First Cholinesterase Inhibitor for Mild Cognitive Impairment

Larry Schuster

April 07, 2003

April 7, 2003 (Honolulu) — The results of the first study of a cholinesterase inhibitor for the treatment of mild cognitive impairment (MCI) showed a "very modest" improvement in cognitive function for those treated with donepezil (Aricept).

The randomized, placebo-controlled, double-blind six-month study of donepezil in 269 patients showed improvement on memory performance tests and in patient self-assessment compared with placebo, said Steven Salloway, MD, director of the neurology and memory disorders program of Butler Hospital in Providence, Rhode Island. Dr. Salloway presented his study results here at the American Academy of Neurology 55th annual meeting.

In the study, patients improved on the Alzheimer's Disease Assessment Scale (ADAS)-cognitive subscale by three points compared with a one-point improvement by the placebo group. On patient self-assessment, about 10% of the treatment group said their memory had improved while 14% of those receiving placebo said their memory had worsened.

Overall, 61.4% of the donepezil group reported they felt better compared with 50% of the placebo group.

On the ADAS-cognitive subscale Immediate Word Recall test, the donepezil group performed significantly better than the placebo group (P = .034), and "there was a tendency toward significance on the Delayed Recall test (P = .053)," Dr. Salloway and his colleagues wrote in their study abstract.

In addition, scores in favor of donepezil reached significance on the NYU Paragraph Immediate and Delayed Recall tests and the Digit Span Backwards test (P < .05). Some improvement, which approached significance for donepezil, was seen on the Symbol Digit Modalities test (P = .059).

There was no significant difference between donepezil and placebo on the improvement in scores on the Clinicians Global Impression of Change-MCI test.

The patients involved in the study were diagnosed with the amnestic type of MCI, in which impaired memory is the dominant feature, and the condition is considered a precursor to Alzheimer's disease. The study excluded patients diagnosed with Alzheimer's or dementia. The average age of the patient was 72 years.

Patients in the treatment arm of the study received 10 mg of donepezil daily for six months. Gastrointestinal adverse effects were the most common reason for patients to drop out.

"These results provide preliminary support for the initiation of donepezil therapy in MCI but suggest that further research is needed," the researchers concluded in the abstract.


In an interview with Medscape, Dr. Salloway said this is about improving public health for an increasing proportion of the population, noting that about 10% to 15% of patients diagnosed with MCI convert to Alzheimer's disease each year. "We need to figure out how to keep them healthy," he said.

The study also confirmed the utility of the ADAS-cognitive subscale as a sensitive measurement tool for use in documenting change in cognitive function in patients with MCI, which is critical for determining the value of any intervention. It is currently used for patients with mild and moderate Alzheimer's disease.

The improvement was characterized as "fairly modest" by Bill Thies, MD, vice president of medical and scientific affairs at the Alzheimer's Association in Chicago, Illinois. Still, he said, "it doesn't put to rest the question of whether everybody with MCI should be treated. It's a good first step in clarifying treatment options."

In interviews both Thies and Neil Buckholtz, PhD, chief of the dementias of aging division of the National Institute on Aging in Bethesda, Maryland, said to their knowledge this was the first study presenting results of a cholinesterase inhibitor for MCI.

They both said this field has grown rapidly in the five years or so sincethe concept of MCI was first proposed by Ronald Petersen, from the Mayo Clinic, Rochester, Minnesota.

A key reason is that MCI patients are thought to be in a transition state that progresses to Alzheimer's disease, making it a very rich population for determining outcomes of interventions. Dr. Thies said that according to Dr. Petersen, about 4,000 MCI patients currently are in intervention, magnetic resonance imaging, or other studies.

One major study funded by the National Institute on Aging, and led by Dr. Peterson, is a three-year trial with 769 patients at 60 U.S. sites that is comparing donepezil, vitamin E, and placebo, Dr. Buckholtz told Medscape. Researchers hope the trial will determine if either of the two therapies will delay conversion from MCI to Alzheimer's disease. The study will be complete in January 2004.

Meanwhile, Dr. Buckholtz said, some physicians have already begun to treat MCI. "Now, if this is positive and other studies are positive, if this is confirmed, clearly that would open the door to treat this group of people."

AAN 55th Annual Meeting: Abstract S48.001. Presented April 3, 2003.

The study was supported by Eisai Inc. and Pfizer Inc.

Reviewed by Gary D. Vogin, MD