Alzheimer's Disease

Description

Medications

Most drugs currently being used or that are under investigation to treat Alzheimer's are aimed at slowing progression. To date, none are cures. In fact, the improvements from some of these drugs may be so modest that even the patients and their families are not aware of them. Even in these cases, however, the drugs may delay the need for admission to nursing homes. Since nearly all the studies are conducted on Alzheimers patients in mild to moderate stages of the disease, it is important to seek out clinical drug trials as soon as Alzheimers disease is diagnosed. Caregivers need to be available to help patients comply with any experimental therapies.

There are currently two drug classes that have been approved by the U.S. Food and Drug Administration (FDA) to treat the cognitive symptoms of Alzheimer's disease: cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Cholinesterase inhibitors are generally used to treat mild-to-moderate Alzheimer's. In October 2003, the FDA approved memantine (Namenda)-- an NDMA receptor antagonist-- the first drug of this class to be used for treating Alzheimer's and, more importantly, the first drug approved for the treatment of the moderate-to-severe stage of this disease.

Cholinesterase Inhibitors

Cholinesterase inhibitors are designed to protect the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's. These drugs work by preventing the breakdown of the brain chemical acetylcholine and are recommended for the treatment of mild-to-moderate Alzheimer's. The first cholinesterase inhibitor, tacrine, was approved in 1993 but is rarely prescribed today due to safety concerns. The three most commonly prescribed cholinesterase inhibitors are donepezil (approved in 1996), rivastigmine (approved in 2000), and galantamine (approved in 2001). Cholinesterase inhibitors may increase the risk for gastrointestinal bleeding or ulcers, and patients should be cautious about concurrent use of NSAIDs (which can also cause gastric irritation). Common side effects of cholinesterase inhibitors, especially when taken at higher doses, may include nausea, vomiting, diarrhea, and upset stomach.

• Donepezil. Donepezil (Aricept) is taken once a day and has only modest benefits but it does help slow loss of function and reduce caregiver burden. It works equally in patients with or without ApoE4. In a study published in 2004, donepezil appeared to help improve memory and daily living ability in patients with moderate-to-severe Alzheimer's when taken in combination with memantine.
• Rivastigmine. Rivastigmine (Exelon) targets two enzymes (the major one, acetylcholinesterase, and butyrylcholinesterase). It is taken twice a day. This agent may be particularly beneficial for patients with rapidly progressing disease. This drug has slowed or slightly improved disease status even in patients with advanced disease. (Rivastigmine may cause significantly more side effects than donepezil, including nausea, vomiting, and headache.) As with all anticholinergics, the drug is not a cure.
• Galantamine (Reminyl). Galantamine not only protects the cholinergic system but also acts on nicotine receptors, which are also depleted during Alzheimer's. Studies report that it improves daily living, behavior, and mental functioning, including in patients with mild to advanced-moderate Alzheimer's disease and those with a mix of Alzheimer's disease and vascular dementia. Some studies have suggested that the effects of galantamine may persist for a year or longer and even strengthen over time.
• Tacrine. Tacrine (Cognex) was the first cholinergic protective drug. It needs to be taken four times a day, has only modest benefits, and has no benefits for patients who carry the ApoE4 gene. In high doses, it can also injure the liver. In general, newer cholinergic protective drugs that do not pose as great a risk for the liver are now used for Alzheimer's.

About half of patients with mild to moderate disease show slight improvement. Comparative studies to date have reported little differences in effectiveness among them. All drugs have gastrointestinal side effects, including nausea. Of note, some of the drugs used often used in elderly Alzheimer's disease patients are known as anticholinergics and may offset the effects of the Alzheimer's disease pro-cholinergic agents. Such drugs include antihistamines, antipsychotic drugs, and some anti-incontinence drugs.

In any case, the benefits of these drugs are far from dramatic. In fact, many experts have reservations about developing any additional drugs that affect the cholinergic system, since, at best, they only slow progression and do not appear to affect the basic destructive disease process. When patients go off the drugs the deterioration continues. Some experts suggest that switching from one to another may be helpful for patients who do not respond to one.

