Neurotransmitter changes in alzheimer's disease: Implications to diagnostics and therapy

Changes in the cholinergic, serotonergic, noradrenergic, dopaminergic, GABAergic and somatostatinergic neurons were investigated to determine their roles in Alzheimer's disease (AD). Markers for these systems were analyzed in postmorterm brain samples from 20 patients with AD and 14 controls. In the CSF study, markers lor the cholinergic neurons (choline esterase, ChE) and for the somatostatinergic neurons (somatostatin‐like immunoreactivity, SLI) were assayed for 93 and 75 probable AD patients and 29 and 19 controls, respectively. Activity of choline acetyltransferase (CAT) was decreased by 50‐85% in four cortical areas and hippocampus in patients with AD, but not in other areas of the brain, indicating a profound deficit in the function of cholinergic projections ascending from the nucleus basalis to the cerebral cortex and hippocampus in AD. Muscarinic receptor binding was reduced by 18 % in the frontal cortex but not in other areas of the brain in AD. Serotonin (5HT) concentrations were reduced (by 21‐37%) in hippocampal cortex, hippocampus and striatum; and 5HT metabolite levels were lowered (by 39‐54%) in three cortical areas, thalamus and putamen in AD patients. Concentrations of noradrenaline(NA) were reduced (18‐36%) in frontal and temporal cortex and putamen. These data imply that serotonergic and noradrenergic projections are also affected in AD but less than the cholinergic neurons. Dopamine (DA) concentrations in AD patients were reduced by 18‐27% in temporal and hippocampal cortex and hippocampus, while HVA, the metabolite of DA, was unaltered. Glutamic acid decarboxylase activity was not altered in AD. SLI was decreased (28‐42%) in frontal, temporal and parietal cortex, but not in thalamus and putamen in patients with AD. Frontal tangle scores correlated most strongly with cortical CAT activity reduction and less so with decreases of 5HT, NA and DA, indicating a closer correlation with the cholinergic changes and severity of AD than with other neurotransmitter deficiencies. ChE activity and SLI were reduced by 20% and 35 %, respectively, in CSF of the whole group of AD patients as compared to the controls. Comparison of CSF findings between four subgroups of dementia severity indicated that the SLI was already reduced in the group of mildest AD (‐31%), while ChE, activity was not. Although ChE activity in CSF declined in relation to dementia severity, however, the maximal reduction was only modest (‐30%). On the other hand, SLI in CSF showed only a slight further reduction (up to ‐ 41%) as the dementia become more severe. These findings suggest that the cerebral cholinergic deficit in AD is only partly reflected in the ChE activity in CSF, and thus such measurements are not helpful in diagnosing AD. Since SLI change in CSF closely parallelled the cortical SLI reduction, these findings suggest that the cortical somatostatin neurons are involved early during the course of AD. In conclusion, the present study confirms that several neurotransmitter systems, including the cholinergic, somatostatinergic, serotonergic, noradrenergic and possibly dopaminergic neurons, are disturbed in AD. However, of changes in those systems, the cholinergic abnormality is the most severe and most closely related to the severity of the disease. Therefore, in pharmacotherapy of AD, attempts to restore deficits of the transmitter systems should be directed foremost to the cholinergic system.