Do current claims for an Alzheimer's vaccine properly take into account the many defects that the disease causes in the brain

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Do current claims for an Alzheimer's vaccine properly take into account the many defects that the disease causes in the brain?

Viewpoint: Yes, current claims for an Alzheimer's vaccine properly take into account the many defects that the disease causes in the brain—the claims are based on sound experimental results regarding beta-amyloid plaques.

Viewpoint: No, a vaccine based on preventing the formation of beta-amyloid plaques is premature and could well prove ineffective—and possibly even harmful to humans.

By the end of the twentieth century, Alzheimer's disease, a condition once considered very rare, had emerged as the most common cause of dementia. Alzheimer's disease affects approximately four million people in the United States alone. Although almost half of all patients with dementia appear to suffer from Alzheimer's, the disease primarily attacks those over the age of 65. About 4% of the population over age 65 is affected; by age 80 the prevalence is about 20%. Researchers predict that, unless methods of cure or prevention are discovered very soon, the disease will afflict about 14 million Americans by 2050. Although patients in the later stages of Alzheimer's often succumb to infection, the disease itself is probably the fourth leading cause of death in the United States. Unfortunately, despite advances in diagnostic testing, a definitive diagnosis of Alzheimer's disease can only be made at autopsy.

The National Institute of Neurological Disorders and Stroke defines Alzheimer's disease as a "progressive, neurodegenerative disease characterized by memory loss, language deterioration, impaired visuospatial skills, poor judgment, indifferent attitude, but preserved motor function." The early symptoms of the disease, such as forgetfulness and loss of concentration, are often ignored because they appear to be natural signs of aging. A clinical diagnosis of Alzheimer's disease is generally made by excluding other possible factors, such as fatigue, depression, hearing loss, or reactions to various drugs, and applying internationally recognized criteria for Alzheimer's. The disease is characterized by a gradual onset of subtle intellectual and memory problems, which become progressively severe over a period of about 5 to 15 years. As symptoms progress, the patient may display increasing loss of memory, diminished attention span, confusion, inability to recognize friends and family, restlessness, problems with perception and coordination, inability to think logically, irritability, and the inability to read, write, or calculate. Eventually, the patient will need full-time supervision. During the late stage of the disease the patient may be unable to recognize family members, communicate, or swallow. On average, patients die seven to eight years after diagnosis.

Descriptions of senility and dementia are ancient, but the first modern description has been attributed to the French psychiatrist Jean Etienne Esquirol, who wrote of a progressive "senile dementia" in 1838. Alzheimer's disease is named after the German psychiatrist Alois Alzheimer, who described a neurological disorder of the brain associated with progressive cognitive impairment in 1906. Alzheimer's mentor Emil Kraepelin, one of the founders of modern psychiatry, had previously identified the clinical symptoms of the condition. After the death of a 55-year-old patient, Alzheimer studied the patient's brain under the microscope and described the abnormal structures now called senile plaques. According to Alzheimer, these abnormal structures led to a shrinking of the brain.

Theories about the cause of the disease are still a matter of dispute, but since the 1980s researchers have focused their attention on deposits known as senile plaques, composed of a protein called beta-amyloid, found in the brains of Alzheimer's patients. Many researchers believe that the formation of beta-amyloid protein plaques sets off a series of pathological reactions in the brain that ultimately lead to the death of brain cells and the development of the disease. This is known as the amyloid cascade hypothesis. The disease process also involves the formation of neurofibrillary tangles, caused by abnormal tau protein. Scientists are still uncertain as to whether the deposition of plaques leads to the formation of tangles or vice versa. Researchers believe that discovering ways to control the formation of beta-amyloid deposits should lead to effective therapies for curing or preventing the disease.

Other theories about the cause of Alzheimer's disease suggest quite different strategies for cure or prevention. Some scientists believe that Alzheimer's disease is caused by inflammatory processes associated with aging rather than by the formation of beta-amyloid plaques in the brain. Another theory ascribes the development of Alzheimer's disease to the formation of toxic proteins in the brain, possibly derived from beta-amyloid, rather than the buildup of plaques and tangles. The amyloid cascade hypothesis remains controversial, primarily because of the weak correlation between the severity of neurological impairment in the patient and the extent of the deposition of amyloid plaque found at autopsy. Critics of the amyloid cascade hypothesis also point out that amyloid plaque can be found in the brains of people with normal intellectual function. Moreover, it is often found at sites far from the areas with the characteristic nerve loss found in patients with Alzheimer's. Some researchers argue that the action of soluble toxins could explain the lack of correlation between the deposition of amyloid plaque and the progress of the disease. Other scientists suggest that Alzheimer's is caused by the gradual deterioration of the blood vessels that normally maintain the blood-brain barrier, thus allowing toxic substances to enter and accumulate in the brain. The situation might be further complicated by the possibility that Alzheimer's disease is not really a single disease, but a diagnostic term that has been applied to many different diseases with different causes.

