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Alzheimer’s Disease
Prospects for Treatment of Symptomatic Alzheimer’s Disease
a report by
David Knopman, MD
Professor of Neurology, Mayo Clinic
Therapies for Alzheimer’s disease (AD) have been available since 1994. gained an indication for treatment of more severe patients based on
Five drugs have been approved for the treatment of AD, including four clinical trial evidence,
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it is not at all clear what practical benefits
cholinesterase inhibitors—tacrine, donepezil, galantamine, and appear for cholinesterase-treated patients at that level of impairment.
rivastigmine—and the putative glutamate modulator memantine. There have been observations that the cholinesterase inhibitors have
Tacrine is no longer marketed, however, because of its toxicity profile. salutary effects on agitation and disruptive behaviors in AD, but the
There are many ongoing phase II and phase III studies for AD, but as of clinical trials have failed to confirm such benefits.
14
the time of writing (September 2008) it is not possible to predict the
next AD drug that will be approved. There is hope that future AD drugs Memantine is a drug that is thought to be a modulator of glutamate
will include those that attack basic biological mechanisms of the disease, neurotransmission. Questions have been raised about the relevance of
and not simply agents that treat neurotransmitter-related deficits. this mechanism to AD, and also whether it might actually also be a
cholinomimetic agent.
15
In any case, it appears to be a palliative
The cholinesterase inhibitors are clearly palliative therapies. Since the therapy that has no impact on the underlying biology of AD.
late 1970s it has been known that there is a cholinergic deficit in the Memantine was approved for the treatment of moderate to severe AD
brains of patients with AD, which is a result of degenerative changes based on two trials, one of which was with memantine monotherapy
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in the cholinergic neurons of the basal forebrain. These neurons are and one with memantine added to a background of donepezil.
17
In
susceptible to the neurofibrillary tangle pathology of AD. A number of these trials, both objective measures of cognition specially adapted for
clinical trials of six-month duration have shown that the three currently more impaired patients and clinician’s global impressions favored the
marketed agents all have superior performance to placebo on memantine-treated patients. Trials of memantine monotherapy in mild
cognition and global rating measures.
1–9
A Cochrane review has to moderate AD have also yielded positive results.
18,19
It is difficult to
asserted that the cholinesterase inhibitors show benefits in mild to compare effect sizes between the memantine monotherapy trials and
moderate AD.
10
Only a few studies have had a duration as long as one the cholinesterase inhibitor trials, but it appears that the magnitude of
year.
11,12
One of the most illustrative studies is a one-year study of the effect on the cognitive outcome measure—the Alzheimer’s Disease
donepezil conducted to determine whether donepezil delayed the Assessment Scale-cognitive (ADAScog)—were roughly the same. On
significant loss of daily functioning.
12
Compared with placebo-treated the other hand, a trial of memantine added to a background of
subjects, patients receiving donepezil were less likely (49 versus 62%) donepezil in mild to moderate AD failed to show benefits for
to have lost the pre-specified level of ability. memantine plus donepezil compared with donepezil alone.
20
The
practice of adding memantine to donepezil in mild AD patients has no
There has been much uncertainty about the duration of the effect of empirical basis.
cholinesterase inhibitors, but with few studies lasting longer than 12
months, together with the problem of attrition in clinical trials, there is Several agents that were commercially available for the treatment of
no definitive answer. A combination of inferences from the six-month other diseases have also been tested for efficacy in AD, but
trials and other sources suggests that the cholinesterase inhibitors unfortunately none has proved effective. The ones receiving the most
delay progression of symptoms by about six to nine months. After that, attention were anti-inflammatory agents and estrogen. The
it appears as if functional loss and cognitive impairment proceed at the
same rate as in untreated patients. However, withdrawal of a
David Knopman, MD, is a Professor of Neurology at Mayo
cholinesterase inhibitor after six months has been shown to result in
Clinic College of Medicine, a Consultant in Neurology at
rapid decline.
6
An important point for practitioners and families is not the Mayo Clinic, and a co-investigator in the Mayo
to take the concept of duration of therapy of cholinesterase inhibitors
Alzheimer’s Disease Research Center. He is an Associate
Editor of Neurology. Professor Knopman graduated from
too literally, as the medications seem to still provide some advantages
Dartmouth Medical School and the University of
beyond the nominal period of benefit. Minnesota Medical School, completing his internship at
Hennepin County Medical Center, Minneapolis, and his
residency at the University of Minnesota.
All of the cholinesterase inhibitors are approved in the US for
treatment of mild to moderate AD, defined by scores on the Mini-
knopman@mayo.edu
Mental State Examination of 26 to about 12. While donepezil also
© TOUCH BRIEFINGS 2008
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