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Biological markers and the cholinergic hypothesis in Alzheimer's disease

Alzheimer’s disease, senile dementia of Alzheimer type (AD / SDAT) is a progressive neurodegenerative disease for which early reliable markers must be considered of utmost importance for diagnostic and therapeutic purposes. Most research has been focused on the brain but there is growing evidence that AD/SDAT is not exclusively confined to the brain. Neurochemical data for AD/SDAT have mostly been obtained from in vitro analysis of transmitter levels, enzyme activities and receptor densities in brain tissues obtained at autopsy or neurosurgery. Deficits in more than one transmitter has been described (1,2, 3). The most consistent and pronounced changes have been found for the cholinergic system in brain and those changes correlate with cognitive function (4). The cholinergic hypothesis of AD/SDAT emerged from the findings of a reduced activity of the enzyme choline acetyltransferase (ChAT) in postmortem AD/ SDAT brain tissues ( 5 , 6, 7). Deficits in several presynaptic markers such as the high affinity choline uptake, (8) the synthesis (9) and release (10) of acetylcholine (ACh) and high affinity nicotinic receptors (11, 12) have later been detected in cortical areas of AD/SDAT brains (for review see Table 1). The cholinergic muscarinic receptors, mainly postsynaptically located, are preserved in AD / SDAT. Receptor binding studies have shown unchanged or increased number of muscarinic receptors in AD/SDAT brain tissue compared to control tissue (13, 14). Recent molecular biology studies confirm these observations by showing increased synthesis of mRNA in cortical AD/SDAT tissue (15). The cholinergic deficits in AD/SDAT brains are localized to cortical and hippocampal areas although biochemical deficits have also been observed in other areas such as the putamen, caudate nucleus and amygdala. The nerve terminals in the cortex and hippocampus originate from deeper regions such as the medial forebrain nucleus basalis of Meynert and the medial septum. A loss of cell has been found in these nuclei of AD/SDAT paDepartment of Pharmacology, Uppsala UniverI sity, Box 591, S-751 24 Uppsala, Sweden