The Cholinergic Hypothesis Of Ad And Current Pharmacotherapies

In the mid to late 1970s and early 1980s, there were a series of landmark papers published describing a loss of cholinergic neurons in the brains of AD patients (11, 83, 84). This led to the formulation of the "cholinergic hypothesis" of AD (85-87), which briefly stated posited that loss of cholinergic function in the CNS was the basis for the dementia in AD. There was palpable optimism in the papers published during that period, which is poignant in retrospect. The feeling was that this might be the breakthrough in AD that would be analogous to the dopaminergic hypothesis of Parkinson's disease—perhaps treatment with cholinomimetics or acetylcholinesterase inhibitors might do for AD patients what l-DOPA had done for Parkinson's patients.

It is now clear that this is not going to be the case. AD has a complex pathophysi-ology, and the cholinergic treatment route is not nearly as efficacious as it was hoped to be. Nevertheless, augmenting cholinergic function does provide symptomatic ameliorative effects in a subpopulation of patients. In other words, augmenting acetylcholine function helps improve some of the cognitive effects in earlier stages of AD, for some patients. The efficacy of the treatment declines as the disease progresses. Acetylcholine-targeted treatments do not affect or slow the underlying pathogenesis of AD (see reference 88).

All of the currently available drugs prescribed for AD act to augment acetyl-choline function in the CNS by inhibiting acetylcholinesterase, which is the enzyme that breaks down acetylcholine, converting it to acetate and choline. The specific drugs available at present are donepezil (Aricept), rivastigmine (Exelon), galantamine (Reminyl), and tacrine (Cognex).

Aside from providing a rationale for drug development, the selective loss of cholinergic neurons in AD raises an additional interesting point. How is it that cholinergic neurons get selectively targeted? Some AD-related process is clearly picking cholinergic neurons out of the diverse array of central neurons in a highly selective manner. Recent work from a number of groups has suggested a partial answer to this question. It turns out that amyloid beta peptide binds with extremely high affinity to CNS nicotinic acetylcholine receptors (see figure). This provides an insight into how cholinergic neurons might be targeted—amyloid beta peptide selectively

All About Alzheimers

All About Alzheimers

The comprehensive new ebook All About Alzheimers puts everything into perspective. Youll gain insight and awareness into the disease. Learn how to maintain the patients emotional health. Discover tactics you can use to deal with constant life changes. Find out how counselors can help, and when they should intervene. Learn safety precautions that can protect you, your family and your loved one. All About Alzheimers will truly empower you.

Get My Free Ebook

Post a comment