One of the most promising but controversial avenues of research is a vaccine (AN-1792) that appears to prevent or reverse the formation of the amyloid plaques associated with Alzheimer's disease. In testing this strategy in genetically altered mice that developed the amyloid plaques associated with Alzheimer's disease, researchers found evidence that the vaccine appeared to retard or even reverse the development of the amyloid plaques. When immature mice were inoculated with a peptide that caused the formation of antibodies that attacked the precursor of brain plaques, little or no plaque was later found in the brains of the treated mice. Significant amounts of plaque developed in the control group. Further experiments suggested that the vaccine could reduce the amount of plaque in older mice. However, researchers acknowledged that the results in mice might not be directly applicable to the situation in human patients. Although the transgenic mice used in these experiments produce amyloid plaque, they do not exhibit the extensive neuronal loss and other signs found in Alzheimer's disease patients. Some scientists, therefore, believe that vaccines may ultimately cause extensive damage in human patients. That is, if the vaccines cause the production of antibodies that penetrate the blood-brain barrier, the antibodies may trigger a massive and dangerous immune response.

Despite the uncertainly about the safety and efficacy of the experimental vaccine, human clinical trials for AN-1792 were initiated in December 1999. Early trials indicated that the vaccine appeared to be safe and that further tests to determine efficacy could be conducted. Evaluating the efficacy of the vaccine in humans, especially the impact of treatment on the subtle defects in memory, mood, and logical thinking, will be a time-consuming and difficult enterprise.

Although, as yet, no drugs can cure or prevent Alzheimer's disease, physicians believe that early diagnosis and treatment are important in delaying the onset of severe symptoms. Patients with mild to moderate symptoms may benefit from medications such as tacrine (Cognex), donepezil (Aricept), and rivastigmine (Exelon). According to a survey released by the Pharmaceutical Research and Manufacturers of America in 2001, 21 new drugs for Alzheimer's disease were either in clinical trials or awaiting final approval by the Food and Drug Administration. Those who question the safety and efficacy of experimental vaccines believe that more resources should be devoted to the search for more conventional therapeutic drugs.

Despite continuing debates about the cause of Alzheimer's and the most appropriate strategy for treating and preventing the disease, all researchers, physicians, and concerned citizens agree that finding ways to prevent or cure Alzheimer's disease must be a key health-planning priority.

— LOIS N. MAGNER

Viewpoint: Yes, current claims for an Alzheimer's vaccine properly take into account the many defects that the disease causes in the brain—the claims are based on sound experimental results regarding beta-amyloid plaques.

Scientists from Elan Pharmaceuticals in South San Francisco, California, stunned the world in July 1999 with their announcement: A new vaccine tested in mice seemed to prevent the buildup of beta-amyloid deposits in the brain, one of the hallmarks of Alzheimer's disease. Suddenly, there was a glimmer of hope where before there had been nothing but dread. Alzheimer's is an incurable brain disorder that usually occurs in people over age 60. The effect on the brain has been likened to gradually turning off all the lights in a house, room by room.

Living with Alzheimer's disease is a very difficult experience, not only for people with the disease, but also for their family members and friends. At present, there is nothing that can be done to stop it. Not surprisingly, then, word that there might be a vaccine on the horizon was greeted with great excitement. The news was especially welcome at a time when the number of older adults in the United States is growing rapidly. It is estimated that about 4 million Americans already have the disease, and that number is expected to rise to 14 million by mid-century unless a means of curing or preventing the disease is found. But is an Alzheimer's vaccine a realistic hope or just hype? Today, many scientists say the promise is quite real.

