ALZHEIMER'S DISEASE

The strategy to sell Alzheimer’s disease (AD) drugs is based on hope, fear, and guilt: hope that one of these drugs might “work,” fear that if one of these drugs is not started quickly, all will be lost; and guilt if family members have not made the decision to “fight” the disease with expensive, sometimes dangerous, drugs.

The strategy is working. According to a front-page article in the April 7, 2004, New York Times that questions the actual benefits of these drugs, “A million Americans take them, at an overall cost of $1.2 billion a year.” A professor at Johns Hopkins University School of Medicine who is an expert in Alzheimer’s disease was quoted in the article. He placed the value of the current crop of Alzheimer’s drugs in perspective when he said, “You can name 11 fruits in a minute instead of 10. Is that worth 120 bucks a month?”[1]

Recent reviews by the U.S. Preventive Services Task Force and the American Academy of Neurology are appropriately skeptical of the use of these drugs. The Alzheimer’s Disease Assessment Scale—Cognitive Subscale (ADAS-Cog) is the main test used to measure cognitive improvement in patients with Alzheimer’s disease and it consists of a 70-point measure of cognitive functioning. For the four cholinesterase inhibitor drugs discussed in this chapter, the average improvement between patients being given one of the drugs and those patients randomized to get a placebo was 1.36 to 3.4 points out of a total of 70 points.[2] This statistically significant but clinically questionable result is in accord with the above-mentioned improvement in remembering fruits. The task force also thought that the effect of the drugs on physical function, assessed by activities of daily living, is inconclusive.

The American Academy of Neurology concluded that these drugs (cholinesterase inhibitors) “should be considered in patients with mild to moderate AD although studies suggest a small average degree of benefit.” They further pointed out, referring to all drugs, not just the cholinesterase inhibitors, that “there is no standard approach to determining the effect size of antidementia agents.”[3] Some careful clinicians who use these drugs will give them a two-month trial and will discontinue the drugs if no improvement is seen.

Alzheimer’s disease is a progressive deterioration of the brain that significantly impairs cognition and the ability to perform daily activities. It is the most common cause of dementia among the elderly, accounting for 50 to 60% of all dementia cases.[4],[5] Currently, 4.5 million people in the United States suffer with the disease, and by year 2050, an estimated 11.3 million to 16 million Americans will have AD.[6]

In general, there are two forms of Alzheimer’s disease: familial and sporadic.[4] Familial Alzheimer’s disease, known also as early-onset, is a rare form of this disorder occurring before the age of 60. The sporadic form, known also as late-onset Alzheimer’s disease, is the most common form of the disorder and occurs after 60 years of age.

It is not understood what causes Alzheimer’s disease. However, there are several factors that play a role in its development, including advanced age, family history, and genetics.[5],[7] The greatest risk factor for Alzheimer’s disease is age. Over 10% of individuals 65 years and older have Alzheimer’s disease and nearly half of those over 85 years of age are affected with the disease as well.[6] Family history is another factor that increases the risk up to two to three times.[4]

Research has identified a genetic link for Alzheimer’s disease. Three genes were identified to be associated with the development of early-onset Alzheimer’s: presenilin 1, presenilin 2, and amyloid precursor protein.[7] Another gene coding for apolipoprotein E-4 (ApoE-4), which is involved in cholesterol transport, may also be a factor in the development of late-onset Alzheimer’s.[7],[8] An estimated 35 to 60% of patients with late-onset Alzheimer’s possess at least one copy of the ApoE-4 gene.[4]

With the gradual loss of brain cells, common symptoms associated with Alzheimer’s disease include memory loss, difficulty performing familiar tasks, language problems, disorientation to time and place, problems with abstract thinking, misplacing things, changes in mood or behavior, changes in personality, and loss of initiative.[4]

A definitive diagnosis of Alzheimer’s disease is determined only by examination of brain tissue upon autopsy.[5] Therefore, a possible or probable diagnosis of Alzheimer’s disease may be determined through a complete medical history, physical assessment, neurologic and mental evaluation, laboratory tests, and radiologic findings.[7] No one test that can diagnose Alzheimer’s disease exists at this time.[6] The disease progression for Alzheimer’s varies from 3 to 20 years after the onset with an average life span of 8 to 10 years after the diagnosis.[9]

There are no medical treatments to cure or stop the progression of Alzheimer’s disease. Current drug therapy includes four drugs known as acetylcholinesterase inhibitors. These are donepezil (ARICEPT), rivastigmine (EXELON), galantamine (REMINYL), and tacrine (COGNEX). These drugs increase the level of acetylcholine, a brain transmitter, with the assumption that this might improve Alzheimer’s-associated dementia.

The newest drug for treating Alzheimer’s, memantine (NAMENDA), was approved by the FDA in 2003 for the treatment of moderate to severe dementia of the Alzheimer’s type. It works in a different way from the acetylcholinesterase inhibitors by blocking a receptor called the N-methyl-D-aspartate (NMDA) receptor. Memantine is not a new drug; it has been used in Europe since the 1980s. Although approved for moderate to severe dementia, without comparative studies it is unclear whether memantine is any better at treating dementia than previously approved Alzheimer's drugs, which have shown only questionable clinical benefits.[10] Furthermore, the data for memantine’s efficacy on severe AD is weak.[10]

Although these drugs show statistically significant improvements on certain memory and thinking tests, it is unclear how a few extra points on a mental exam relates to an Alzheimer’s disease patient’s daily functioning in the real world. These drugs do not change the underlying course of the disease, but rather they have a modest, but clinically questionable, effect on cognition and global impression scales for a minority of Alzheimer’s disease patients. Moreover, these drugs carry significant safety risks. For these reasons, all currently approved treatments for Alzheimer's are listed as Do Not Use.