Scientists are working at a stepped-up pace to examine a number of compounds that might delay the onset of AD, slow its progress, or prevent it altogether. These compounds include:
One of the hallmarks of AD is inflammation in the brain, but whether it is a cause or an effect of the disease is not yet known. Epidemiologic evidence strongly suggests that anti-inflammatory agents, such as prednisone (a steroid) and nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and indomethacin, are associated with a decreased risk of AD. NIA has supported a study to compare the effects of prednisone versus a placebo (inactive pill) on patients with diagnosed AD to see whether progression of the disease can be slowed. This study, the results of which are presently being analyzed, was conducted through the Alzheimer’s Disease Cooperative Study (see p. 46 for a description of the ADCS). Another ADCS study with AD patients, which will begin at the end of 1999, will compare treatment with a traditional NSAID to treatment with a COX2 inhibitor, a more specific type of NSAID with pain relieving qualities but without some of NSAIDs’ side effects on the gastrointestinal system.
Estrogen and Estrogenic Compounds
Estrogen use also has been associated in epidemiologic studies with a decreased risk of AD and with enhanced cognitive function. It has both antioxidant and anti-inflammatory effects and enhances the growth of select neurons that release acetylcholine. Researchers hope that three current estrogen and AD studies may be able to determine whether estrogen actually affects development or progression of AD. The first is a small ADCS study of estrogen replacement therapy (ERT) in post-menopausal women who have had a hysterectomy. Results of this study, which evaluated the effects of ERT on cognitive decline in AD, are now being analyzed. The second study, called the Women’s Health Initiative Memory Study, is a component added to the NIH’s Women’s Health Initiative. This component, which is being supported by Wyeth-Ayerst Laboratories, will determine whether hormone replacement therapy decreases the incidence of cognitive decline and dementia. The third study, which is in the patient recruitment phase, is a multi-site, NIA-supported clinical trial to determine whether the use of estrogen in women without AD but with a family history of the disease may prevent the development of AD. Scientists at Columbia University are coordinating this study.
Estrogen replacement therapy is limited to women because of its potential feminizing effects in men. In women, compliance is limited by side effects, including increased risk of cancer. Researchers are developing synthetic compounds, such as those called selective estrogen receptor modulators (SERMS), that mimic the positive effects of estrogen on various organ systems, including the brain, without having the negative side effects of estrogen itself. The first SERM to be approved by the Food and Drug Administration (FDA) for replacement therapy is raloxifene. A recently awarded NIA grant has added analysis of age-related cognitive decline and onset of dementia onto an ongoing Eli Lilly and Company-supported study that is testing the effects of raloxifene on osteoporosis.
Over-production of free radicals, produced in normal levels during metabolism, can result in oxidative damage to cells. Researchers hypothesize that free radicals may play a role in the Alzheimer’s disease process, and they are studying agents that inhibit and protect against oxidative damage. One of the most important antioxidants is vitamin E (alpha-tocopherol), which was shown in a recent study to delay by about 7 months several important dementia milestones, such as patients’ institutionalization or progression to severe dementia (Sano et al., 1997). Many Alzheimer’s patients are currently taking vitamin E, and a new NIA-supported study–the Memory Impairment Study–will examine this agent further to see if it can prevent patients with mild cognitive impairment from developing AD (see the accompanying box for a description of this trial). Another potentially promising compound is ginkgo biloba, an extract derived from the leaves of the ginkgo tree. It appears to have antioxidant properties as well as anti-inflammatory and anticoagulant properties, and a recent meta-analysis of previously published clinical trials suggested a slight positive effect on AD symptoms (Oken et al., 1998). The NIH’s National Center for Complementary and Alternative Medicine is supporting a new clinical trial of this compound to determine whether it can delay or prevent dementia in older individuals.
Nerve Growth Factor (NGF) and Other Neurotrophic Factors
NGF is the best known of a class of compounds known as neurotrophic factors and has been well studied in animal models for its regenerative properties. NIA is currently supporting a clinical trial of AIT-082, a promising neurotrophic factor (see sidebar on p. 43 for more on AIT-082)
Novartis Pharmaceuticals, a company based in Switzerland with U.S. headquarters in New Jersey, is sponsoring a clinical trial to compare the length of time of progression from MCI to a clinical diagnosis of AD in participants taking a placebo or an experimental cholinesterase inhibitor called rivastigmine. This drug is under review with the FDA as a treatment for AD. Participants in the 3-year study will be assessed every 3 months for any adverse reactions to the drug as well as for vital signs, ability to carry out activities of daily living, and signs that they may have converted from MCI to dementia.
National Institutes of Health
National Institute on Aging
1999 PROGRESS REPORT ON ALZHEIMER’S DISEASE