N-methyl-D-aspartate (NDMA) Receptor Antagonist

Memantine (Namenda) is the first NDMA receptor antagonist to be approved in the U.S. for the treatment of Alzheimer's disease. Marketed in Europe under the trade names Exira and Axura, memantine was first approved in Germany in 1982 for various neurological conditions, and was approved throughout Europe in 2002 for the treatment of Alzheimer's disease. It received its U.S. approval in October 2003, and has been commercially available since January 2004.

Memantine is the first drug indicated for the treatment of moderate-to-severe Alzheimer's disease (cholinesterase inhibitors are generally used to treat mild-to-moderate stages of the disease). By blocking NDMA receptors, memantine protects against the overstimulation of glutamate, an amino acid that excites nerves and, in excess, is a powerful nerve-cell killer.

In one study of effects on moderate-to-severe Alzheimer's, patients who received memantine showed a small but statistically significant benefit in cognitive function and performance of daily abilities compared with those patients who were given placebo. In another study, published in 2004, memantine was added to the drug regimen of patients with moderate-to-severe Alzheimer's who had taken donepezil for at least six months. In comparison to patients who took only donepezil, patients who received the combination donepezil-memantine therapy showed a greater improvement in measures of cognitive function, activities of daily living, and behavior parameters.

Although cholinesterase inhibitors and memantine are the best available medications for Alzheimer's, their benefits are, unfortunately, quite modest. More effective methods of prevention and treatment are urgently needed.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) as Treatment

There has been considerable controversy over whether NSAIDs may help in the treatment of Alzheimer's disease. As inflammation is involved in the destruction of brain cells, it has been postulated that anti-inflammatory drugs might be able to halt this process and thus slow the progression of the disease. In a rigorous 2003 study, patients with mild-to-moderate Alzheimer's were randomized to receive either the anti-inflammatories naproxen (Aleve) or rofecoxib (Vioxx) or placebo. After 12 months of treatment, patients in the anti-inflammatory groups did not show any difference in cognitive improvement compared to those patients who received placebo.

Results from another large study, published in 2004, also failed to demonstrate improvement in cognitive function for patients with mild-to-moderate Alzheimer's who were treated with rofecoxib. While these results appear to diminish the hope that NSAIDS could provide a treatment alternative for Alzheimer's, research is continuing to investigate their possible use as a preventive measure. As mentioned earlier, patients should be cautious about taking NSAIDs in combination with cholinesterase inhibitors as they may increase the risk of gastrointestinal bleeding.

Nicotine Replacement

Nicotine enhances the actions of the cholinergic system (which is depleted in Alzheimer's disease) and is known to improve concentration and memory in the short term. Some studies have suggested that nicotine may protect nerve cells and help prevent the formation of beta amyloid. One study indicated that nicotine might help protect against Alzheimer's disease in carriers, but not noncarriers, of the ApoE4 gene. Another reported improvement in verbal recall and word retrieval in healthy relatives of Alzheimer's disease patients who wore a low-dose nicotine patch. Research to date, however, has found no strong evidence of improvement in Alzheimer's disease patients with nicotine replacement methods. No one should smoke to prevent or treat Alzheimer's disease.

Alternative Treatments

Ginkgo Biloba. Ginkgo biloba is a common herb that has antioxidant properties and appears to increase blood flow to the brain. The herb is available over the counter, although a 2002 study of healthy people who took over-the-counter ginkgo for six weeks reported no differences in memory or mental function. Studies are reporting that a ginkgo biloba extract, called Egb 761, may slightly improve the memory of patients with mild to moderate Alzheimer's disease. Ginkgo has only minimal side effects. The agent poses a small risk for bleeding, which may be hazardous in combination with other blood-thinning medications, such as warfarin or high-doses of vitamin E. (Although there are no standards in the US by which to regulate it, the website www.naturaldatabase.com compares brands by quality of ingredients.)

Turmeric. Interestingly, studies suggest that curcumin, a compound found in the spice turmeric, has properties that may protect against Alzheimer's disease process.

Melatonin. Melatonin, a natural hormone involved in sleep regulation, is of interest. It is an antioxidant, it may break down beta amyloid, and it is able to pass through blood-brain barrier. Deficiencies have been observed in patients with Alzheimer's disease. A number of studies (but not all) report that melatonin may improve sleep habits in these patients. Some even reported some slower progression in mental impairment.