Beta-Amyloid Plaques

To understand how a vaccine might work, it helps to know a bit about how Alzheimer's affects the brain. Our knowledge of this comes largely from scientists who have looked through microscopes at slices taken from the brains of people who died from one cause or another while having the disease. Scientists have noted two main hallmarks of Alzheimer's: dense clumps, called plaques, found in the empty spaces between nerve cells and stringy tangles found within the cells themselves. For decades, a debate has raged about which of these features is more important in causing the disease. The Alzheimer's vaccine targets the plaques, which consist of a protein fragment called beta-amyloid. Research on the vaccine may go a long way toward settling the dispute.

Plaques show up early in Alzheimer's disease, forming first in parts of the brain used for memory and learning. Eventually, the spaces between nerve cells can become cluttered with them. There is only a weak relationship between the density of the clumps and the severity of a person's symptoms, however. Also, plaques are found even in the brains of healthy older people, although in smaller quantities. Still, the plaques seem to play a crucial role in the disease process. Perhaps the most telling evidence comes from genetics. Beta-amyloid is a short fragment of a larger protein called beta-amyloid precursor protein (bAPP). One rare, inherited form of Alzheimer's is caused by mutations in the gene that carries the instructions for making bAPP. Others are caused by defects in genes that carry the instructions for an enzyme that snips apart bAPP to make beta-amyloid.

How does beta-amyloid do its damage? One theory is that the brain sees tiny bits of beta-amyloid as foreign invaders, so it mounts an immune system attack against them. Immune cells called microglia are called out to clear away the beta-amyloid. As the microglia continuously go about their mission, the result is a state of chronic inflammation—the same immune response that causes a cut to become red, swollen, and tender when it is infected. Over time, the constant inflammation is thought to lead to the death of nearby nerve cells. Among the strongest pieces of evidence to support this view are studies suggesting that the long-term use of anti-inflammatory drugs such as ibuprofen reduces the risk of getting Alzheimer's.

Of course, the formation of beta-amyloid plaques is not the only change seen in the brains of people with Alzheimer's. Scientists have not forgotten about the twisted threads, called neurofibrillary tangles, that form inside the nerve cells. The chief component of these tangles is a protein called tau. In the central nervous system, tau is best known for its ability to bind and help stabilize microtubules, which are part of a cell's internal support structure. Think of the transport system within a nerve cell as a railroad. The microtubules are the tracks, while tau makes up the ties that hold them together. When the tau gets tangled up, it no longer can hold the tracks together, and communication between the cells is derailed.

The Story of AN-1792

Given the presence of tangles, can a vaccine that targets just the plaques really work? Many scientists now believe it can. Perhaps the most vocal advocate is Dr. Dale Schenk, a neurobiologist at Elan Pharmaceuticals, who with his colleagues developed the groundbreaking vaccine called AN-1792. Schenk's inspired idea was deceptively simple: If vaccines could prevent everything from measles to polio, could one help stop Alzheimer's disease as well?

Schenk's team first genetically altered mice so that they developed the same kinds of plaques in their brains as people with Alzheimer's. The scientists then injected some of the mice with a synthetic form of beta-amyloid, in hopes that their immune systems would mount an attack against it. When the immune system detects foreign invaders in the body, it produces tailor-made molecules called antibodies to counteract them. Most vaccines are made of weakened or killed bacteria or viruses, which cause the body to make antibodies against a particular disease. Schenk thought the body might view the injected beta-amyloid as foreign and make antibodies against it, just as if it were a disease-causing germ.

The gamble paid off. The results, published in July 1999 in the scientific journal Nature, were astounding. In one experiment, the researchers gave monthly injections of the vaccine to a group of mice starting at six weeks old, when they had yet to form plaques in their brains. Other groups of young mice did not get the vaccine. By the time all of the mice were 13 months old, those who had received the vaccine still had virtually no plaques, while those in the other groups had plaques covering 2% to 6% of their brains. In another experiment, the researchers gave injections of the vaccine to mice starting at 11 months old, when plaque formation already had begun. Once again, other groups of same-age mice did not get the vaccine. After seven months, plaque development was greatly slowed in the treated mice compared to the untreated ones. Some even seemed to have a decrease in the plaques that had existed before the treatment had started.

