Neurotransmitter Abnormalities

Cholinergic transmission

Multiple neuronal pathways are altered or destroyed during the course of Alzheimer's disease. It is noted that damage or disruption of transmission occurs in any neuronal area filled with amyloid plaques.

The cholinergic pathways are significantly damaged in AD. The majority of cholinergic transmission emanates from a community of neurons at the base of the forebrain known as the Nucleus Basalis of Mynert, an important area implicated in integration of complex thoughts.

	Basal Nucleus
	Septum

Cholinergic Pathways affected in the Alzheimer brain

Projections from the nucleus basalis innervate the frontal cortex and the hippocampus - areas involved in memory and cognition. Observations of diminished levels of acetylcholine, and cholinergic cell loss in AD lead to the development of the cholinergic hypothesis.

Unfortunately, as in the case of dopamine replacement in Parkinson's disease, increasing acetylcholine levels does not cure AD. Cholinergic neuron loss is a consequence of the neuropathological changes described in the previous sections, not the initiating cause of AD. Pharmacological interventions that target enhancement of cholinergic transmission are generally believed to be ineffective in preventing disease progression, but do slow the rate of disease progression in a number of patients.

Other neurotransmitters
Among the neurotransmitters, acetylcholine has received the largest amount of study in AD. However, it is important to realize that multiple other systems are affected throughout the course of the illness.

Levels of CNS serotonin decrease, reflecting the destruction of serotonergic neurons in the raphe nuclei. Levels of monoamine oxidase type B (MAO-B) increase. Norepinephrine-producing cells in the locus ceruleus are destroyed and in the latter stages of the disease, dopaminergic neurons in the substantia nigra are lost, often seen clinically as the development of extrapyramidal symptoms.

Alterations in serotonin and norepinephrine are linked to the high incidence of depression in AD. Low levels of serotonin may also be implicated in the development of behavioral symptoms.

Dysregulation of glutamate activity may play a role in neuronal destruction in AD. Glutamate is an excitatory amino acid in the brain, particularly found in the cerebral cortex and hippocampus. Normally, glutamate acts as a neurotransmitter for learning and memory, but if it remains in the synapse for extended periods of time, glutamate can destroy neurons. The toxic mechanism is postulated to be increasing levels of intracellular calcium and accumulation of free radicals. Memantine acts as an NMDA (N-methyl-D-aspartate) receptor antagonist and may modulate glutamatergic systems in AD. ^7,8 . It has been approved in the US for moderate to severe AD.