Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?

The observations of the loss of cholinergic function in neocortex and hippo campus in Alzheimer's disease (AD) developed the hypothesis that replacemen t of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylc holine (ACh) precursors, stimulation of ACh release, use of muscarinic or n icotinic receptor agonists and acetylcholinesterase (AChE) or cholinesteras e (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE in hibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numerous compounds in development for the treatmen t of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant ben efit of these drugs on all symptom domains of AD. The first attempts in the treatment of AD with cholinergic precursors did not confirm a clinical uti lity of this class of compounds in well controlled clinical trials. However , cholinergic precursors most largely used such as choline and phosphatidyl choline (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways such as CDP-choline, choline alphoscerate and phosphatidylserine clearly enhanced ACh availability or release and provided a modest improvement of cognitive dysfunction in AD, these effects being more pronounced with choline alphosc erate. Although some positive results cannot be generalized due to the smal l numbers of patients studied, they probably would justify reconsideration of the most promising molecules in larger carefully controlled trials. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.