Mechanisms of Ageing and Development 122 (2001) 2025–2040 Treatment of cognitive dysfunction associated with Alzheimer’s disease with cholinergic precursors. Ineffective treatments or inappropriate approaches? Francesco Amenta a, *, Lucilla Parnetti b , Virgilio Gallai b , Anders Wallin c a Clinical Research Unit, Department of Pharmacological Sciences and Experimental Medicine, Uniersity of Camerino, Via Scalzino 3, 62032 Camerino, Italy b Department of Neurosciences, Uniersity of Perugia, Perugia, Italy c Institute of Clinical Neuroscience, Go ¨teborg Uniersity, Sahlgrenska Uniersity Hospital, Mo ¨lndal, Sweden Accepted 11 May 2001 Abstract The observations of the loss of cholinergic function in neocortex and hippocampus in Alzheimer’s disease (AD) developed the hypothesis that replacement of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numer- ous compounds in development for the treatment of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant benefit 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 utility of this class of compounds in well controlled clinical trials. However, cholinergic precursors most largely used such as choline and phosphatidylcholine (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic www.elsevier.com/locate/mechagedev - * Corresponding author. Tel.: +39-0737-403-311; fax: +39-0737-630-618. E-mail address: amenta@cambio.unicam.it (F. Amenta). 0047-6374/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0047-6374(01)00310-4