THE PHARMACOTHERAPY OF ALZHEIMERS-DISEASE BASED ON THE CHOLINERGIC HYPOTHESIS - AN UPDATE

Alzheimer's disease (AD) is a neurodegenerative disorder with impairme nt of cognitive function and personality. The synaptic loss, neuronal atrophy and degeneration of cholinergic nuclei in the basal forebrain may be associated with a reduction in oxidative metabolism of glucose, a fall in acetyl CoA and ATP. Current pharmacological strategies, aim ed at increasing cholinergic activity include acetylcholinesterase (AC hE) inhibitors, cholinergic agonists, acetylcholine (ACh) releasers an d stimulants of nerve growth factors (NGF). AChE inhibitors, physostig mine and Tacrine can slow the decline of cognitive function and memory in some patients with mild or moderate AD, if given for at least 3-6 months in sufficient doses to inhibit brain AChE. Their main disadvant ages are low oral bioavailability, peripheral cholinergic hyperactivit y and liver toxicity with Tacrine. Newer, less toxic AChE inhibitors, with selective central activity, formulations of physostigmine, select ive M(1) and nicotinic agonists are becoming available with improved b ioavailability and pharmacokinetics. These may increase the likelihood of therapeutic benefit in AD. Nootropic drugs, e.g. piracetam, which release ACh and are relatively non-toxic could possibly slow the progr ession of the disease. A combination of an AChE inhibitor, piracetam a nd a stimulator of NGF may show additive effects on memory processes b ut with a lower incidence of untoward effects. (C) 1995 Academic Press Limited.