Top Alzheimer research advances of 2000

Alzheimer's Association
Friday, 19 January 2001

Alzheimer research began only two decades ago when people with the disease and their families had very few options and no treatments were available.

But our understanding of Alzheimer's disease is growing rapidly, and the pace of discovery is accelerating. Because Alzheimer's is very complex, many lines of research are underway to unravel the mysteries of this devastating disease.

Today, we are learning more about the underpinnings and causes of Alzheimer's and investigators are exploring many promising therapies for its prevention. Researchers are getting closer to conquering Alzheimer's, with breakthrough studies published almost weekly.

"The Alzheimer's Association will continue to be the driving force behind much of the promising research taking place," said Edward F. Truschke, President and CEO of the association. "Funds provided by the association help scientists gain a deeper understanding of Alzheimer's disease to ultimately find a prevention or cure."

In recognition of the achievements and developments in basic and clinical research that may have a significant impact on prevention and treatment of Alzheimer's disease from which four million Americans suffer, here are the top Alzheimer research advances of 2000:

Diagnosis

There is no single proven laboratory diagnostic test for Alzheimer's disease. Current clinical methods combine physical and neuropsychological testing with caregiver input and the physician's judgment. This method is about 90 percent accurate in diagnosing Alzheimer's disease.

One major group of experimental diagnostic studies is focusing on brain imaging techniques such as magnetic resonance imaging (MRI) and others are looking at positron emission tomography (PET) scanning to see if the early cognitive markers of Alzheimer's -- telltale changes in mental abilities and personality -- can be linked to early biological changes in the brain. These brain imaging and scanning techniques are getting closer to pinpointing brain abnormalities that might enable physicians to diagnose people with Alzheimer's disease before symptoms appear.

In the journal the Proceedings of the National Academy of Sciences, UCLA researchers published a study comparing PET scans that showed brain function of people at high risk for developing Alzheimer's disease with scans showing brain function of people who were not at high risk.

According to the researchers, initial PET scans showed that the group carrying the Alzheimer's disease gene APOE-4 had significantly lower function in specific areas of the brain located above and behind the temples. After a two-year follow-up, UCLA researchers found that the group carrying the APOE-4 gene demonstrated a five percent decline in function in the same two regions of the brain that appeared in their initial scans. According to the researchers, the group without the Alzheimer's disease gene showed decline only in an area located in the front of the brain which is consistent with normal aging.

Drugs -- Existing and in Development

Despite years of frustration, researchers and doctors are now hopeful that they may be able to delay, and someday, prevent the onset of Alzheimer's disease.

This year, the U.S. Food and Drug Administration (FDA) approved a new drug treatment for Alzheimer's disease, rivastigmine (Exelon®). In addition to rivastigmine, there are two other drugs, donepezil (Aricept®) and tacrine (Cognex®), currently available to treat symptoms of Alzheimer's by improving cognitive function. Another drug, galantamine (Reminyl®) is under review by the FDA.

And many new drugs designed to either prevent or slow the progression of the disease, as many as 60, are in various stages of development.

Researchers also continue to investigate anti-inflammatory drugs to reduce the inflammation that accompanies plaque formation. Previous studies have indicated that ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDS), including arthritis drugs called Cox-2 inhibitors, appear to reduce the risk of Alzheimer's.

In February, the National Institute on Aging (NIA) launched a clinical trial to determine whether treatment with certain NSAIDS will slow cognitive and clinical decline in people with Alzheimer's disease. The study will evaluate two NSAIDS: rofecoxib, a new cyclooxygenase (COX-2) inhibitor, and naproxen. This is the first clinical trial to test both classes of anti-inflammatory drugs prospectively in people with Alzheimer's disease.

The journal Neurology published a research study of the steroid prednisone, another anti-inflammatory drug. According to the researchers, a low-dose regimen of prednisone is not effective in the treatment of Alzheimer's disease. The researchers looked for changes over a one-year period in the cognitive performance and behavior of study participants as determined by a cognitive component of the Alzheimer's Disease Assessment Scale (ADAS) and other tests. According to the researchers, the testing showed that low-dose prednisone did not slow the rate of cognitive decline when those taking the drug were compared with those on placebo.

"It is encouraging to see that the NIA is conducting a study to determine whether certain NSAIDS will slow cognitive decline," said Bill Thies, Ph.D., Alzheimer's Association vice president of medical and scientific affairs. "More research like this is needed to clarify the role anti-inflammatory drugs may play in reducing the risk of Alzheimer's," he said.

