The cholinergic deficit in Alzheimer's disease: impact on cognition, behaviour and function

Although the neurodegeneration occurring in Alzheimer's disease (AD) affects multiple neurotransmitters, the cholinergic system has received the greatest attention. Acetylcholine (ACh) is fundamental to mnemonic function, assisting in the septal hippocampal pathway and facilitating cortical activation. One of the earliest pathological events in AD is the degeneration of ACh-synthesizing neurons in the subcortical nuclei of the human basal forebrain. Indeed, the loss of cholinergic function in AD is correlated with the density of histopathological markers of AD, the severity of cognitive dysfunction and disease duration. However, the precise mechanism by which the cholinergic system influences cognition, and behaviour, is unknown. Recent preliminary data from functional imaging and ligand-binding studies implicate a dynamic interaction between the nicotinic-muscarinic cholinergic receptor systems. The relatively preserved thalamic nicotinic system, compared with the dysfunctional cortical muscarinic system, may facilitate thalamocortical metabolic excitation in the failing AD brain. Thus, it is hypothesized that thalamic influence within frontal-subcortical circuits is augmented in AD patients who demonstrate a marked improvement to cholinesterase inhibitor therapy. Understanding the cholinergic basis of the cognitive, functional and behavioural deficits in AD, and the differential treatment response to various agents, will ultimately improve patient care and neuropharmacological insights. This paper reviews the current understanding of the cholinergic influence in cognition, behaviour and, as a result, function in AD patients.