Prospects for Treatment of Symptomatic Alzheimer’s Disease

Prospects for Treatment of Symptomatic Alzheimer’s Disease

Knopman David
Published: BTG - FUTURE DIRECTIONS IN NEUROLOGY
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Therapies for Alzheimer’s disease (AD) have been available since 1994. Five drugs have been approved for the treatment of AD, including four cholinesterase inhibitors—tacrine, donepezil, galantamine, and rivastigmine—and the putative glutamate modulator memantine. Tacrine is no longer marketed, however, because of its toxicity profile. There are many ongoing phase II and phase III studies for AD, but as of 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 will include those that attack basic biological mechanisms of the disease, and not simply agents that treat neurotransmitter-related deficits.

The cholinesterase inhibitors are clearly palliative therapies. Since the late 1970s it has been known that there is a cholinergic deficit in the brains of patients with AD, which is a result of degenerative changes in the cholinergic neurons of the basal forebrain. These neurons are susceptible to the neurofibrillary tangle pathology of AD. A number of clinical trials of six-month duration have shown that the three currently marketed agents all have superior performance to placebo on cognition and global rating measures.1–9 A Cochrane review has asserted that the cholinesterase inhibitors show benefits in mild to moderate AD.10 Only a few studies have had a duration as long as one year.11,12 One of the most illustrative studies is a one-year study of donepezil conducted to determine whether donepezil delayed the significant loss of daily functioning.12 Compared with placebo-treated subjects, patients receiving donepezil were less likely (49 versus 62%) to have lost the pre-specified level of ability.

There has been much uncertainty about the duration of the effect of cholinesterase inhibitors, but with few studies lasting longer than 12 months, together with the problem of attrition in clinical trials, there is no definitive answer. A combination of inferences from the six-month trials and other sources suggests that the cholinesterase inhibitors delay progression of symptoms by about six to nine months. After that, it appears as if functional loss and cognitive impairment proceed at the same rate as in untreated patients. However, withdrawal of a cholinesterase inhibitor after six months has been shown to result in rapid decline.6 An important point for practitioners and families is not to take the concept of duration of therapy of cholinesterase inhibitors too literally, as the medications seem to still provide some advantages beyond the nominal period of benefit.

All of the cholinesterase inhibitors are approved in the US for treatment of mild to moderate AD, defined by scores on the Mini- Mental State Examination of 26 to about 12. While donepezil also gained an indication for treatment of more severe patients based on clinical trial evidence,13 it is not at all clear what practical benefits appear for cholinesterase-treated patients at that level of impairment. There have been observations that the cholinesterase inhibitors have salutary effects on agitation and disruptive behaviors in AD, but the clinical trials have failed to confirm such benefits.14

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