facts for health--alzheimer's--other medication therapy

In disorders where no effective treatment has been available, the search for remedies is understandably broad. For reasons that are not understood, some individuals may have temporary slowing of Alzheimer's disease (AD) while taking an unproven remedy. Thankful for any improvement or slowing of progression of an otherwise untreatable disease, patients, family members and practitioners involved in those positive experiences are understandably appreciative and may believe the unproven treatment is effective for the disease. This process of belief and faith in a remedy is understandable but not scientific. We are all free to believe whatever we wish and to act on our beliefs. Knowledge requires a higher standard of proof. The scientific method requires careful experiments that control for beliefs that may bias results and mislead us to incorrect conclusions.

The highest standard of evaluation of new treatments is the randomized, placebo-controlled, double-blind trial. Individuals with a well-defined disorder are assigned (randomly) by chance to receive either the new and presumably helpful treatment or a placebo, an inert substance packaged in exactly the same form as the new treatment under study. To control bias, both patients and doctors are blinded (hence double-blind) to which treatment patients are receiving. All five medications with FDA approval for AD were successful in these randomized, placebo-controlled, double-blind trials.

An important ethical rationale for placebo-control is that individuals receiving a new and untested treatment deserve a chance of not being harmed by that new treatment, should it prove to have dangerous side effects. The cholinesterase inhibitors are a case in point. Tacrine, while effective in treating Alzheimer's disease, can harm the liver and this toxicity required careful monitoring of liver function in patients receiving tacrine. When donepezil, which does not cause significant liver problems, became available, use of tacrine declined abruptly. It would now be difficult to advocate tacrine use as a treatment for Alzheimer's disease when other FDA-approved medications are as effective and have not been associated with liver injury. With this long preamble, what is known about non-FDA-approved medications advocated as treatment for Alzheimer's disease?

Neurotrophic agents
Certain proteins called neurotrophic factors are involved in the growth and survival of neurons, and may help repair damaged neurons. These neurotrophic factors are proteins consisting of polypeptides (poly = many and peptides = amino acids) and when used as medications they are called neurotrophic agents. Although no one has demonstrated a loss of neurotrophic factors in Alzheimer's disease (AD), it is logical that neurotrophic agents might protect neurons from the processes that damage them in AD. Several neurotrophic agents are being studied for treatment of AD.

Nerve growth factor (NGF) increases the function of neurons associated with acetylcholine in older animals and might help AD patients who have lost many cholinergic cells. Oral and even intravenous NGF does not reach the brain because of a blood-brain barrier that protects the central nervous system from many things that could injure it. A complicated process to deliver NGF to the brain regions that need it most involves genetically modifying a person's own skin cells to produce NGF. These modified cells are then implanted in the brain. Obviously, this procedure is costly and involves more than minimal risks, so unless proven safe and effective, it will not be made available. Other agents are in much earlier stages of clinical testing.

Nootropic agents
This class of drugs, also referred to as cognitive enhancers or "smart drugs", includes piracetam (Nootropil), pramiracetam (NeuPramir), aniracetam (Ampamet), oxiracetam (Neuromet), and cerebrolysin. They have complex effects in the brain including enhancing protein synthesis, modulating neurotransmitters such as acetylcholine and dopamine, and modifying membrane properties. None are FDA-approved for use in the United States, but some are marketed in other countries for treating dementia and for other indications. Several are currently being investigated in this country as possible treatments for Alzheimer's disease.

Ampakines are a related class of investigational drugs that appear to regulate excessive stimulation of neurons by interacting with a receptor known as the AMPA-glutamate receptor.

Anti-inflammatory agents
Since brain inflammation occurs in those with Alzheimer's disease (AD), anti-inflammatory agents might be helpful and are being studied. Epidemiological (population-based) studies have shown that those taking the class of medications known as nonsteroidal anti-inflammatory drugs or NSAIDs (such as ibuprofen [Advil, Motrin and others], naproxen [Aleve and Naprosyn] and indomethacin [Indocin] but not acetaminophen [Tylenol]) for pain or inflammation were less likely to develop AD. The benefit was clear for groups that used these NSAIDS for at least two years while benefit for shorter periods was negligible. These studies suggest that NSAID use may also slow the rate of disease progression in those with AD. Studies are underway to see if some drugs work better than others.

Specific clinical studies of NSAIDs had high drop-out rates, often because of stomach upset or even ulcers. A newer class of NSAIDs called COX-2 inhibitors (e.g., celecoxib [Celebrex] and rofecoxib [Vioxx], no longer available) cause less upset stomach than the older NSAIDs, but the first placebo-controlled studies for AD did not find them more effective than placebo. Even these newer NSAIDs have side effects, so until they are shown to be effective, their use will be considered experimental.