Schenk and his colleagues still were missing some key pieces of the puzzle, however. For one thing, the mice in the studies did not develop the neurofibrillary tangles seen in the brains of people with Alzheimer's. The only way to know for sure if AN-1792 would be safe and effective for humans was to try it. The first step in human testing for a new drug in the United States is phase-one clinical trials. These small, early studies are designed to find out how a drug acts in the human body and whether it is safe. The phase-one trials for AN-1792 involved 100 people with mild to moderate Alzheimer's disease. No obvious safety problems were found, and some people did make antibodies in response to the vaccine. Testing then moved ahead to the next step, phase-two trials. These are larger studies designed to test a drug's effectiveness as well as its safety. A two-year phase-two trial for AN-1792, launched in 2001, is expected to include 375 people with mild to moderate Alzheimer's disease in the United States and Europe. Even if the results are positive, the drug still must go through lengthy, larger phase-three trials before it can be approved for sale.

More Vaccine Research

Meanwhile, other research teams had begun testing the vaccine in mice with similarly encouraging results. First and foremost, there was the chicken-or-egg question to answer: Since it had never been proved for certain which came first, plaques or Alzheimer's, just showing that a vaccine could reduce the plaques was not enough; scientists also needed to show that it could decrease Alzheimer's-like changes in thinking and behavior.

Two studies published in Nature in December 2000 showed just that. One study was led by Dr. Dave Morgan at the University of South Florida at Tampa; the other was led by Dr. Christopher Janus at the University of Toronto in Canada. In both cases, the researchers gave genetically altered mice repeated injections of the beta-amyloid vaccine, much as Schenk had done. They then gave the mice different versions of learning and memory tests in which the animals had to swim through a water maze until they learned the location of an underwater platform. Later, the mice were tested to see how well they remembered where the platform was. Both studies found that mice who received the vaccine did much better than those who did not. Yet a mystery remained: although the improvement in memory was large, the reduction in plaques was not. One possible explanation is that there is a critical threshold of plaques needed to cause learning and memory problems, and even a relatively small decrease in plaques can push the number below that level. Another possibility is that there is a toxic subset of beta-amyloid that is not being teased out by current methods.

These studies were a vital link in the chain, since they showed that a beta-amyloid vaccine alone could lead to behavioral improvements, at least in mice. The case for the vaccine also was strengthened by a third study that appeared in the same issue of Nature. This study, headed by Dr. Guiquan Chen at the University of Edinburgh in Scotland, focused on the genetically altered mice that have played such a crucial role in other research. The scientists found that the mice, who develop plaques but not tangles in their brains, do indeed show more Alzheimer's-like changes in behavior as they age than normal mice. This finding backed up the belief that beta-amyloid may be at the root of the disease.

Granted that the vaccine seems to work in mice, how exactly does it do so? That remains an open question. One possible explanation: When the vaccine is injected into the body, the immune system makes antibodies to it. These antibodies start circulating throughout the body in the blood. A few of them leak into the brain, where they may bind to plaques and act as flags for microglia to come to the area and clean it up. At first, some scientists feared that this process might actually make symptoms worse, by leading to the kind of inflammation that is thought to cause the death of nearby neurons. Fortunately, that did not prove to be the case. According to Morgan, "We started out expecting that the vaccine would overactivate the microglia, causing inflammation and perhaps neuron death, and certainly not helping the mice. It did just the opposite. While the microglia were activated, it didn't seem to be at a high enough level to cause neuron loss." Another possibility is that the 99.9% of antibodies that stay in the blood are the critical ones, rather than the 0.1% that leak into the brain. Antibodies bind to beta-amyloid in the bloodstream. In an effort to restore levels of the substance in the blood, the body may withdraw some beta-amyloid from the brain.

Problems and Solutions

In all of the animal studies described so far, mice were given the vaccine in multiple injections. Similarly, in the phase-one human trials of AN-1792, people were given shots in the arm. However, a study led by Dr. Howard Weiner of Harvard Medical School holds out the hope that the vaccine might one day be given by a less painful means. In Weiner's study, published in the October 2000 issue of Annals of Neurology, scientists used the same type of beta-amyloid vaccine as previous researchers, but gave it to the genetically altered mice in a nasal spray. They found that treated mice had 60% fewer plaques than untreated ones—not as dramatic a decrease as that seen with injections, but still impressive.

One concern about the beta-amyloid vaccine is that the vaccine itself may prove toxic. When the whole beta-amyloid molecule is used, it can form tiny fibers called fibrils. These fibrils can attract other molecules and cause them to clump together. If some of the beta-amyloid in a vaccine were to cross from the blood into the brain, as it is capable of doing, it might even contribute to plaque formation there. Dr. Einar Sigurdsson and his colleagues at the New York University School of Medicine think they may have found a novel solution to this problem. Their new vaccine is a modified form of beta-amyloid. Because the vaccine does not have fibrils or create clumps, it may be a safer alternative. A study published in the August 2001 issue of the American Journal of Pathology found that the new vaccine was very effective, reducing plaques in genetically altered mice by 89%.

