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DONEPEZIL AND VITAMIN E FAILED TO PREVENT ALZHEIMER DISEASE IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT

MIAMI BEACH—Is it possible to reduce the risk of developing Alzheimer disease (AD) in people with mild cognitive impairment (MCI)? A new study examined two therapies – vitamin E and donepezil, a cholinesterase inhibitor, which are used to treat AD – and found that neither therapy slowed the progression of MCI to Alzheimer disease at three years. MCI has been defined as a transitional state between the cognitive changes of normal aging and early AD.

The large, randomized, double-blind, placebo-controlled trial – the Alzheimer Disease Cooperative Study in mild cognitive impairment (ADCS-MCI) – was spearheaded by Ronald C. Petersen, MD, Professor of Neurology and Director of the Mayo Clinic Alzheimer's Disease Center in Rochester, MN. For his work, Dr. Petersen was awarded the AAN Potamkin Prize for Research in Pick's, Alzheimer's and Related Diseases this year at the AAN Annual Meeting. He accepted the award in a plenary session at the meeting.

STUDY FINDINGS

Vitamin E did not reduce the risk of developing AD at any time point, while donepezil did appear to slow AD progression for 12 months and improved overall cognitive function, memory, and language for up to 18 months. The benefits of donepezil were more robust in the subgroup of patients with MCI who carried the apolipoprotein E4 (APOE e4) gene linked to Alzheimer disease.

“Although vitamin E benefits patients with moderate to advanced AD, this study does not lend support for using vitamin E in mild cognitive impairment,” said Dr. Petersen. In addition, he said, the data are not strong enough to recommend donepezil for mild cognitive impairment, “but they are sufficiently provocative to warrant a discussion with patients [with mild cognitive impairment] about the possibility of taking donepezil if their symptoms are bothersome,” he said.

Dr. Petersen does not recommend routine APOE e4 testing in patients with MCI, because “it's an imperfect predictor on an individual basis.” But if a patient has already been tested and was positive for the gene, then the discussion with the patient should include information about the ability of donepezil to slow conversion to AD and improve symptoms for 12 to 18 months.

STUDY POPULATION

The study included 769 subjects with MCI enrolled at 69 sites in North America who were randomized to receive either vitamin E 2,000 IU/day, donepezil 10 mg/day, or placebo. All subjects also took a multivitamin. The mean age of patients was 73 years old; 45 percent were women; and 55 percent were positive for alleles of the APOE e4 gene.

Patients in the placebo group developed AD at a rate of 16 percent per year, with about 45 percent of that group having AD at the end of the 36-month trial, said Leon J. Thal, MD, a study co-author who presented the results at a plenary session at the AAN Meeting. Dr. Thal is Chair of the Department of Neurosciences at the University of California-San Diego.

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Dr. Ronald C. Petersen: “Although vitamin E benefits patients with moderate to advanced AD, this study does not lend support for using vitamin E in mild cognitive impairment.”

“By contrast, progression was reduced with donepezil at the end of six months and at the end of one year. However, by the end of three years, conversion rates were similar in the placebo, vitamin E, and donepezil group,” Dr. Thal told listeners. “So overall, there was no difference among the three groups in the rate of conversion to AD.” Two hundred and fourteen patients progressed to dementia by the end of the trial, with 212 classified as probable AD.

Dr. Thal said that early on, there were few converters in the donepezil group, but after a year, the rate of conversion continued to escalate. At the end of the study 76 percent of carriers of the APOE e4 gene had developed AD.

COGNITIVE IMPROVEMENT

Since treatment effects varied over the course of the trial, the investigators evaluated the therapies at six-month intervals. At six months, one year, and 18 months, improvements were seen on most measures of cognitive function – including executive function, language, and visuospatial measures – in patients treated with donepezil compared with placebo. Results for donepezil in a subgroup of APOE e4 carriers were similar on measures of cognitive function, but more robust, he noted. Vitamin E had little effect on cognitive and functional domains.

Generally, both donepezil and vitamin E were well tolerated. No increase in adverse events was seen with vitamin E compared with placebo. Side effects encountered with donepezil were similar to those associated with cholinesterase inhibitors: diarrhea, muscle cramps, nausea, insomnia, and abnormal dreams. A total of 230 subjects discontinued treatment during the double-blind phase: 92 in the donepezil group; 72 in the vitamin E group; and 66 in the placebo group. No difference in death rate was seen among groups.

Figure

Dr. Leon J. Thal: “… by the end of three years, conversion rates were similar in the placebo, vitamin E, and donepezil group.”

EXPERTS COMMENT

Discussing the study at the AAN plenary session, David Knopman, MD, Professor of Neurology at the Mayo Clinic in Rochester, MN, said that dementia is an obvious milestone in mild cognitive impairment.

“The study raised questions about genotyping [because of the results in APOE e4 carriers],” said Dr. Knopman, who was not involved with the study.

The more robust effects of donepezil in APOE e4-positive patients could represent a biological interaction between this genotype and cholinergic function, he explained. “There is more incipient AD in APOE e4-positive subjects, and these patients had a greater decline, so it is easier to show results of treatment in this group,” he said.

Dr. Knopman contends that “APOE genotyping should not be done prior to initiation of donepezil in mild cognitive impairment.”

In the future, MRI may be able to identify patients with MCI who are at risk for progression to AD, Dr. Knopman said. Two lines of evidence suggest a role for neuroimaging; the first is that hippocampal atrophy [seen on neuroimaging] is associated with a higher rate of conversion to AD. The second is the development of Pittsburgh compound B (PIB) that binds to amyloid beta peptide; PIP is being studied to determine its predictive accuracy in identifying patients at risk for AD.

Currently, it is not clear which patients with MCI are likely to develop AD. “Results of the study by Petersen and colleagues should be discussed with patients and families, and the pros and cons of treatment should be presented. Donepezil is not cost effective and does not provide benefit from a public health point of view. But a one-year reduction rate of 58.1 percent in converting to AD may be meaningful to patients,” Dr. Knopman emphasized.

NO RATIONALE FOR DONEPEZIL, VITAMIN E

In a separate interview, Howard Chertkow, MD, Professor of Neurology at McGill University in Montreal, Canada, said that the study did not justify using either donepezil or vitamin E in patients with MCI.

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Dr. David Knopman: “APOE genotyping should not be done prior to initiation of donepezil in mild cognitive impairment.”

“The critical issue for patients is whether donepezil has a role in preventing progression to Alzheimer disease, and the study was negative for that primary end-point,” Dr. Chertkow commented.

The study by Dr. Petersen and colleagues along with an earlier study led by Stephen P. Salloway, MD, (Neurology 2004;63(4):651–7) found measurable improvement with donepezil in patients with mild cognitive impairment over the short term, “but is this improvement clinically significant enough to warrant treatment? The feeling among neurologists and geriatricians is that it is not,” Dr. Chertkow said.

“I doubt that this study will convince physicians to put patients with mild cognitive impairment on donepezil. In fact, I think it will prompt physicians, who have put their patients with mild cognitive impairment on donepezil in anticipation of this study, to take them off the drug,” he said.

Although this study was negative for vitamin E, Dr. Chertkow does not think that the oxidative stress theory of aging “is dead.” Perhaps antioxidants are needed when people are young and have not yet developed mild cognitive impairment, he suggested.

“Vitamin E is not the best antioxidant available,” he said. “We haven't seen the last of antioxidants yet.”

ARTICLE IN BRIEF

  • ✓ Anew study examined two therapies – vitamin E and donepezil, a cholinesterase inhibitor, which are used to treat AD – and found that neither therapy slowed the progression of MCI to Alzheimer disease at three years.