Alzheimer's disease: more than a 'cholinergic disorder' - evidence that cholinergic-monoaminergic interactions contribute to EEG slowing and dementia.

The loss of cognitive (particularly mnemonic) abilities constitutes a prominent symptom of Alzheimer's disease (AD). These cognitive symptoms occur in close relation to the slowing of the electroencephalogram (EEG), and it is likely that the inability of cortical circuits to maintain an activated state contributes to the behavioral disorganization in AD. The 'cholinergic hypothesis' of AD suggests that many of the cognitive and EEG symptoms are related to the atrophy of basal forebrain cholinergic neurons, which innervate the neocortex and hippocampus, among others. However, data from behavioral and electrophysiological studies in rats suggest that selective reductions in cholinergic transmission result in relatively small mnemonic impairments, and only a partial reduction in EEG activation. Thus, cholinergic atrophy alone may not be sufficient to cause the marked changes in cognition and cortical activity typical of AD. Cholinergic deficits do, however, make neural circuits susceptible to additional neurodegenerative processes. In rats, lowered serotonergic or noradrenergic activity alone often produces only minor impairments in learning/memory tasks and does not block EEG activation. The same monoaminergic deficits, however, result in severe behavioral impairments, and reduce or abolish EEG activation when they occur in a brain already affected by lowered cholinergic activity. There is an abundance of evidence that monoamines are reduced in AD. These degenerative processes, when occurring in a neural environment compromised by cholinergic atrophy, may then contribute to the disturbances in cortical processing and cognition/behavior in AD. A prediction derived from this theory is that an enhancement of monoaminergic functions may have beneficial effects on behavior and cortical activity. Preliminary experiments support this idea: combined cholinergic-monoaminergic stimulation can be more effective in reversing behavioral (Morris water maze) impairments and EEG slowing in rats with multiple neurotransmitter deficiencies than cholinergic enhancement alone. Thus, a stimulation of monoaminergic activity, in conjunction with cholinergic therapies, may provide an effective treatment option for AD.