Clinical Diagnosis of Alzheimer’s
May Be Delayed, Says Major Clinical Trial
In a study of people with mild cognitive impairment
(MCI), those who took the drug donepezil were at reduced
risk of progressing to a diagnosis of Alzheimer’s disease
(AD) during the first year of the trial, but by the
end of the 3-year study there was no benefit from the
drug. Vitamin E was also tested in the study and was
found to have no effect at any time point in the study
when compared with placebo.
These findings, from the Memory Impairment Study, are
the first to suggest than any agent can delay the clinical
diagnosis of AD in people with MCI. The effects of the
drug measured in this study “did not provide support
for a clear recommendation for the use of donepezil” generally
to forestall the diagnosis of AD in people with MCI,
the researchers stated in their report, but they did
note the potential importance of the findings for some
patients. The data, they said, “could prompt a discussion” between
clinicians and patients on the possibility of donepezil
therapy in certain cases.
The findings were reported in the April 14, 2005, online
The New England Journal of Medicine by principal investigators
Ronald Petersen, Ph.D., M.D., of the Mayo Clinic, Rochester,
MN, Leon Thal, M.D., of the University of California,
San Diego, and colleagues. The research was funded in
part by the National Institute on Aging (NIA) and was
conducted as part of the Alzheimer’s Disease Cooperative
Study (ADCS), a nationwide clinical trials consortium
supported by the NIA, a component of the National Institutes
of Health, U.S. Department of Health and Human Services.
“While the delay in progressing to Alzheimer’s disease
had a limited effect in this case, it comes at an early
stage of memory loss, a critically important time for
patients and families hoping that the disease can be
held at bay,” says Neil Buckholtz, Ph.D., chief of the
Dementias of Aging Branch at the NIA.
As part of the study, the researchers examined the
effect of donepezil and vitamin E on delaying diagnosis
of AD among a subset of people with MCI with apolipoprotein
E-4 (APOE-ε4), the only known genetic risk factor for
late-onset AD. While the overall rate of progression
to AD was greater in this group, use of donepezil in
the APOE-ε4 subset was beneficial for up to 36 months
in reducing the risk of an AD diagnosis. The researchers
did not recommend APOE-ε4 genotyping for people with
MCI, suggesting more research would be needed to understand
the mechanism of action of the drug and other factors.
Additional important factors in the study were the
success in diagnosing MCI on a reliable basis in a multi-site
study and the finding that MCI can be predictive of
AD. A condition whose characterization in the medical
community is relatively new, MCI is a transitional state
that occurs between the cognitive changes of normal
aging and the very early stage of AD. The amnestic subtype
of MCI, the focus of this research, involves memory
problems not severe enough to be classified as dementia.
Previous studies have shown that approximately eight
in 10 people who meet criteria for amnestic MCI progress
to AD within 6 years of diagnosis and that people with
the APOE-ε4 gene progress to AD more rapidly.
In this trial, donepezil and the antioxidant vitamin
E were each compared to placebo to learn whether either
treatment might delay or prevent progression to AD among
people with MCI. Participants were randomized to three
groups, one taking 2000 International Units daily of
vitamin E, the second receiving 10 mg of donepezil daily,
and the third on placebo. All participants also took
daily multivitamins. The average age of the participants
at baseline was 73 years.
Among the 769 study participants enrolled at 69 sites
in the U.S. and Canada, 212 developed possible or probable
AD within the 3-year study period. The overall rate
of progression from MCI to AD for all three treatment
groups combined was 16% per year. The study found that
the group on donepezil’s risk of progression to a diagnosis
of AD was reduced by 58 percent one year into the study,
36 percent at 2 years, but there was no risk reduction
at the end of the full 3 years of the study.
“These findings give me a great deal of hope,” says
Petersen. “We have not answered the question of whether
donepezil reduces the underlying brain changes in Alzheimer’s
disease, but now we know that for some people, drug
therapy did make a real, clinical difference. I think
there will be real opportunities in the future to test
other therapies for patients with MCI.”
Donepezil, a cholinesterase inhibitor, is currently
prescribed for mild to moderate stages of AD to improve
memory and other cognitive functions. Cholinesterase
inhibitors work by delaying the breakdown of the neurotransmitter
acetylcholine in the brain. Acetylcholine helps communication
between the nerve cells and is important for memory.
The trial received primary support from the NIA, with
additional funding provided by Pfizer, Inc., and Eisai,
Inc. Pfizer and Eisai also contributed the donepezil
study medication, and vitamin E was provided by DSM
Nutritional Products, Inc.
The report will appear in the June 9, 2005, print version
of The New England Journal of Medicine.
For more information on participation in an AD clinical
trial, visit http://www.clinicaltrials.gov/ (search
for Alzheimer’s disease trials), or the Alzheimer’s
Disease Education and Referral (ADEAR) Center website
at http://www.alzheimers.org. ADEAR may also be contacted
toll free at 1-800-438-4380. The ADEAR Center is sponsored
by the NIA to provide information to the public and
health professionals about AD and age-related cognitive
change and may be contacted at the website and phone
number above for a variety of publications and fact
sheets, as well as information on clinical trials. |