Understanding the beneficial and detrimental effects of donepezil and rivastigmine to improve their therapeutic value.

Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases (ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits.