Medications:

Most drugs used to treat Alzheimer's, and those under investigation, are aimed at slowing progression. There are no cures to date. In addition, the improvements from some of these drugs may be so modest that patients and their families may not notice benefit.

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 (generally used to treat mild-to-moderate Alzheimer's; donepezil is also approved for treatment of severe dementia )
• N-methyl-D-aspartate (NMDA) receptor antagonists (used to treat moderate-to-severe Alzheimer's)

All of the drugs currently approved for treatment of Alzheimer's disease are expensive. While there are generally no serious risks associated with these medications, these drugs can have a number of bothersome side effects, including indigestion, nausea, vomiting, diarrhea, loss of appetite, muscle cramps, and fatigue.

Patients and caregivers should ask their doctors the following questions about when and if to use these drugs:

• Will there be a noticeable change in behavior or function of the patient? The published studies that enabled approval of these drugs for treatment of Alzheimer's disease demonstrated modest benefit when evaluating patients using cognitive and functional scales. While these scales are important for consistency of recording and performing studies, the benefit demonstrated in these studies does not necessarily translate into any significant clinical benefit in how patients function in their daily lives. There is, in fact, no evidence that use of these medications extends the time before a patient requires care in an institutional setting, such as a nursing home.
• Is it better to use these drugs early in the course of Alzheimer's disease? Treating patients with mild cognitive impairment (persistent mild memory loss of recent events but no diagnosis of Alzheimer's disease) does not seem to prevent patients from developing Alzheimer's 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 using these medicines with 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 the only Alzheimer's drug approved for all stages of dementia, from mild to severe. It is taken once a day and has only modest benefits at best.
• Rivastigmine. Rivastigmine (Exelon) targets two enzymes: Acetylcholinesterase and butyrylcholinesterase. It is taken as a pill twice a day. (The FDA approved a skin patch version of the drug in 2007.) Rivastigmine may cause significantly more side effects than donepezil, including nausea, vomiting, and headache.
• Galantamine (Razadyne). Galantamine protects the cholinergic system and acts on nicotine receptors, which are also depleted during Alzheimer's.
• 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.

Comparative studies have reported little differences in effectiveness among these drugs. All drugs have gastrointestinal side effects, including nausea. Of note, some of the drugs often used in elderly Alzheimer's disease patients are known as anticholinergics and may offset the effects of the Alzheimer's disease pro-cholinergic drugs. Such drugs include antihistamines, antipsychotic drugs, and some anti-incontinence drugs.

In any case, the benefits of these drugs are far from dramatic and may often not be noticeable in everyday life. In fact, many doctors 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.

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

Memantine (Namenda) is approved for treatment of moderate-to-severe Alzheimerâ ' s disease. (Most cholinesterase inhibitors are 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.

Memantine is prescribed either alone or in combination with donepezil. Studies indicate that memantine may help modestly improve cognitive function and delay the progression of Alzheimerâ ' s disease for up to 1 year. Side effects are generally mild but may include dizziness, drowsiness, or fainting.

Investigational Drugs

A number of drugs are being investigated for treatment and prevention of Alzheimer's disease. Intense areas of research are focusing on drugs that prevent or reduce beta amyloid build-up.

Drugs in late-stage clinical trials include:

• Bapineuzumab is an anti-beta amyloid monoclonal antibody drug being studied as a treatment for patients with mild-to-moderate Alzheimerâ ' s disease. It is currently in Phase III trials.
• Dimebon is an antihistamine that may help improve the course of the disease. It is being studied in combination with donepezil in patients with mild-to-moderate Alzheimerâ ' s disease. The drug is currently in Phase III trials.
• PBT2 is a drug designed to stop the formation of beta-amyloid plaques. It is being studied in patients with early-stage Alzheimerâ ' s disease and is currently in Phase II trials.

Treating Symptoms Associated with Alzheimer's

Depression. 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.

Apathy. Depression is often confused with apathy. An apathetic patient lacks emotions, motivation, interest, and enthusiasm while a depressed patient is generally very sad, tearful, and hopeless. Apathy may respond to stimulants, such as methylphenidate (Ritalin), rather than antidepressants.

Psychosis. Antipsychotic drugs are used to treat verbally or physically aggressive behavior and hallucinations. Because older antipsychotic drugs, such as haloperidol (Haldol), have severe side effects, most doctors now prescribe newer atypical antipsychotics, such as risperidone (Risperdal) or olanzapine (Zyprexa).

However, these newer antipsychotic drugs still can cause serious side effects, including confusion, sleepiness, and Parkinsonian-like symptoms. In addition, studies indicate that their safety risks may outweigh any possible benefits. Studies indicate that both atypical and older antipsychotics produce a slightly increased rate of death in patients with Alzheimerâ ' s disease or dementia and that atypical antipsychotics work no better than placebo in controlling psychosis, aggression, and agitation in patients with Alzheimerâ ' s.

Most doctors recommend delaying prescribing antipsychotic medication unless absolutely necessary. They recommend first trying behavioral treatments and controlling changes in the patientâ ' s environment and routine. Anti-seizure drugs, such as carbamazepine (Tegretol) or valproate (Depakote), can also sometimes treat agitation and other psychotic symptoms.

Disturbed Sleep. Patients with Alzheimer's disease commonly experience disturbances in their sleep/wake cycles. Moderately short-acting sleeping drugs, 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. Sleep hygiene methods (regular times for meal and bed, exercise, avoiding caffeine) may also be helpful. [For more information, see In-Depth Report #27: Insomnia.]