This thesis describes studies of the effects on cognition of drugs that stimulate or inhibit the cholinergic system by direct or indirect mechanisms. The central question of this thesis is if the... Show moreThis thesis describes studies of the effects on cognition of drugs that stimulate or inhibit the cholinergic system by direct or indirect mechanisms. The central question of this thesis is if the integration of pharmacokinetics (PK), CNS pharmacodynamics (PD) and clinical assessments in early phase drug development is feasible for drugs for Alzheimer’s disease. All study designs included extensive pharmacodynamic testing, in various phases of drug development and in subjects with normal or impaired cognition, or in healthy volunteers with a previously pharmacologically impaired cognitive system (challenge studies). Cognitive decline is a complex process with many potential pathophysiological mechanism that allow many approaches, and we have only studied the cholinergic system. However, for all interventions it would be ideal if there were good biomarkers of the severity of the disease that were shown to respond to interventions. It is obvious that more efficient development paradigms are necessary to keep the pharmacological development trajectories economically feasible. Rapid evaluation of the most promising treatments in the right dose requires preclinical and early development, already directed towards the final clinical value based endpoint. Rapid elimination of interventions that do not work will help to focus limited resources on the more hopeful ones. Show less
