Cure Research for Alzheimer's Disease


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Research discussion: The NINDS conducts and supports research on neurodegenerative and dementing disorders, including AD. For example, although the cause of AD is still unknown, new research has shown that a vaccine, aimed at preventing or reversing the formation of AD-associated pathologic lesions, might be a useful therapy. Recent results using a transgenic mouse model suggest that immunological interventions may retard and even reverse the development of some of the pathologic changes associated with AD. Early clinical trials to test the vaccine are still in progress but offer hope for a future therapy. The National Institute on Aging and the National Institute of Mental Health also support research related to AD. 1

Pursuing another avenue, researchers at NIA are looking at Down's syndrome because it shares some traits with AD. Down's syndrome is caused by a birth defect in which the person has three, rather than the normal two, copies of chromosome 21. Down's syndrome is associated with mental retardation and the development of AD pathology. Because the gene for APP has been mapped to chromosome 21, some researchers believe that Down's syndrome is related to the "overexpression" of APP. 2

According to one new theory about the causes for sporadic AD, as neurons age, they may begin to make errors in translating the information contained in the gene's sequence of bases into the correct protein for beta-amyloid, causing a buildup of abnormal proteins in the neuron (van Leeuwen et al., 1998). 2

The researchers found that nuns who had had the infarctions in certain brain regions had more clinical symptoms of dementia than could be explained by the number of plaques and tangles in the cerebral cortex. These findings suggest that at least some brain infarcts, which do not themselves cause dementia, may play an important role in increasing the severity of the clinical signs of AD. In addition, other signs of disease related to the brain's blood vessels or blood supply, such as atherosclerosis, may be involved in the development of AD. Further research is needed to understand whether preventing these types of blood vessel diseases in the brain can help reduce the clinical signs of AD. 2

However, scientists are now studying a new generation of cholinesterase inhibitors, which might have greater usefulness and fewer side effects. In studies on animals, scientists at NIA (Patel et al., 1998) have preliminary evidence suggesting that one such drug, called phenserine, may be useful in treating AD patients. In animal models of cognitive decline, phenserine was significantly more effective in enhancing performance and learning in a maze test than drugs currently marketed to treat AD. Phenserine is undergoing toxicology testing (studies to find safe doses and identify any potentially problematic side effects). And NIA scientists recently found that a drug called arecoline seems to improve cognitive function and the process whereby chemical messages are sent across synapses in animals. Arecoline artificially stimulates acetylcholine receptors. Researchers now are studying the effects of arecoline in people.

Another drug that inhibits acetylcholinesterase, called physostigmine, is helping researchers to understand how these drugs can improve brain functions such as working memory, the form of memory that enables people to hold information such as telephone numbers for a short period of time. NIA researchers (Furey et al., 1997) used PET scans to study the beneficial effect of physostigmine on working memory in humans. Because physostigmine has a shorter duration of action than the drugs that are already approved for AD treatment, researchers are developing a longer-acting form. 2

Oxidative changes are seen in the brains of AD patients. Studies of compounds that fight oxidation are part of the effort to understand processes that damage cells and find ways to treat and possibly prevent AD. The NIA-supported ADCS trial of selegiline (l-deprenyl or Eldepryl) and alpha-tocopherol (vitamin E) is one such study. Both selegiline and vitamin E act as anti-oxidants. Selegiline, which has been used to treat patients with Parkinson's disease, works by inhibiting an enzyme in the brain that impairs certain neurotransmitter systems. 2

There is growing interest in the use of ginkgo biloba extract for the treatment of AD. Ginkgo biloba extract is a traditional Chinese medicine made from the leaves of the ginkgo tree. It apparently has anti-oxidant, anti-inflammatory, and anti-coagulant properties. In the first American trial of ginkgo against AD, the authors (Le Bars et al., 1997) found a "fairly modest" positive effect. However, there have been several reports linking ginkgo to hemorrhages, and other possible side effects are as yet unknown. NIA is funding some investigations into the use of ginkgo in treating AD. 2

Some pharmacological agents already are being tested in human patients. NINDS's Experimental Therapeutics Branch is participating in a multicenter trial of HWA285 (propentofylline). HWA285 is believed to have anti-inflammatory and neuroprotective properties, and it is hoped that it will slow the rate of intellectual decline in patients with dementia. The results of this trial currently are being analyzed. The Branch also is testing Ampalex (CX516, AMPAKINE), a new drug that may improve thinking and memory, in patients with mildly to moderately advanced AD. Ampalex has been shown in preclinical trials to be highly promising in improving cognitive function, and has been relatively free of serious side effects. AMPAKINEs enhance the functioning of a receptor, called the AMPA receptor, which plays a key role in memory formation and communication within and between different regions of the brain. 2

NIMH-supported scientists at the University of Pennsylvania (Streim et al., 1997) recently conducted a double-blind study of regular versus low-dose nortriptyline, an anti-depressant with anti-cholinergic activity. The response to nortriptyline in cognitively intact patients was found to increase with blood levels of the drug within the therapeutic range established in younger and healthier patients. However, patients with AD were less likely to respond and showed no significant relationship between plasma levels and clinical response. These findings suggest that the neuropharmacological processes underlying depression and the responses to anti-depressant medications in cognitively intact older patients are similar to those that are operative in younger and healthier individuals. However, in patients with AD they are quite different. Meeting the mental health needs of patients with AD requires specific knowledge that must be derived from research conducted on this special population. 2

Medical research for Alzheimer's Disease: medical news summaries: The following medical news items are relevant to medical research for Alzheimer's Disease:



Footnotes:
1. excerpt from NINDS Alzheimer's Disease Information Page: NINDS
2. excerpt from NIA's Progress Report on Alzheimer's Disease, 1998: NIA

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