This randomized, double-blind, placebo-controlled, multicenter study compared vitamin E; donepezil, an Alzheimer's treatment drug; and placebo for delay or prevention of progression to Alzheimer's disease in mild cognitive impairment patients. The study's results will be presented at the 9th International Conference on Alzheimer's Disease and Related Disorders in Philadelphia on Sunday, July 18. The Alzheimer's Association described the trial as "among the most anticipated studies" to be presented at the conference.
"This is the first study to demonstrate any positive treatment effect on mild cognitive impairment with respect to progression to Alzheimer's disease," says Ronald Petersen, M.D., Ph.D., Mayo Clinic neurologist and lead investigator of the trial. "We are optimistic because this means we have begun to make progress toward delaying the development of Alzheimer's disease and the cognitive decline that accompanies it."
The study investigators report that vitamin E did not have an effect on slowing the progression to Alzheimer's disease. However, over the first half, or 18 months, of the three-year trial, mild cognitive impairment patients treated with donepezil had a reduced risk of progressing to Alzheimer's disease compared to patients who took placebo; the average delay in disease progression was about six months in those subjects who progressed to Alzheimer's disease. Although the patients treated with donepezil initially progressed to Alzheimer's disease at a slower rate than patients treated with vitamin E or placebo, this risk-reduction effect was short term. By the end of the study, the risk of progression to Alzheimer's disease was the same among all three treatment groups.
"Donepezil appeared to exert its effect during the first half of the study," says Dr. Petersen. "There were a lot of complicating factors, however, and there was no overall risk reduction effect of donepezil by the end of the study. It looks like donepezil had a time-limited, modest effect."
The investigators do not know exactly why donepezil's effect dropped off over time. Theories are that the drug's effect wore off after 18 months, or that the drug exerts a modest effect and then the disease process outweighs the chemical effect of the drug, indicates Dr. Petersen.
Previous studies show that without treatment, about 10 to 15 percent of individuals with mild cognitive impairment progress to Alzheimer's disease each year. Not every patient with mild cognitive impairment will progress to Alzheimer's disease, however.
During the three-year study, the trial participants developed Alzheimer's disease at a rate of 13 percent per year. Among those who progressed to Alzheimer's disease, patients treated with donepezil averaged 661 days until diagnosed with Alzheimer's disease, while those treated with vitamin E averaged 540 days until Alzheimer's diagnosis and those treated with placebo averaged 484 days to Alzheimer's disease.
Due to the complexity of the study's results, the investigators point out that more analysis will be critical to assess the practical implications of the new information and make recommendations for clinical practice.
This study involved 769 participants at 69 medical centers in the United States and Canada. All participants met established criteria for mild cognitive impairment and were randomized to receive vitamin E, donepezil or placebo treatment. Patients who received donepezil were given 5 mg per day for the initial six weeks and then 10 mg till the study's end, and those treated with vitamin E were given 1000 IU per day for the first six weeks and then 2000 IU per day until the study's end. The other participants were given an inactive pill, or placebo. The investigators designed the study to compare the rate of progression from mild cognitive impairment to Alzheimer's disease in each participant group.
The FDA has not approved any treatments for mild cognitive impairment. Vitamin E and donepezil were selected for testing because vitamin E has been shown to delay disease progression in Alzheimer's disease patients and donepezil relieves symptoms of Alzheimer's disease, according to Brad Boeve, M.D., also a Mayo Clinic neurologist and a co-investigator of the trial.
According to the investigators, patients who have mild cognitive impairment have memory impairment that is out of proportion to that expected for their age, yet they do not meet commonly accepted criteria for Alzheimer's disease or other types of dementia. These patients are in a transitional state between early aging and Alzheimer's disease. They can think and reason well, but recent memory is deficient for their age. Researchers have also found that those who have mild cognitive impairment show brain volume loss in the hippocampus, the area of the brain that controls the sorting, storage and recall of information. The condition can be diagnosed on the basis of five criteria:
- Memory complaints
- Abnormal memory for age
- Ability to carry out normal activities of daily living
- Normal general cognitive function
- Lack of dementia
The National Institute on Aging funded this study, with additional support from Pfizer, Eisai and DSM Nutritional Products.
Friday, July 16, 2004
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