What works in mice does not always work in humans, of course. There still is much research to be done on the Alzheimer's vaccine. Even if all goes well in human trials, the vaccine will have its limits. For some older people, it may not be effective, since the immune system's ability to mount an antibody response tends to decline with age. For those who already have advanced Alzheimer's disease, it simply may be too late. Although the vaccine may halt or slow the disease, it will not bring dead nerve cells back to life.

Yet the potential value of such a vaccine is enormous. In people with early stages of the disease, it may keep the symptoms from getting worse or at least slow them down. In people with rare genetic defects that cause inherited Alzheimer's, it may keep the disease from ever starting. For the rest of us who could one day develop garden-variety, noninherited Alzheimer's, the prospects are bright as well. According to Sigurdsson, "Right now, scientists are trying to find ways to diagnose Alzheimer's disease before any symptoms appear. If you could detect plaques with a brain scan, for instance, before a person's memory and thinking become impaired, you could start the vaccine then and perhaps prevent the disease from occurring."

—LINDA WASMER ANDREWS

Viewpoint: No, a vaccine based on preventing the formation of beta-amyloid plaques is premature and could well prove ineffective—and possibly even harmful to humans.

Alzheimer's Disease and Its Manifestations

Alzheimer's disease (AD) is the most common cause of dementia—the general loss of cognitive, or intellectual, ability. As of 2001, AD is irreversible and incurable. This degenerative neurological disease primarily affects individuals in the over-65 age group, causing progressive loss of cognitive, functional, language, and movement ability, and ultimately death. According to the Alzheimer's Association, in the late 1900s and early 2000s, 1 in every 10 people over the age of 65 years and half of those over the age of 85 years suffered from the disorder. While its exact cause remains unknown, researchers know that the disease is manifest by the degeneration and death of cells in several areas of the brain. The only way to diagnose AD positively is to perform an autopsy on the brain to identify telltale protein deposits called amyloid plaques and neurofibrillary tangles consisting of a protein called tau. Researchers believe these plaques and tangles cause the degeneration and death of brain cells that result in AD.

Cognitive, behavioral, and functional deficits are universal in patients with AD and progress as the disease advances. Early signs include forgetfulness, lack of concentration, and loss of the sense of smell. Deficits increase gradually over time, at a rate that varies from patient to patient, but the disease eventually causes severe memory loss, confusion, personality changes, impaired judgment, language defects, and behavioral disorders, among many other deficits. Sufferers lose the ability to pay attention, respond to visual cues, recognize faces (even of closest relatives), express thoughts, and act appropriately. Behavioral deficits include restlessness and extensive wandering, physical and verbal aggression, inappropriate social behaviors, and disruptive vocalizations. Functionally, tasks that usually require little thought are often performed backward, such as sitting down before getting to the chair or, when dressing, putting on outerwear before underwear. In advanced stages, the verbal repetition of over-learned or ritual material, such as prayers, songs, or social responses, occurs. The wide range of functional and behavioral deficits seen in AD may be, at least in part, caused by changes in thought processes that result in the inability to monitor and control behavior.

Searching for Causes and Cures

While there are many theories about what causes AD, no specific cause has yet been identified. Similarly, while there are several treatments in the clinical trial stage, none has yet been proven to arrest, reverse, or cure the disease in humans. There is considerable optimism about a vaccine called AN-1792, an experimental immunotherapeutic agent being developed by the Elan Corporation of Ireland in collaboration with the Wyeth-Ayerst Laboratories in the United States. The development of this drug is based on the hypothesis that beta-amyloid (A [.integral] 42), a prominent protein fragment in amyloid plaques seen in AD, is not just a marker (identifier) of AD, but basically is the cause of the disease; this hypothesis has not yet been proven.

