Cholinesterase Inhibitors in Alzheimer's Disease

Abstract

Data generated to date by a number of large studies (Eagger et al, Davis et al, Farlow et al, and Murphy et al) indicate that aminoacridines, as a class of compounds, have a statistically significant effect to diminish, slightly, some of the cognitive symptoms of Alzheimer's Disease. The clinical significance of this acetylcholinesterase induced change is the central issue that will determine whether regulatory bodies will ultimately approve these agents. Clinical global improvement has been found in some of these studies, but not others. However, the possibility exists that patients have been underdosed, as a consequence of the potential hepatotoxicity that reflected in the elevation of transaminase levels that occur in a substantial number of patients. Nonetheless, higher doses of the amino acridines, if tolerated, might produce larger effects that would be more apparent to the clinician, or, alternatively, other cholinesterase inhibitors than aminoacridines that are devoid of the hepatic problems so far encountered might be administered in larger doses, particularly if they are relatively brain selective, to produce a level of enhancement of central cholinergic activity that would maximize symptom improvement. There is little doubt that responsivity to cholinesterase inhibitors exists in only a subgroup of patients, and is robust in a further subgroup. Thus, a critical question is the biological substrate for the absence of efficacy of cholinesterase inhibitors in many Alzheimer's patients. One obvious explanation is that Alzheimer's disease is far more than simply a cholinergic deficit. Animal models have been utilized to address the heterogeneity of responsivity. The efficacy of cholinesterase inhibitors to reverse the deficit in passive avoidance learning that is caused by a nucleus basalis lesion has been studied in animals in whom either a noradrenergic, serotonergic, or somatostatinergic deficit has been added to the cholinergic deficit. These data indicate that cholinomimetic compounds are just as efficacious in reversing the deficit in learning on a passive avoidance task following a nucleus basalis lesion when that lesion is combined with either a serotonergic or a somatostatinergic deficit. However, the combination of a noradrenergic lesion produced by either the injection of 6-hydroxydopamine or DSP-4 into the ascending noradrenergic bundle from the locus coeruleus, with a nucleus basalis lesion, completely obliterates the ability of a cholinergic compound to reverse the passive avoidance learning deficits. However, by combining drugs that enhance noradrenergic activity with those that enhance cholinergic activity it is once again possible to normalize the behavior of these animals with both noradrenergic and cholinergic deficiencies on passive avoidance learning tasks. Thus, these data encourage the use of drugs that will reverse multiple neurotransmitter deficits.