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Jay Luxenberg, M.D., is an internationally known expert in the field of geriatrics and has written and lectured extensively on the treatment of diseases in the elderly. Currently the Medical Director for the Jewish Home for the Aged in San Francisco, Dr. Luxenberg is studying drug therapies for Alzheimer's disease patients and environmental changes which improve the functioning and quality of life of the residents. Dr. Luxenberg's newest book is Residential Care: Your Role in the Health Care Team published by Fisher Books.
FCA: Dr. Luxenberg, given your years of experience in diagnosing and treating adults with Alzheimer's Disease and in working with their families, what do you see as the key trends in treatment of this disease?
Dr. Luxenberg: I see the key trends concerning treatment of Alzheimer's over the next few years to all be related to the direct translation of the recent advances in understanding the biology of Alzheimer's disease into a new generation of drugs much more specific and effective.
The most recent treatments available are either the result of serendipity or reflect knowledge of neurotransmitter deficits that were recognized more than a decade ago. Starting with the first FDA approved drug for Alzheimer's (tacrine) and more recently with the advent of donepezil (Aricept) we are using the strategy of increasing the concentration in the brain of one of the neurotransmitters, acetylcholine, that is diminished in Alzheimer's disease.
Soon we will see several other drugs that use another strategy to increase the effect of this neurotransmitter on the brain - they will directly bind to the acetylcholine receptor. An example of this new class of drugs include milameline. At least theoretically, there will be a role for combining therapy with one of these drugs with a drug like Aricept.
Unfortunately, it seems the benefit of increasing the effect of acetylcholine on the brain is only a temporary one, and drug therapies based on this approach seem to cause a modest improvement of symptoms. They do not dramatically alter the progressive damage to the brain from Alzheimer's disease, and therefore the patient soon returns to the degree of impairment they had prior to starting the drug therapy. Of course, we all would prefer a drug treatment that would slow the progression of the brain damage, or even halt it!
FCA: What about media reports about ibuprofen and other drugs?
Dr. L.:The drugs that have been recently noted to actually slow the progression of the disease were all actually noticed through serendipity - they are drugs that are used for other purposes and only later was it noticed that they may slow Alzheimer's. In this category estrogen, ibuprofen and other nonsteroidal anti-inflammatory drugs, vitamin E and selegiline all have shown promise in slowing the progression of the disease or delaying its onset. As exciting as this progress is, none of these drugs reflects any of the breakthroughs in the basic science of understanding Alzheimer's disease that has occurred over the past few years.
FCA: Do you see any breakthroughs?
Dr. L.: I am absolutely thrilled at the progress that scientists have made in the past few years understanding the biology of the plaques, tangles, amyloid deposits and cell death that characterize Alzheimer's disease.
Much of this progress has followed the isolation of several genes involved in the relatively rare autosomal dominant hereditary forms of Alzheimer's disease. Many such abnormal genes have been identified, and the protein products of these genes are now widely believed to be important in the actual disease process that we call Alzheimer's disease. Two of the gene products, now called presenilin I and presenilin 2, are receptors for the precursor protein for amyloid.
We now have a glimmer of understanding of how these proteins interact, and the role of the activation of several other receptors, including the "RAGE" or receptor for advanced glycation endproducts, to cause the death of brain cells and the deposition of amyloid in the brain.
A very recent advance is the recognition of a previously unsuspected brain lesion in Alzheimer's. The new lesions are known for now as "AMY plaques," because they were initially mistaken for amyloid plaques. They appear to be nearly as widespread in the brains of Alzheimer's patients as the more familiar plaques and tangles of tau proteins. As yet, the genes and proteins involved in this lesion have not been identified.
Apoptosis (programmed cell death) is a form of cellular suicide that is a useful and important part of development of the brain but seems to be abnormally activated in Alzheimer's disease. Several links have been identified between apoptosis and the gene products already identified as having a role in Alzheimer's disease.
My prediction is that the in the next few years drugs will be developed that directly take advantage of this knowledge. The binding of the amyloid precursor to the presenilins may be a site of action, or perhaps the chain of events that leads to apoptosis. The RAGE or other neuronal receptors may be blockable with drug therapy, or the abnormal protein handing that leads to the formation of "tangles" might respond to some new drug. It sure makes sense that it should be easier to find a drug when you have an idea what you are looking for, rather than relying on luck!
By interfering with the mechanism of brain cell destruction, I'm hoping we can arrest the disease progress in a very early stage, or even prevent the disease in those who have a hereditary predisposition.
Another area of recent progress has been advances in understanding the biological basis for some of the troubling behaviors in Alzheimer's disease. The drugs we currently use, including antipsychotics, antidepressants, antianxiety drugs, etc. were all developed to treat other conditions and only due to desperation were tried in dementia. We generally have no blood tests or other logical guidance to determine which drugs will work on which patient, and we have very primitive means of measuring the benefit of whatever drug we chose to try.
I am hoping that we will soon be able to translate our understanding of the biological basis for the behavioral signs and symptoms of Alzheimer's into a new generation of behavioral and pharmacologic approaches to treatment.
FCA: So what's the prognosis for Alzheimer's treatments?
Dr. L.: In general there is always a lag period between basic scientific advances and practical applications. I think that can look forward to some real progress soon on the practical side of the equation, because there has been so much progress on the basic science side. I am more optimistic than ever before about Alzheimer's disease therapy.
Interview Date: August 1997
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