The cholinergic hypothesis

The pathological changes in AD are localized both structurally and functionally. Plaques and tangles first occur in the hippocampus before spreading to involve other regions. Some areas of the brain are relatively preserved—the occipital lobe is affected relatively late and the cerebellum appears to be spared from neuritic change (neurofibrillary tangles and the fully matured plaques, although diffuse amyloid deposits do occur). Functional localization was demonstrated by evidence of the relatively greater and earlier loss of cholinergic neurotransmission. At postmortem there is evidence of significantly greater neuronal loss in the cholinergic nucleus basalis of Meynert and loss of cholinergic markers.(4 43 and 44> These observations led to the cholinergic hypothesis, which stated that the cognitive impairment of AD was due to a disorder predominantly affecting cholinergic neurones. It was this hypothesis that led to the development of pharmacological strategies to rectify cholinergic loss and the introduction of the first compounds specifically designed for and efficacious in AD. However, the cholinergic hypothesis was something of a simplification as other neurotransmitter systems (e.g. serotonergic and noradrenergic) are also affected in AD.

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