The objective of this project is to determine the clinical efficacy of combining two very different noradrenergic agents, clonidine and desipramine, with the acetylcholinesterase inhibitor, tetrahydroaminoacridine (THA) in the treatment of patients with Alzheimer's Disease. Neuropathologic studies of brain specimens of patients with AD have demonstrated degenerative changes involving several neurotransmitter systems in addition to the well described cholinergic deficit. In particular, a subgroup of patients with early illness onset shows a profound loss of noradrenergic cell bodies associated with diminished cortical levels of norepinephrine and dopamine-beta-hydroxylase. Previous treatment strategies aimed at reversing the cholinergic deficit have yielded only modestly successful results; the most promising agent yet to be tested in AD is THA. In this study, the potential usefulness of adding, respectively, a noradrenergic agonist and reuptake inhibitor or pharmacotherapy with THA will be investigated in separate protocols. Each protocol will take place in three phases: a placebo controlled dose-finding procedure to determine an optimal dose of THA administered alone, required because of the inverted-U shaped response of cognitive improvement over increasing doses of cholinomimetic, followed by a second placebo controlled dose- finding procedure in which clonidine in the first study, and desipramine in the second, are added to the previously determined optimal dose of THA, and finally, a double-blind crossover treatment study in which the clinical efficacy of THA alone is compared to THA plus clonidine or desipramine, respectively, and to placebo. This methodology will insure that these two potentially useful drug combination are tested in a carefully monitored setting, will permit an optimal treatment regimen to be discerned for each patient as he or she undergoes sequential dose finding studies, and will provide the comparative data necessary to determine if the addition of either noradrenergic agent improves the efficacy of THA in the treatment of AD.