What about a more potent anti-inflammatory agent such as the steroid prednisone as a proof of the anti-inflammatory concept? Low dose prednisone was ineffective in a well-done study of 138 patients with AD. While higher doses might be effective, the dangerous side effects of high dose prednisone would not be acceptable.

The experience with anti-inflammatory agents shows again how easy it is to produce theories and how difficult it is to prove that theories translate into useful treatments. Anti-inflammatory drugs could still be useful for prevention or delay of onset of AD, even if they do not benefit patients with established disease.

Statins
Statins (atorvastatin [Lipitor], fluvastatin [Lescol], lovastatin [Mevacor], pravastatin [Pravachol], rosuvastatin [Crestor], and simvastatin [Zocor]) are drugs that are effective in decreasing blood levels of low density lipoprotein (LDL). High levels of LDL are associated with increased risk of coronary heart disease (CHD). Risk of both CHD and AD increase with age and some epidemiological studies noted decreased risk of AD, as well as CHD, in people taking statin medications. Several mechanisms have been postulated to explain this beneficial effect. Some evidence supporting these theories has been found in animal models of AD and in small clinical trials. However, not all data on statins are positive. In one study, female (but not male) mice treated with lovastatin had increased amounts of beta-amyloid and plaques, raising the concern that statins might be a risk factor for AD, rather than reducing risk. Results from animal models of AD may or may not be applicable to humans. The use of statins to delay the onset of AD must be carefully evaluated in placebo-controlled studies done over several years. The ability of statins to treat AD once present can be answered in shorter studies lasting several months. Both kinds of studies are underway. Until results of studies designed to answer these specific questions are available, the use of statins in prevention or treatment of AD is experimental.

Estrogen
As women are more likely than men to develop Alzheimer's disease, one logical theory was that reduced estrogen after menopause might be associated with the onset and progression of Alzheimer's disease. Consequently, estrogen has been prescribed for some women suffering Alzheimer's disease. Unfortunately, randomized placebo-controlled, double-blind studies of estrogen treatment of Alzheimer's disease have not found estrogen in standard doses to improve symptoms of Alzheimer's disease in postmenopausal women. Furthermore, a May 2003 report of a large study of estrogen plus progestin in postmenopausal women found an increased occurrence of probable dementia for women starting on the estrogen-progesterone combination at age 65 or older. Researchers concluded that the risks of adverse effects from estrogen plus progestin treatment (e.g., heart disease or stroke as well as probable dementia) outweigh the benefits of that combination treatment. Some women may still be prescibed estrogen or an estrogen-progesterone combination to help manage post-menopausal symptoms such as hot flashes and sweating.

Selegiline (Eldepryl)
Selegiline is a monoamine oxidase inhibitor (MAOI) that is used to treat Parkinson's disease and in the form of a transdermal skin patch to treat depression. In a double-blind study finding benefit for vitamin E in treating Alzheimer's disease, selegiline was also effective when used alone. Interestingly, the combination of these agents was not more effective than either one alone. Selegiline is only available by prescription; it has side effects and a potential for dangerous interactions with certain other drugs. Vitamin E is discussed under vitamins, nutritional and herbal therapy. Other MAOIs are also understudy for AD.

Lithium and valproate
Basic science research, mainly in cell cultures, has suggested potential for both lithium (Lithobid and generics) and valproate (Depakote, Depakene and others) as treatments for Alzheimer's disease. While these drugs are better known as treatments for other disorders, such as bipolar (manic-depressive) disorder, they also have neuroprotective properties and may actively stimulate the growth of nerve cells. Both have been shown to affect tau proteins in ways that may reduce the formation of neurofibrillary tangles. While of great interest, these findings are quite preliminary and, at present, neither drug could be recommended as a treatment for AD.

Finding clinical trials of new medications
Clinical trials refer to research studies looking at the safety and effectiveness of medications or other treatments. These studies take place at research facilities, hospitals and doctors' offices. Currently there are many clinical trials in progress evaluating new medications for the treatment of Alzheimer's disease and other dementias. The following two web sites can direct you to many of these clinical trials:

This clinical trials database is a joint project of the U.S. Food and Drug Administration (FDA) and the National Institute on Aging (NIA). Clinical drug trials on AD and other dementias currently in progress and known to the public throughout the U.S. can be found on this site. You can search by city or state to find studies. Also, you can search by specific medication to find out where studies on a particular medication are being conducted. Additionally, the process of participating in a study is described and answers to frequently asked questions are given.

The Alzheimer's Association provides information on the latest research projects and developments. Information on many current clinical drug trials is given, as well as information on general research, such as on the genetics of AD. In addition to locating research sites in the U.S., the Association provides fact sheets summarizing specific treatments under investigation. There are also links to other research related web sites.