The purpose of AN-1792, a form of A [.integral] 42, is to stimulate an individual's immune system to prevent the development, and possibly to reverse the buildup, of the beta-amyloid plaques associated with AD. According to a fact sheet published by the Alzheimer's Association, researchers hope that treatment with AN-1792 will "produce antibodies that would 'recognize' and attack plaques." Promising results of animal studies using the drug were published in Nature in July 1999. In this study, Dr. Dale Schenk, the vice president of discovery research at Elan Pharmaceuticals, and his team tested AN-1792 on transgenic (TG) mice—animals especially bred and genetically engineered to overproduce beta-amyloid plaques that are structurally and chemically similar to those found in the brains of humans with AD. According to Kenneth J. Bender, writing for the Psychiatric Times in September 2000, vaccinating these mice with AN-1792 "appeared to prevent plaque deposition in the brains of the youngest animals. The vaccine also appeared to markedly reduce the extent and progression of the plaques and associated neuropathology in older specimens."

In two subsequent studies, one at the University of Toronto and another at the University of South Florida at Tampa, behavioral tests using TG mice immunized with AN-1792 showed their improved short-term memory performance over mice treated with a "similar but nonactive vaccine." In an elaborate water maze test, the location of an exit ramp was frequently changed. Relying on their short-term memory was the only way the mice could determine the current exit location. Changing the exit location caused mice with elevated beta-amyloid levels to become confused.

However, David Westaway of the University of Toronto research team urged caution, stating that the relationship between the accumulation of plaque and memory and learning may not be straightforward. Bender, in his Psychiatric Times article, wrote, "While such evidence of beneficial effect on function as well as pathology is encouraging, Schenk cautioned against yet assuming that it is a harbinger of clinical improvement in patients with AD. 'Of course, mice aren't humans,' he [Schenk] remarked to an Associated Press reporter." Again, other experts warned that the mouse maze test did not address other key mental abilities destroyed by AD, including language and judgment.

From Animals to Humans

The first clinical trial of the vaccine in humans, a phase-one study aimed at assessing the safety of the drug, was completed in July 2001. Approximately 100 patients with mild to moderate AD participated in the trial in both the United States and the United Kingdom. Dr. Ivan Lieberburg, the executive vice president and chief scientific and medical officer of the Elan Corporation, announced the trial results with enthusiasm. "The product showed that it was safe for patients and we didn't see any significant problems with it other than sore arms at the injection site…. More importantly, as well we saw that in a significant proportion of the patients they were able to demonstrate an immune response. Their antibody levels went up and that indicates that this was having an effect in these patients." However, the scientists noted that no cognitive or memory improvements were seen in those patients. According to an Alzheimer's Association fact sheet, much research is yet required to determine the drug's efficacy in AD patients. "One key question about AN-1792," reads the fact sheet, "is whether it will actually improve mental function in humans."

Also, the role beta-amyloid plaques play in AD remains to be determined. While evidence suggests that the abnormal deposits contribute to brain cell damage, neurofibrillary tangles also appear to contribute, and may even be the culprit. Again, according to the Alzheimer's Association fact sheet, even if AN-1792 does prevent accumulation of—or even clears—plaque from the human brain and therefore arrests brain cell damage, "we cannot predict the degree of the drug's effectiveness, and it will not target other disease mechanisms that may be at work in Alzheimer's disease."

A further concern regarding the vaccine's use in humans "is the possibility that by provoking an immune reaction to one of the body's own proteins, AN-1792 could stimulate an autoimmune reaction in which the body mobilizes a wholesale assault on its own tissues." Yet another question remaining is how effectively the drug will stimulate antibodies in humans, as antibody production was detected only in a portion of phase-one trial participants. "AN-1792 may create a stronger immune response in mice, for whom the substance is a foreign protein, than it produces in humans," reads the Alzheimer's Association fact sheet. Also, while AN-1792 generates antibodies against A [.integral] 42 in some individuals and is an important element in breaking down or slowing down the disease process, "A [.integral] 42 is only one element in complex molecular disruptions that occur in Alzheimer's."

In a report on the Web site ABCNews.com entitled "Memory in Mice Improved," the authors quote Dr. Karl Herrup, the director of the Alzheimer's Center at Case Western Reserve School of Medicine in Cleveland, Ohio: "The Alzheimer's model was engineered in mice, and while it bears many similarities to the human disease, there are differences as well. The biology of the human disease may or may not be blocked by plaque removal…. The human animal may respond differently in some if not all cases." The report also quotes Dr. Zaven Khachaturian, a senior science adviser to the Alzheimer's Association in Chicago, who said, "Although the findings that vaccination as a treatment strategy eliminated or reduces the amyloid in the brain has great scientific significance, its ultimate clinical value remains to be determined. No patient goes to the doctor for the 'amyloid in their brain,' they go to get help for memory loss or behavioral problems."