In addition, scientists are investigating certain cholesterol-lowering medications. Two studies published this year have shown that there is a relationship between certain cholesterol-lowering medications (statins) and decreased occurrence of Alzheimer's disease.

In a study published in The Lancet, researchers at Boston University School of Medicine found that individuals who were prescribed certain cholesterol-lowering medications were about 70 percent less likely to have dementia compared to people who had no diagnosis of high cholesterol or exposure to other cholesterol-lowering medications. Individuals not treated with the cholesterol-lowering medications did not have a significantly reduced risk of dementia. A paper published in the Archives of Neurology researched similar conclusions.

"The Alzheimer's Association is encouraged by the two studies showing a relationship between certain cholesterol-lowering medication (statins) and decreased occurrence of Alzheimer's disease," said Bill Thies, Ph.D., Alzheimer's Association vice president of medical and scientific affairs. "Observational studies of this sort indicate a relationship but do not prove causation. The Association advocates that appropriate clinical trials using statins as a potential preventive for Alzheimer's disease should be conducted," he said.

Enzymes

For more than a decade, Alzheimer researchers have been looking for enzymes that might be central to the formation of beta amyloid -- tiny protein fragments -- that accumulate into dense, insoluble plaques in the brains of people with Alzheimer's. Scientists have hypothesized that these plaques cause cell death and lead to the decline in a person's cognitive functions.

In February, the journal the Proceedings of the National Academy of Sciences published a study suggesting that researchers have identified a subset of the enzyme beta secretase —one enzyme believed to be involved in the formation of beta amyloid. By inhibiting the action of beta secretase, the researchers suggest that it may also be possible to inhibit the development of beta amyloid, preventing plaques from forming in the brain and thus preventing the progression of Alzheimer's disease.

And, in June, researchers wrote in Nature that by inhibiting another enzyme believed to cause amyloid plaques, gamma secretase, it may also be possible to inhibit the development of amyloid plaques, consequently preventing the progression of Alzheimer's.

"These findings represent a significant body of work and may be the foundation upon which the next generation of therapeutic drugs will be built," said Thies. "But until clinical trials are conducted, we won't know whether inhibiting these enzymes will affect the course of the disease," he said.

Nerve Growth Factor (Neurotrophic Factor)

The rapid pace of Alzheimer research over the past several years has opened many pathways that could lead to effective treatments for the disease. One general approach focuses on substances in the brain, including an essential chemical called nerve growth factor. How nerve growth factor works is not completely clear, but it is known to be one of several growth factors, or neurotrophic factors in the brain. While nerve cells in the brain do not divide in sufficient quantities to overcome Alzheimer's disease, they can repair themselves after injury, and neurotrophic factors promote this regeneration.

Last year, researchers from the University of California, San Diego published a study in the Proceedings of the National Academy of Sciences on a gene therapy technique involving nerve growth factor, suggesting that they were able to revive or restore brain cells in aging monkeys to nearly their original state. The researchers took skins cells from older monkeys, inserted a gene that makes human nerve growth factor, and then injected the modified cells into the brains of four monkeys. Once in the monkeys' brains, the modified cells began making nerve growth factor and appeared to revive brain cells.

In January, the researchers received approval from the Food and Drug Administration (FDA) to conduct Phase I clinical trials of the gene therapy experiment in humans. The researchers plan to enroll only eight people in this Phase I study. There are several requirements participants must meet to be considered for enrollment – one of these requirements is the ability to travel to San Diego, Calif., up to nine times in the first year of the study.

"The researchers describe a fascinating technique for producing nerve growth factor," said Thies. "By moving this research from animal trials to human trials, researchers have taken a step closer to determining whether this technique will have the ability to affect the course of Alzheimer's disease."

Meanwhile, human clinical trials are continuing on a number of nerve growth factor drugs.

Vaccine

In 1999, scientists at Elan Corporation published a study in Nature on the immunization of mouse models with a form of the protein that begins the accumulation process of amyloid plaques in the brains of people with Alzheimer's disease. The researchers found that in transgenic mouse models -- mice genetically engineered to accumulate amyloid in their brains -- immunization with a synthetic protein fragment called AN-1792 significantly reduces existing plaques and prevents further plaques from developing.

The results from the study, if replicated in humans, would enable scientists to test amyloid reduction as a possible treatment strategy for Alzheimer's disease. Because the immune system of a mouse is very different from that of a human being, it is difficult for scientists to predict whether AN-1792 will be effective in humans.

In 2000, scientists at Elan began conducting Phase I safety trials on the compound of AN-1792 in other animals and initiated multi-dose Phase I clinical trials in humans. Initial results of the Phase I clinical trial, announced at World Alzheimer Congress 2000, showed that the potential vaccine was well tolerated in humans, according to scientists at Elan.

