Abnormalities in Non-Cholinergic Neurotransmitter Systems in Alzheimer’s Disease

Abstract

The identification of an abnormality in cholinergic transmission in Alzheimer’s disease (AD) was a pivotal observation in the history of research into the disease. It prompted reappraisal of the mechanistic basis for the symptoms of AD; it stimulated research into the significance of other neurotransmitter systems in the disease and it provided a clear pharmacological target for therapeutic drug development. However, the view that all the symptoms of AD are predominantly (or exclusively) a reflection of a deficit in cholinergic transmission is now difficult to sustain. The enormity of the overt structural alterations evident throughout the CNS of patients dying with AD does not equate with the minor contribution (numerically) of acetylcholine to synaptic transmission compared to major excitatory and inhibitory amino acid neurotransmitters. It is now evident that, at least postmortem, there are abnormalities in a wide variety of neurotransmitter systems. This is consistent with studies of the structural pathology of AD which indicate that there are few brain regions which do not exhibit some degree of neuropathological change. Moreover, the widespread nature of the dysfunction of neurotransmitter systems accords with the spectra of cognitive and behavioural changes observed during the course of the disease.