Estrogen and Anti-Inflammatory Drugs

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Through epidemiologic research, scientists have identified two kinds of drugs that may slow or stop AD: estrogen and anti-inflammatory drugs. Epidemiologists study AD incidence, prevalence, and various risk factors in culturally-diverse populations. Incidence is the rate at which new cases of a disease occur. Prevalence is the percentage of the entire population with the disease at a given time.

When epidemiologic studies showed some potential benefits of estrogen and anti-inflammatory drugs in treating AD, the National Institute on Aging’s (NIA’s) Alzheimer’s Disease Cooperative Study (ADCS) launched pilot studies to assess their effectiveness. The ADCS is part of the Federal Government’s AD research effort (see the accompanying article). Dr. Leon Thal directs the ADCS and the Alzheimer’s Disease Center (ADC) at the University of California in San Diego. According to Dr. Thal, these are the first attempts to gauge the therapeutic potential of these drugs in AD in controlled research studies.

“The epidemiologic research is not completely reliable because it is based partly on the recall of people with AD. Further, it does not show whether the medications actually benefit those who have the disease,” says Dr. Thal. “Only one small-scale controlled study of an anti-inflammatory drug–indomethacin–has been done, and no adequately sized and properly controlled studies have involved estrogen,” he adds. Controlled clinical studies are needed to confirm and add to these epidemiologic findings.

Biological evidence suggests that both estrogen and anti-inflammatory drugs may help treat and possibly prevent AD. Estrogen is a hormone, a chemical with important roles in the brain and other parts of the body such as the female reproductive system. Scientists have found that estrogen has positive effects on motor and cognitive abilities, mood, and behavior. Researchers now believe that cells in brain areas severely affected by AD (including the limbic system, cerebral cortex, and hippocampus) use estrogen. The cerebral cortex is the part of the brain most involved in learning, language, and reasoning. The hippocampus is a structure deep in the brain involved in memory storage.

Estrogen appears to interact with nerve growth factor (NGF) to help brain cells–particularly those that use acetylcholine–develop and survive. NGF is a substance that helps promote the repair of cholinergic neurons (nerve cells that contain or are stimulated by acetylcholine).

Estrogen may work as an anti-oxidant, stopping the harmful action of oxygen molecules. Oxygen molecules combine readily with other molecules and, in doing so, sometimes damage cells.

The current ADCS trial of prednisone (a steroidal anti-inflammatory drug) is for “proof of the concept,” Dr. Thal notes. Evidence shows that an inflammatory response by the body’s immune system may be associated with the production of beta-amyloid. Beta-amyloid is an abnormal protein fragment that makes up the neuritic plaques (deposits of amyloid mixed with pieces of dead and dying neurons) found in the brains of AD patients. Beta-amyloid is cut out from the larger amyloid precursor protein (APP).

“Prednisone has proven useful in another inflammatory central nervous system disorder–lupus. It also has more general effects in the central nervous system than other anti-inflammatory drugs. Therefore, tests of prednisone provide the best chance of identifying a positive effect, if there is one.

If the pilot study with prednisone is encouraging, then researchers may begin to home in on a better long-term therapy, perhaps one of the nonsteroidal, anti-inflammatory drugs (NSAIDs),” says Dr. Thal. NSAIDs are a drug class that includes ibuprofen and aspirin. In general, NSAIDs have less serious side effects than prednisone. And, recent findings using data from the Baltimore Longitudinal Study of Aging (BLSA) suggest that regular use of NSAIDs may lower the risk of AD by as much as 60 percent. These results are from a study of 1,686 BLSA participants (older people) who were followed for 1 or more years between 1980 and 1995.

Even if results from the ADCS’s pilot studies of estrogen and prednisone are promising, much work still must be done before medical experts will recommend these drugs for everyday use in battling AD. For example, researchers will need to find safe and effective anti-inflammatory drugs with reasonably few side effects after extended use.

Source: Connections Magazine [Volume 6(1), Spring 1997]

References

Aisen, P.S.; Davis, K.L. Inflammatory Mechanisms in Alzheimer’s Disease: Implications for Therapy. American Journal of Psychiatry. 151(8): 1105-1113. August 1994.

Paganini-Hill, A.; Henderson, V.W. Estrogen Deficiency and Risk of Alzheimer’s Disease in Women. American Journal of Epidemiology. 140(3): 256-261. August 1, 1994.

Rogers, J.; et al. Clinical Trial of Indomethacin in Alzheimer’s Disease. Neurology. 43(8): 1609-1611. August 1993.

Simpkins, J.W.; Singh, M.; Bishop, J. The Potential Role for Estrogen Replacement Therapy in the Treatment of the Cognitive Decline and Neurodegeneration Associated With Alzheimer’s Disease. Neurobiology of Aging. 15(Suppl 2): S195-S197. 1994.

Stewart, W.F.; et al. Risk of Alzheimer’s Disease and Duration of NSAID Use. Neurology. 48(3): 626-632. March 1997.

Tang, M.X.; et al. Effect of Oestrogen During Menopause on Risk and Age at Onset of Alzheimer’s Disease. The Lancet. 348(9025): 429-432. August 17, 1996.

Thal, L. Future Directions for Research in Alzheimer’s Disease. Neurobiology of Aging. 15(Suppl 2): S71-S72. 1994.

Whitehouse, P.J. Cholinergic Therapy in Dementia. ACTA Neurology Scandinavia. Suppl 149: 42-45. 1993.

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