Advances in Alzheimer therapy: cholinesterase inhibitors.

Summary After a decade of intense study of cholinergic therapies for Alzheimer's disease, three conditions in this field are apparent: 1) The potential that cholinergic agents will ameliorate the memory dysfunction of Alzheimer patients (as l-dopa benefits Parkinson patients) is still a stimulus for research. 2) Cholinergic neuropharmacology and its impact on the therapy of memory disorders associated with cholinergic dysfunction needs to be further characterized and understood. 3) While there is still a search for a symptomatic treatment for AD, the path to find a treatment for the Alzheimer disease process must first pass through a phase of basic research to find the cause of Alzheimer's disease. At the meeting, there was an undercurrent of concern that the cholinergic deficit is too severe to be treated, that the cholinergic systems are too complex to respond to a pharmacologic therapy and that too many other systems are involved in Alzheimer's disease for a cholinergic treatment to be successful. However, this concern was balanced by the evidence of basic scientific experiments which indicate that the central cholinergic system mediating memory can be positively manipulated in animal lesion preparations and Alzheimer tissue. Also there were reports that improved pharmacological approaches and psychological measures are being developed. It appears that Alzheimer therapy is at the stage that cancer chemotherapy was 20 years ago: the promising agents cause nausea without producing clear effects but the basic laboratory studies strongly suggest that substantial benefits are possible and several agents have shown encouraging results. Meanwhile, patients and scientists are becoming increasingly interested in the field. However, several areas need to be more carefully addressed, particularly preclinical determination of drug effects, patient evaluation techniques and experimental design. At the preclinical stage, many old drugs are being rediscovered, new agents are being synthesized and drugs affecting many systems are being studied. The precise effects of these drugs on the nervous system need to be more clearly characterized and understood. Are they specific? Are they working presynaptically or postsynaptically? Is their net effect on the target systems positive? It is also important to determine the availability of the drug to the receptors and the long-term effects on those systems. Animal models need to be developed which can accurately predict whether these drugs will have any benefit for human memory. Learning and memory functions observed in the rat have been difficult to relate to human capacities. A computerized paradigm for testing memory consolidation in the primate would be useful. A primate model of Alzheimer's disease would offer the best test, but none has yet been validated. There are serious design problems in studying psychological processes. Memory has been a particularly difficult area and probably involves many brain systems. Memory problems in Alzheimer patients are still more difficult to assess, and the level of function may fluctuate day to day as much as 20%. With similar fluctuations expected in specific measures of cognitive function, a drug effect which only produces a 10% improvement will be hard to detect. Thus, there is a need to develop better methods for reliably and precisely determining dementia severity as well as the permanent level of impairment of specific types of cognitive function. Experimental design has not successfully met the challenge of evaluating drugs in Alzheimer patients. Clinical pharmacology has long relied on the double-blind cross-over design for comparing drugs. However, even with this time-honored method, many drugs have shown positive effects in some studies while not in others. There was a call during the conference for an open-phase adjustment of medication regimen with repeated measures which would then be followed by the double-blind cross-over phase. Dose effect interactions should also be more carefully considered. However, there is a lack of adequate active placebos and positive control drugs to serve for comparison. Acute studies are confounded by day-to-day fluctuations of dementia severity while longer studies can not adequately account for the variability of disease progression. With so many dependent variables being measured in each case, it is also difficult to assess the claims of statistical significance, especially when conflicting results are found in similar studies. These studies need to have larger numbers of patients in whom the heterogeneity is better characterized both biologically and clinically, especially in terms of the question of responders and non-responders. For progress it is important that investigators meet more often to discuss their approaches and findings. The multicenter THA trial and this conference serve as examples. As the methodological flaws are solved, new experimental systems will lead to the discovery of successful treatments and the eventual prevention of Alzheimer's disease.