal test would reveal the underlying pathology, letting a specialist determine how much healthy tissue has been replaced by the plaques and tangles of Alzheimer’s. It’s not hard to fashion a molecule that will highlight the wreckage.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.
       

---

 

Alzheimer’s patients go back in time May 3, 2002 — One new approach has made a very big difference for patients and their families. NBC’s Jim Cummins reports.

---

        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.

What is Alzheimer's disease? How common is it? What causes it? How is it diagnosed? Can it be treated? What are the warning signs?

Alzheimer's is a degenerative brain disease that usually begins gradually, causing a person to forget recent events or familiar tasks. How rapidly it advances varies from person to person, but the disease eventually leads to confusion, personality and behavior changes and impaired judgment. Communication becomes more difficult as the disease progresses, leaving those affected struggling to find words, finish thoughts or follow directions. Eventually, most people with Alzheimer’s disease become unable to care for themselves. One in 10 people over 65 and nearly half of those over 85 suffer from Alzheimer’s disease. Today, 4 million Americans have the condition. That number could jump to 14 million by the year 2050 unless prevention methods are developed. Scientists still are not certain of the disease's cause. Advancing age and family history are risk factors. Researchers are exploring the role of genetics in the disease, but most agree it's caused by a variety of factors. There is no single, comprehensive diagnostic test for Alzheimer’s disease. Instead, doctors rule out other conditions through a process of elimination. They usually conduct physical, psychological and neurological exams and take a thorough medical history. Diagnosis is about 90 percent accurate, but the only way to confirm it is through autopsy. There is no medical treatment currently available to cure or stop the progression of Alzheimer's disease. There are currently four FDA-approved Alzheimer's drugs -- Cognex, Aricept, Exelon and Reminyl -- that may temporarily relieve some symptoms of the disease. Several other drugs are in development. Common symptoms of Alzheimer's disease include: Memory loss that affects job skills Difficulty performing familiar tasks Problems with language Disorientation to time and place Poor or decreased judgment Problems with abstract thinking Placing items in inappropriate places Rapid changes in mood or behavior Dramatic changes in personality Loss of initiative

Source: Alzheimer's Association

Printable version

       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.

Next Frontiers: Health and Medicine NEWSWEEK explores new science that lets doctors detect Alzheimer's and improve eyesight, hearing and speech. •  Fixing Your Brain •  The Disappearing Mind •  Was Blind But Now I See •  How to Recharge The Second Sense •  Healthy Shocks to the Head •  The Mind: Magnets That Move Moods •  Wiring the New Docs •  Is the Cadaver Dead? •  Your Next... •  The Quest for Artificial Blood •  Tiny Weapons With Giant Potential •  Unraveling the Genome •  A Year Later, The Beat Goes On

        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.
       
 

---

With Anne Underwood and Andrew Murr
       
       © 2002 Newsweek, Inc.