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
According to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD). Early in the disease process, before clinical... Show moreAccording to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD). Early in the disease process, before clinical symptoms, an increase in Aβ concentrations leads to formation of toxic Aβ oligomers. These oligomers drive the neurodegeneration in AD brain. An important therapeutic strategy is to lower Aβ concentration in the CNS. Theoretically, this can prevent all subsequent pathological processes. Aβ is the final product of sequential proteolytic cleavages of the precursor protein APP. The drug effects on the individual pathways of APP processing are hard to predict, because these are regulated by a complex biochemical network. In this research, a 'systems pharmacology' approach was applied, integrating available knowledge of biology and pharmacology of system reactions into mathematical models. The APP-system-pharmacology-model provides important information about the APP processing pathways: (i) Aβ production inhibition leads to a relatively greater decrease in Aβ oligomers compared to monomers (ii) dissociation of oligomers contributes to the drug effect; (iii) Aβ42 is the major Aβ variant that contributes to the oligomer pool; (iv) inhibition of the enzyme GS stimulates alternative processing of APP by feedback. The APP-system-pharmacology-model can be of value in development of therapeutic interventions for AD. Show less
