Part I of What's Hot, What's Not in Dementia Drugs appeared the September 1997 issue of the Journal of Gerontological Nursing on pages 52-54.
Part II of this column describes three of the more promising non-cholinergic therapies currently under investigation that have one important thing in common - all have already been approved for use in the treatment of other conditions besides Alzheimer's disease (AD). Why is this commonality significant? Because drug innovation is an expensive and time-consuming venture. The Pharmaceutical Research and Manufacturers of America estimates that it takes around 12 years, $500 million, and thousands of human subjects to bring a drug from the laboratory to the pharmacy shelf (Alzheimer's Disease Education & Referral Center, 1997). Estrogen, anti-inflammatory drugs, and antioxidants are well-known compounds currently being tested for their ability to help nerve cells survive by preventing damage from inflammation and oxidation (Alzheimer's Disease Education & Referral Center, 1997).
Estrogen, a hormone, has been shown to have positive effects on motor and cognitive abilities, mood, and behavior. Scientists have postulated that cells in the limbic system, cerebral cortex, and hippocampus regions of the brain that involve memory, learning, language, and reasoning, use estrogen (Alzheimer's Disease Education & Referral Center, 1997). Interestingly, estrogen's neuroprotective properties are not related to its feminizing effects. Estrogen and estrogen-like therapies may be effectively administered at low doses over many years, and may be helpful in other central nervous system diseases such as Parkinson's disease and stroke (Alzheimer's Disease Education & Referral Center, 1997).
Estrogen protects neurons, and may interact with nerve growth factor (a substance that promotes repair of cholinergic neurons), to help brain cells develop and survive. It may also work as an antioxidant to stop the harmful action of oxygen molecules correlated with cell death.
A number of epidemiological studies have suggested that estrogen loss that occurs as a natural part of the aging process in women may exacerbate the effect of AD. Postmenopausal women who receive hormone replacement therapy (HRT) have been found to score better on selected tests of cognitive function than women who have not received HRT. Estrogen may also slow the emergence of symptoms, but further systematic testing - such as is currendy underway in the Alzheimer's Disease Cooperative Study (ADCS) sponsored by the National Institute on Aging - is needed.
Anti-inflammatory drugs are receiving increasing attention as more studies emerge suggesting a link between immune mechanisms and use of these pain relievers. The hypothesized mechanism of action is that anti-inflammatory drugs somehow impact the brain's inflammatory response to amyloid protein deposits - an abnormal protein fragment that makes use of the neuritic plaques found in the brains of persons with AD (Alzheimer's Association, 1996) thereby reducing the risk of developing AD or slowing the progression of symptoms.
A number of drugs fall into this category including the corticosteroids such as prednisone, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, and nonaspirin NSAIDs such as Ibuprofen and naproxen. The latter category is often recommended because of the side effects associated with corticosteroids and the stomach irritation and ulcers that can occur with aspirin. However, current widespread trials of prednisone 10 mg per day are underway.
A growing body of research suggests some protective effects of NSAIDs (Breitner, 1997). For example, investigators noticed that persons with rheumatoid arthritis (usually treated with NSAIDs) seldom developed AD. Among twins, (especially women and persons over the age of 70), those who regularly took NSAIDs for more than a year had about one fourth the risk of developing AD, compared to their twin who had not taken the drugs. Similarly, recent findings from a large scale longitudinal study revealed that NSAID users had about half the risk of developing AD compared to non-users. Some investigators suggest that duration of use rather than anti-inflammatory potency may be the critical protective factor (Breitner, 1997).
At present most of the positive findings are from retrospective epidemiologic or observational studies. There is still insufficient evidence from randomized clinical trials to say with certainty that NSAIDs delay or prevent the onset of AD, although the mounting evidence is promising.
Antioxidants such as selegiline (or L-deprenyl), a monoamine oxidase inhibitor (MAO) type B that is an approved therapy for maintaining motor function in Parkinson's disease, and vitamin E are being studied in the multicenter ADCS. Support for the use of these compounds is based on an oxidative stress model, which suggests that free radicals generated through oxidative mechanisms can play a role in the development of AD and other chronic illnesses such as cancer (Buckwalter, 1995).
In Alzheimer's disease, scientists speculate that free radicals (molecules with an unpaired electron in their outer shells), may act in a variety of ways, including: 1) attacking molecules of fat in nerve cell membranes and upsetting mechanisms that regulate what passes through them, 2) altering proteins associated with the development of AD, and/or 3) targeting the internal support structures of nerve cells (Alzheimer's Disease Education & Referral Center, 1997).
At daily doses of 5 to 10 mg, selegiline may also increase dopamine levels in the central nervous system and have anti-neurotoxic potential. Both selegiline and vitamin E fight oxidation, and studies to date have shown they result in mild improvement in cognitive function, as well as positive behavioral effects. Other MAO-B inhibitors are also currently under investigation, as well as a transdermal form of selegiline.
Research is dramatically increasing our understanding of what goes awry in the brains of persons with AD. Three compounds approved for use in other conditions, estrogen, anti-inflammatory drugs, and antioxidants, are currently under study based on their ability to promote cell metabolism and survival, counteract inflammatory responses, and protect neurons from oxidative damage. All three show promise in terms of treating and possibly preventing Alzheimer's disease.
- Alzheimer's Association. (1996, Summer). Advances in Alzheimer's research, 6(2), 3.
- Alzheimer's Disease Education & Referral Center. (1997). Connections. Alzheimer's disease drug research: The search for new treatments, 6(1), 2-6.
- Breitner, J.CS. (1997, Spring). Can antiinflammatory drugs prevent Alzheimer's disease? The Caregiver. Durham, NC: Duke Family Support Program, pp. 3-4.
- Buckwalter, K.C. (1995). "Free radicals" are not a 60s rock group. Journal of Gerontological Nursing, 21(10), 3-4.