Mixed Feelings about Possible Outcomes

The next step, a phase-two clinical trial, will assess AN-1792's effectiveness and identify the optimal dosage in an attempt to determine whether it will improve mental function in humans. This trial is expected to begin sometime near the end of 2002 and will last approximately two years. "We're hoping that if we see anything like what we saw in our mice experiments in people in phase two clinical study, that this would be a truly remarkable result," said Lieberburg. However, until the human trial is completed, the only thing yet understood about the vaccine as it relates to humans is that it is "safe and well tolerated." The question of its effect on cognitive ability, let alone on behavioral and functional ability, remains unanswered.

In a July 23, 2001, article written for CNN, Rhonda Rowland quoted Dr. William Thies, the vice president of medical and scientific affairs at the Alzheimer's Association, who said, "While we don't know whether the product is going to work, we're going to find out an awful lot of valuable information no matter what the outcome of the trial is…. If it turns out that the vaccine clears the protein out and it still doesn't affect the disease, then that's a clear indication that amyloid is not the causative factor." As Rowland then pointed out, even if the vaccine does interrupt the disease process and arrest it in its current stage, arrest does not imply a cure. "For people who have well-established disease, the vaccine can do nothing to return dead brain cells and certainly can't return memories," commented Thies.

Different Experiment, Similar Concerns

A recent surgical study that has completed phase-one clinical trials supports Thies's statement about dead brain cells. Under the guidance of Dr. Mark Tuszynski at the University of California, San Diego School of Medicine, researchers hope to "protect and even restore certain brain cells and alleviate some symptoms, such as short-term memory loss, for a period that could last a few years." The procedure consists of taking a small sample of the patient's own skin cells and inserting nerve growth factor (NGF) genes taken from the patient's nervous system tissue. These genetically modified cells multiply in vitro (in a culture medium in a laboratory), producing large quantities of NGF. The NGF cells are then surgically implanted at the base of the frontal lobe of the patient's brain, an area that undergoes extensive degeneration and death of cells during the course of AD.

The human trial was based on results from experiments in normal aging rats and monkeys in which 40% of the cholinergic neuron cell bodies had atrophied. In his study findings published in the September 14, 1999, edition of the Proceedings of the National Academy of Sciences, Tuszynski reported that cholinergic neuronal cells were returned to almost normal following the implantation of NGF cells. In a February 2001 report in the same journal, Tszynski's team also reported that axons (necessary in carrying messages from one neuron to the next) that had shriveled and even disappeared in old monkeys were actually restored to, and sometimes exceeded, normal levels following implantation.

In this study, as in the AN-1792 study, human application may have different results than in animal models. Tuszynski pointed out, "Animals do not suffer from Alzheimer's disease." This is an important factor to keep in mind in the AN-1792 trials, particularly in light of the fact that rats do not naturally produce A [.integral] 42 plaques and must be genetically modified to do so. Again, as researchers have noted, these plaques are only similar to those seen in human AD patients and the animals do not literally suffer from AD.

Hopefully, however, with continued studies such as those referred to above, and perhaps with the combination of treatment techniques, the devastating effects of AD eventually can be brought under control and maybe even prevented.

—MARIE L. THOMPSON

KEY TERMS

ANTIBODY:

A molecule that the immune system makes to match and counteract foreign substances in the body (antigens).

BETA-AMYLOID:

A protein fragment snipped from a larger protein called beta-amyloid precursor protein (bAPP).

BETA-AMYLOID PLAQUES:

Dense deposits, made of a protein fragment called beta-amyloid, found in the empty spaces between nerve cells.

COGNITIVE FUNCTION:

Mental process of knowing, thinking, learning, and judging.

IMMUNE RESPONSE:

The way an organism responds to the presence of an antigen (foreign invader in its body).

NERVE GROWTH FACTOR (NGF):

One of several naturally occurring proteins found in the brains of all vertebrate animals that promotes nerve cell growth and survival.

NEUROFIBRILLARY TANGLES:

Abnormal structures in various parts of the brain consisting of dense arrays of paired helical filaments (threadlike structures) composed of any of a number of different proteins (such as tau) and that form a ring around the cell nucleus.

TAU PROTEIN:

A family made by alternative splicing of a single gene. Although found in all cells, they are major components of neurons and predominantly associated with the axons.