Cholinomimetic therapies for AD (Alzheimer's disease) have met with only limited success. Although a sub-group of patients have a modest, albeit clinically significant improvement with cholinesterase inhibitors, this is hardly as a robust a treatment as L-dopa for Parkinson's disease or even haloperidol for schizophrenia. Clearly, one problem with a purely cholinergic approach to the psychotherapeutics of AD is that AD is not simply a cholinergic deficit. Evidence for a noradrenergic deficit in AD derives from studies which demonstrate a loss of LC neurons, most evident among subjects with the greatest neurocortical plaque formation and is correlated with severity of dementia. Furthermore, norepinephrine content in several brain areas is reduced and this reduction is associated with greater severity of intellectual deterioration among patients with AD. Thus, there are compelling data to indicate probably influence the symptoms of the disease and the efficacy of a strictly cholinergic approach. Despite the development of safe, easier to use cholinesterase inhibitors, such as Aricept, only a portion of treated patients have a modest effect. Evaluation of the data from Phase III trials of Aricept shows that 62.3% of substantial numbers of non- responders to a purely cholinergic approach to treatment therefore necessitate the need to develop alternative approaches. Animal studies provide convincing evidence to support such an alternative approach, particularly one which enhances both cholinergic and noradrenergic activity. Therefore, our overall aim to determine whether the co- administration of the selective alpha-2 noradrenergic receptor agonist, guanfacine, with the acetylcholinesterase inhibitor, Aricept, is clinically more effective in treating cognitive symptoms of Alzheimer's disease than administration of Aricept alone. We propose to treat 72 AD subjects in a 14 week double blind, placebo controlled, parallel design, protocol, with an additional 3 week placebo washout phase. Subjects will be treated with a combination on measures of cognitive and global functioning.
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