New Hope for Alzheimers Treatment

There is now widespread agreement among research scientists and medical professionals that Alzheimer's Disease (AD) is a problem quickly growing to vast proportions. As the life expectancy of Americans continues to rise, increasing the percentage of the population over 65 years of age, so does the number of Alzheimer's cases.

It is currently estimated that people over 65 years of age have a 10% chance of developing Alzheimer's, while those over 85 have a 50% likelihood of developing AD, making it the leading cause of dementia among older people. Though the disease is associated primarily with memory loss, its effects also comprise a number of other severe disabilities, including changes in personality, disorientation, difficulty with speech and comprehension, and a lack of ability to move normally.

Consequently, most Alzheimer's patients require a great deal of care, costing society close to $100 billion annually. According to Christian Fritze, Ph.D., Director of the Antibody Products Division at Covance Research Products, "The impact of Alzheimer's Disease on our society will only increase as our population ages. The prevalence of the disease and disabling effects on the patient are significant by themselves. In addition we are becoming increasingly aware of the far-reaching effects on families, care-giver networks and the economics of our health care system. The drive for progress towards effective treatments by the research and drug development community is growing stronger every day."

A New Consensus

But recent developments in the medical research community do provide some hope. During the last two years, there has been a growing consensus among Alzheimer researchers about the cause of Alzheimer's disease, providing focus for scientists exploring the new treatment options.

The focus is on amyloid beta oligomers, a new wrinkle on an older hypothesis called the "amyloid cascade hypothesis". Widespread acceptance of this new conclusion is something of a milestone in the history of Alzheimer's research. As Dr. Fritze says, "The decades old quest for the causative agent in Alzheimer's Disease has recently focused on the precursors of amyloid plaques. These precursors are part of a bewildering array of processed (APP) Amyloid Precursor Protein) variants, Tau isoforms and secretase components that play a role in neuronal cytotoxicity and subsequent brain dysfunction."

Amyloid plaques are sticky protein deposits in the brain containing amyloid beta peptide. Researchers have associated the buildup of this plaque with Alzheimer's disease since its discovery in 1907. But despite the clear correlation, scientists were not sure what, exactly, spurred the onset of Alzheimer's Disease.

The hypothesis that amyloid beta accumulation in the brain is the major cause of Alzheimer's Disease1 has been the focus of much attention over the past decade. Although this hypothesis was the leading explanation for the cause of AD, it had several weaknesses. The most obvious problem with the theory was the fact that the buildup of amyloid beta peptides did not necessarily correspond with the severity of Alzheimer's symptoms.

However, in 19982 and in 20023, researchers proposed that it was not the amyloid beta plaques themselves that were neurotoxic - and therefore the cause of Alzheimer's - but rather precursors to amyloid beta plaques formed by smaller aggregates of amyloid beta. These new ideas are gaining widespread acceptance among the Alzheimer's research community, creating a consensus that had not existed before.

This new focus provides one more spur to action for Alzheimer's researchers, and underscores the need for further advancement. "The AD field demands sophisticated, highly-sensitive research tools to track these components and quantitate the existence of monomeric, oligomeric and fibrillar amyloid forms present in the progression of Alzheimer's disease," says Dr. Fritze.

Antibody Treatment

Two new studies, both released in October 20044, suggest that new treatment options may be on the horizon. The studies are the modification of one of two previous attempts using amyloid beta (Aβ) antibodies in the treatment of Alzheimer's Disease. The previous attempts, though not successful, did at least suggest new courses of action in Alzheimer's research and provided invaluable information for researchers.

In the first of the two previous attempts, researchers injected the antigen itself - pieces of the beta amyloid protein that makes up amyloid plaque - into mice, in the hopes that the injections would generate an immune (antibody) response against amyloid. Results were initially positive. The injected antigen produced Aβ antibodies and slowed the onset of the disease by decreasing Aβ levels. However, when tried on humans, the procedure led to meningoencephalitis (an inflammation of tissue around the brain) in some patients, and was therefore halted.

In the second attempt, a passive immunity therapy was tried in which antibodies to amyloid beta (not amyloid protein) were injected into mice, but hemorrhaging and inflammation ensued due to the high antibody doses required to be effective.

New Hope

But now there appears to be new hope for the use of antibodies as therapeutic agents for the treatment of Alzheimer's patients. In the first of the two new studies that appeared in October conducted by the National Institute for Longevity Sciences, NCGG, and the Center for Neurological Diseases, Brigham & Women's College, Harvard Institute of Medicine, researchers modified the first procedure. Concluding that the meningoenchaphalitis which occurred in some patients was caused by autoimmune T-cell activation, the researchers hoped to develop a vaccine that could minimize this T-cell activation while retaining the production of Aß antibodies.

To accomplish this they created an oral vaccine that attached Aß DNA to an adeno-associated virus vector, which served to mitigate T-cell activation. Thus they were able to decrease Aß levels in the brains of the mice and yet not activate T-cells to the degree they had before, greatly reducing the risk of meningoencephalitis.

In the other new study, conducted at the University of Illinois at Chicago, researchers succeeded in making the passive immunity protocol much safer. This they accomplished by changing the point of entry for the Aß antibodies. Rather than injecting the antibodies into the body of the mice, as was done previously, antibody was injected directly into the brain of the mice. Because the antibodies were injected directly into the brain, smaller doses were needed, and side effects were minimized.

The results of the above studies, and the potential for further optimized immunization strategies may prove to be watershed events in the history of Alzheimer's treatment.

Covance is a leading provider of innovative antibody products and custom antibody development services to the research community for Alzheimer's disease. Visit www.Covance.com for more in-depth information and to view the suite of products for Alzheimer's disease. Boris Predovich is Vice President of Immunology and Surgical Services at Covance Research Products.

Notes

1. J.A. Hardy, G.A. Higgins (1992), Science, 256:184-5.
2. M.P. Lambert et al (1998), Proc Natl Acad Sci, 95:6448-53.
3. D.M. Walsh et al (2002), Nature, 416:535-9.
4. Neelima B. Chauhan et al (2004), Journal of Neuroscience Research, 78, 5:732-741.
Hideo Hara et al (2004), Journal of Alzheimer's Disease, 6, 5:483-488.

R. L. Fielding writes on many health-related topics.

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