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Possible targets for treatment of Alzheimer's disease advanced by recent gene breakthroughs

November 7, 1993

NIA Press Office | 301-496-1752 | nianews3@mail.nih.gov

Allen Roses, M.D., and his colleagues* have found a possible mechanism by which a variant of the Apolipoprotein (ApoE) gene protects against abnormal changes in the brain that are associated with Alzheimer's disease. The research, supported by the National Institute on Aging (NIA), moves scientists one step closer to unraveling the mysteries of Alzheimer's, a devastating disease affecting nearly 4 million Americans and their families.

This latest finding builds on earlier work by Dr. Roses and his colleagues, on the basis of which researchers at Duke University believe they have found a gene that is directly related to late-onset Alzheimer's, the most common form of this fatal disease. Today's report suggests that the E3 variant of ApoE may play a protective role in the progression of Alzheimer's disease and that a drug that imitates its function might be an effective drug for people who have the gene that produces ApoE 4. According to Dr. Roses, "The disease mechanism we favor is that ApoE 3 protects from neurofibrillary tangles being formed, while ApoE 4 does not and because of that, intracelluar metabolic processes are slowly destroyed."

*Michael Goedert and Ross Jakes, from the Medical Research Council Laboratory of Molecular Biology, Cambridge; Li-Ming Dong and Karl H. Weisgraber, from the University of California, San Francisco; and from Duke: Ann Saunders, Margaret Pericak-Vance, Dr. Donald Schmechel and David Huang.

The key to the ApoE findings is the significance of the E4 gene variant in predicting the likelihood of late onset Alzheimer's. Dr. Roses found that a person's risk of developing Alzheimer's disease increased nearly threefold for each E4 gene present. In people with two copies of the ApoE 4 gene, their chances of developing late onset Alzheimer's was found to be 91 percent, a truly definitive result. In people with only genotypes E3/E3 or E2/E3 present, the percentage of those likely to develop late-onset Alzheimer's disease fell significantly, to 45 percent or less, with the presence of the E3 variant being a prime reason for the beneficial effect.

If the effect of the ApoE 4 gene could be reversed or the E3 variant used to block activity of the E4 gene, then various therapies could be developed that would one day lead to the much sought-after cure for this and other types of Alzheimer's disease. With this new understanding of how ApoE impacts Alzheimer's disease, people could have the option of learning if they have inherited a rapidly degenerative form of the disease, if they could be targeted for treatment or prevention, or find out if they are unlikely to develop Alzheimer's as they approach their sixties.

According to Richard Hodes, M.D., Director of the National Institute on Aging, "These recent findings are important steps forward in our understanding of Alzheimer's disease. Finding a cure for Alzheimer's is a top priority for the NIA, and Dr. Roses' work moves Alzheimer's research in exciting new directions." Hodes, who points out that NIA research is primarily generated by investigator-initiated submissions, says the ApoE work is one area where interest is increasing as scientists move on several fronts against the disease. The NIA also supports studies on beta-amyloid, the calcium channels hypothesis, and other ongoing investigations.

Zaven Khachaturian, Ph.D., Associate Director for Neuroscience and Neuropsychology of Aging research at the NIA, believes that findings on the ApoE genetic link and the further discovery of how to possibly block this detrimental effect through the E3 variant, are two of the most interesting pieces of research he has seen recently regarding Alzheimer's. "Given the increased level of concern about Alzheimer's and memory loss we see in the older population, an early and reliable diagnostic test could ease the worries of millions of people. Furthermore, if the mechanism of action of the ApoE variants can be understood, potential treatments can be developed," according to Dr. Khachaturian.

Late-onset Alzheimer's is only one type of Alzheimer's. Some varieties of Alzheimer's disease appear at an earlier age and are related to genetic mutations on chromosomes 14 and 21. While clinicians can accurately diagnose Alzheimer's disease 85 to 90 percent of the time at best, the only way to make a definitive diagnosis is through a microscopic examination of brain sections after the death of a patient. It is important to arrive at a diagnosis however, while the patient is alive, in order to rule out other treatable conditions that can be mistaken for Alzheimer's, such as depression, some forms of dementia, or stroke. There is only one FDA approved drug therapy for Alzheimer's disease available and it provides limited benefit to a few individuals.