In total, about 100 individuals in the United States and the United Kingdom would be involved in the Phase I clinical trials of AN-1792. Individuals in the U.S. received a single dose of the vaccine through injection and, according to the researchers, no obvious safety concerns have been identified. Phase I multiple dose trials currently are underway in the United Kingdom.

"This is an exciting and encouraging study for the prevention and possible treatment of Alzheimer's disease," said Thies. "Announcements like this that are grounded in solid scientific research give us tremendous hope. We now are testing the amyloid hypothesis with this vaccine and traditional drug therapy, and we are moving closer to identifying an intervention that will be able to alter the course of the disease."

Researchers at Harvard Brigham and Women's Hospital also are investigating a potential vaccine. In the journal Annals of Neurology, the researchers write about their study of nasal administration of a potential Alzheimer vaccine that they studied in transgenic mice —mice genetically engineered to develop Alzheimer's disease-like pathology.

According to the researchers, the brains of the mice treated with the nasal spray had significantly fewer Alzheimer disease-like plaques in the brain than the mice that were not immunized. Scientists are interested in testing the delivery of the peptide nasally because it may be better tolerated in people than repeated injections over the long-term. In this study, the strength of antibodies resulting from nasal administration of the vaccine was not as great as that from the injection approach, but it still was significantly effective against plaque formation.

Research advances announced at World Alzheimer Congress 2000

The Alzheimer's Association (U.S.A.) assumed leadership of the world's largest international conference on Alzheimer's disease, World Alzheimer Congress 2000. Over a 10-day span in July, more than 5,000 world leaders in Alzheimer research and care united in Washington, D.C., marking the first time these Alzheimer specialists have come together for the vital purpose of sharing information on research and care to improve the lives of people affected by Alzheimer's disease. Here are some of the highlights of the research advances that were announced during the congress:

Impaired Memory

Danish scientists reported that failing memory may be a symptom of a treatable and reversible condition and not always a sign of Alzheimer's disease. Over a period of 40 months, researchers examined 785 individuals with memory problems. Only 43 percent were diagnosed with Alzheimer's disease or some other form of dementia. Six percent had selective amnesia and 11 percent were found to have some other cognitive deficit. Twenty- eight percent had no serious cognitive deficits and 12 percent were not classified.

In six percent of the people with Alzheimer's disease or some other form of dementia, the researchers found that a potentially reversible primary cause of the memory disorder existed. This does not mean, however, that Alzheimer's disease is reversible, the researchers explain. It does mean that some people with the illness may have an accompanying condition that contributes to or causes memory loss.

Vegetables Rich in Anti-oxidants

New findings reported at World Alzheimer Congress 2000 suggest that eating high amounts of vegetables rich in vitamin E and vitamin C is associated with lower risks of dementia and Alzheimer's disease.

Researchers collected the dietary habits of 5,395 men and women aged 55 and older who were free of dementia. People who participated in the study completed questionnaires about dietary habits and were interviewed by dietitians. The researchers found that on average, people who remained free from either form of dementia had consumed higher amounts of beta-carotene, vitamin C, vitamin E, and vegetables than the people in the study who developed Alzheimer's disease.

Therapy for Moderately Severe Alzheimer's

Researchers reported findings suggesting that memantine, a drug that acts on a key central nervous system receptor, may help slow the progression of moderately severe to severe Alzheimer's disease. The researchers found in their study of memantine that after six months, both the placebo group and the treatment group declined. However, after several assessments to evaluate cognitive function, activities of daily living and behavioral change, the researchers found that the treatment group performed significantly better than the placebo group in cognition and daily activities, without changing behavioral symptoms.

High-Fat Diet

According to research presented at World Alzheimer Congress 2000, a high-fat diet during early and mid-adulthood may be associated with an increased risk of developing Alzheimer's, especially in people with a marker called the ApoE-e4 allele. In a retrospective analysis that examined foods eaten by 304 men and women (72 with Alzheimer's disease and 232 healthy individuals), researchers found that people with the ApoE-e4 allele who also consumed the highest fat diets had a seven-fold higher risk of developing Alzheimer's than people with the marker who ate lower fat diets.

"It has long been hypothesized that early life experiences may affect the development of Alzheimer's disease,"said Thies. "Proper nutrition and a healthy diet are essential for maintaining overall good health and can be beneficial to both people with Alzheimer's and caregivers."

For more information, or to contact Alzheimer's Association, see their website at: www.alz.org