The Alzheimer’s Association estimates that 4.5 million Americans have Alzheimer’s disease. Since 1980, the prevalence of Alzheimer’s disease has more than doubled. And by 2050, the number of Americans suffering from Alzheimer’s disease is estimated to grow aggressively—to 11.3 to 16 million.

Scientists have so far been unable to uncover the causes of Alzheimer’s disease, nor have they been able to develop a cure. However, they have discovered some of the pathologic features that accompany the disease. Specifically, nerve cells in brain that produce acetylcholine die off. Acetylcholine is a chemical in the brain important for memory and cognition.

This discovery led scientists to speculate that raising acetylcholine levels in the brain may help alleviate some of the symptoms seen with Alzheimer’s disease. Cholinesterase inhibitors block the enzyme that breaks down acetylcholine, which in turn leads to higher acetylcholine levels.

Randomized clinical trials have found that cholinesterase inhibitors do, in fact, produce small cognitive improvements in patients with mild to moderate Alzheimer’s disease over 3 to 12 months. However, these studies have not conclusively demonstrated their long-term effectiveness or their ability to significantly improve behavior and functional capacity. A study, known as AD2000, published in the June 26, 2004 issue of The Lancet looked at whether the popular cholinesterase inhibitor donepezil (Aricept) could produce significant improvements in a wide range of behavioral, functional and emotional problems affecting Alzheimer’s patients. And, if donepezil was beneficial, for how long were these benefits sustained?

About the study

Over a three-year period, the study enrolled patients who were referred to memory clinics with a diagnosis of Alzheimer’s disease and were not already taking a cholinesterase inhibitor. After a 12-week pre-treatment period, 486 patients were randomized to receive 5 mg/day donepezil, 10 mg of donepezil, or placebo.

The two primary endpoints were:

  • How long it took subjects to be institutionalized in a nursing home
  • How rapidly subjects became disabled

Secondary endpoints included functional ability, behavioral and psychological changes , cognition, psychological well-being of the primary caregiver, and death from Alzheimer’s disease.

The findings

The groups taking donepezil showed minor improvements in cognitive and functional abilities, which persisted over two years. These findings are similar to the findings of previous clinical trials.

For the primary outcome measures—institutionalization and progression of disability—there was no significant difference between the patients receiving donepezil and placebo. In addition, there were no significant differences between donepezil and placebo for behavioral and psychological changes, psychological well-being of the primary caregiver, and death from Alzheimer’s disease. Also, there was not a significant difference between the 5 mg and the 10 mg donepezil dosage.

How does this affect you?

The study’s authors conclude that donepezil provides disappointingly little benefit and is not cost effective. An accompanying commentary even called into question certain pharmaceutical industry advertisements: “Claims that donepezil stabilizes cognitive decline, or delays nursing-home placement by 2–5 years now can be seen as implausible in the light of AD2000.”

If you have a loved one with Alzheimer’s disease taking donepezil, do these results mean that he or she should stop taking it ? No. Although this trial is one of the largest trials of cholinesterase inhibitors, prescribing behaviors are rarely changed based on the results of one published study. Instead, talk with the physician about donepezil. If you believe it is providing benefit, the physician may agree and want to continue prescribing it. This would certainly be reasonable given the lack of effective alternatives.

The results of this study do bring to light an important question—are the valuable and scare resources being used on cholinesterase inhibitors like donepezil really worth it? Perhaps not.