The National Institute on Aging, part of the National Institutes of Health, leads the Federal effort supporting basic, clinical, epidemiological and social research on aging and the special needs of older people.

ApoE Backgrounder

Two important discoveries by National Institute on Aging (NIA) grantees at Duke University this year establish, for the first time, identifiable genetic markers for late-onset Alzheimer's disease and suggest possible mechanisms for blocking the harmful gene's activities. The work of Dr. Allen Roses and his team at Duke is considered a breakthrough in Alzheimer's research, a disease that has baffled researchers for over twenty years since the disease's presence was first widely accepted. The other scientists contributing to the research include Michael Goedert and Ross Jakes, from the Medical Research Council Laboratory of Molecular Biology, Cambridge; Li-Ming Dong and Karl H. Weisgraber, from the University of California, San Francisco; and from Duke: Ann Saunders, Margaret Periack-Vance, Dr. Donald Schmechel and David Huang.

Alzheimer's disease was named after Dr. Alois Alzheimer, a doctor who, in 1907, detected a pathological condition that would later be noted as the first diagnosis of Alzheimer's in a human being. The principal symptoms of Alzheimer's that were detected by Dr. Alzheimer and are still the chief observational symptoms of the disease today, are: loss of memory, confusion, increasing disorientation and eventual inability to perform even the simplest functions on one's own. The only definitive way to make a diagnosis of Alzheimer's is through microscopic examinations of brain sections after the death of a patient. The portions of the brain of an Alzheimer's patient that deal with memory, emotion and cognitive thinking are riddled with clumps of protein plaques and tangles that are associated with destruction of the brain's ability to transmit information, while a healthy adult brain would display no such symptoms.

Dr. Alzheimer's pathological slides from 1912 of a patient's brain showed the same neurological findings that are still seen in Alzheimer's patients today.

The prevelance of Alzheimer's in the general population was not widely recognized until the 1970's. Today it is estimated that there are close to 4 million Alzheimer's patients in the United States and over 20 million patients worldwide who suffer from some form of the disease. There is no known cure and only recently has an approved treatment been available for cognitive symptoms. The drug, THA, is effective only in some circumstances for a few Alzheimer's sufferers. There have been advances in the ways to deal with and aid Alzheimer's patients, either through behavioral management techniques or psychotropic drugs. Through various organizations such as the Alzheimer's Association and the NIA, a component of the National Institutes of Health (NIH), the public has become better educated about various aspects of Alzheimer's disease. Problems still persist in training people to recognize the differences between simple and normal memory loss as one grows older, and the early signs of Alzheimer's disease. Since late 1987, there have been significant advances in our understanding of the biological aspects of brain function and how Alzheimer's disease may impair certain functions. It has been known for several years that a protein called beta-amyloid is a major component of senile plaques and vascular deposits typically found in the brains of Alzheimer's patients.

This year, Dr. Roses' group discovered that certain variants of the ApoE gene are found on chromosome 19 and that these gene variants are overwhelmingly linked to Alzheimer's disease. In the initial studies, the main culprit was the E4 variant of the ApoE gene, and persons carrying two copies of this gene were found to have an almost certain likelihood of developing Alzheimer's disease if they lived to be 75 years of age. Other variants of the gene and those people with only one copy of the E4 gene had less risk of developing Alzheimer's, but some risk was still evidenced. This research has just recently been corroborated by other researchers.

The next step of Alzheimer's researchers was to develop tests for the presence of the ApoE 4 gene and to find ways to block its harmful effects. Just recently, Dr. Roses' group discovered that the presence of the ApoE 3 gene variant protects against the abnormal changes in the proteins in the brain that would lead to Alzheimer's, while the E4 variant leaves the proteins unprotected. Nerve cells use microtubules to move molecules to places where they are needed in a cell, and ApoE 3 helps keeps the passageways open while ApoE 4 tends to cause blockages along the essential passageways. In other words, the E4 variant is deficient in its functioning while E3 is helpful to this essential process. This research helps to explain a possible mechanism for the pathological linkage of ApoE to Alzheimer's disease neurofibrillary tangles. Researchers believe that with this breakthrough, effective diagnostic methods, treatment, and perhaps a cure for this dreadful disease will be possible.

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