Other Investigative Agents

A number of other agents are being investigated and show promise in early or late trials. Intense areas of research are focusing on agents that prevent beta amyloid build-up, its toxic effects on nerve cells, or other mechanisms of the disease process. Among them are the following:

• Growth factors that stimulate nerve activity in the brain. Cerebrolysin (Cere) is an example of such drugs and is showing promise in clinical trials in improving mental function and other symptoms, with sustained effects even after the drug has been stopped. Leteprinim potassium (Neotrofin) activates genes that produce nerve-growth factor in the brain. Early human trials are suggesting that it may have positive effects on memory and behavior. Insulin and insulin growth factors may prevent beta amyloid accumulation.
• Antioxidants. Indole-3-propionic acid, or IPA (Oxigon), is a natural agent that may interfere with enzymes that contribute to the Alzheimer's disease process. The cognitive effects of vitamin E are being investigated in a clinical trial of aging persons with Down syndrome.
• Vitamins. The homocysteine-reducing effects of vitamins B6 and B12 are being studied to see if they can delay cognitive decline in Alzheimer's patients.
• Huperzine alpha, another acetylcholinesterase inhibitor, improved mental function, behavior, and mood in Alzheimer's disease patients in one Chinese study. Other research also suggests some benefits.
• Piracetam is a nerve protective agent called a nootropic. It has undergone a number of small studies, with few significant results. More research is needed to determine any benefits.
• Researchers are investigating immunotherapies that include vaccines, which use molecules in beta amyloid as targets for the body's immune system, and antibodies that block proteins called CD40-CD40L, which are involved in amyloid deposition. Trials were halted in 2002 when some patients developed inflammation of the brain. However, researchers are now resuming studies with improved variations of the vaccine.
• Tetracyclines. Antibiotics known as tetracyclines, such as tetracycline itself, doxycycline, and minocycline, have anti-inflammatory properties that are now being investigated in a number of chronic inflammatory conditions (such as periodontal disease). They also may have activity against beta amyloid in the brain.
• Statins. Cholesterol appears to play a role in promoting the accumulation of beta myloid into plaque. Research is focusing on statin drugs as agents that may help prevent or treat Alzheimer's as these drugs lower levels of low-density lipoprotein (LDL; bad cholesterol) and reduce cholesterol production.

Investigative Procedures

Low-flow ventriculoperitoneal shunts are implanted devices that drain cerebrospinal fluid from the brain. The theory is that a low flow clearance will also carry off beta amyloid as well. Early studies show some promise in slowing progression of Alzheimer's disease, although the procedure is invasive. A large trial is under way.

Treating Symptoms Associated with Alzheimer's

Depression. Major depression with dementia that occurs in elderly people may be an early sign of Alzheimer's. In such cases, it precedes Alzheimer's by two years or less. (It is, in fact, sometimes difficult to differentiate major depression from early stage Alzheimer's disease.) Antidepressants known as selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft), may be effective in relieving depression, irritability, and restlessness associated with Alzheimer's in some patients, particularly women with low aggression levels.

Apathy. Depression is often confused with apathy, which according to one study is more common than depression in Alzheimer's patients and responds to stimulants, such as methylphenidate (Ritalin), rather than antidepressants. An apathetic patient lacks emotions, motivation, interest, and enthusiasm while a depressed patient is generally very sad, tearful, and hopeless.

Symptoms of Psychosis (Irritability, Aggression, and Hallucinations). Verbally or physically aggressive behavior, and hallucinations have been traditionally treated with standard antipsychotic drugs, such as haloperidol (Haldol), but they have severe side effects. Newer, so-called atypical antipsychotics, including risperidone (Risperdal) and olanzapine (Zyprexa), appear to significantly decrease symptoms of psychosis and aggression while posing a very low risk for severe side effects. They are now the drugs of choice. Carbamazepine or valproate, anti-seizure drugs, may also be effective for agitation and dementia.

Disturbed Sleep. Alzheimer's patients commonly experience disturbances in their sleep/wake cycles. Moderately short-acting sleeping agents such as temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata) or sedating antidepressants such as trazodone (Desyrel, Molipaxin) may be useful in managing insomnia. Some research suggests that exposure to brighter-than-normal artificial light during the day for patients with normal vision may help reset wake/sleep cycles and prevent nighttime wandering and sleeplessness. Trials on melatonin, a natural hormone that helps trigger sleep at night, are in progress.