Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Neurodegenerative Disorders

Alzheimer’s Disease

Alzheimer’s disease, the most prevalent form of demen-tia, afflicts approximately 10% of the population over age 65.


Alzheimer’s disease, the most prevalent form of demen-tia, afflicts approximately 10% of the population over age 65. The cardinal features of Alzheimer’s disease are progressive loss of memory and disordered cognitive function. Alterations in behavior and a decline in lan- guage function can also be observed in the early stages of Alzheimer’s disease. The impairment in cognitive abili-ties occurs gradually, with the loss of short-term memory generally preceding loss of long-term distant memory. In the advanced stages, the individual may not recognize spouse or children, and the levels of arousal and alertness are severely impaired. Other signs of Alzheimer’s disease include reduced verbal fluency, naming deficits, and im-pairment of speech exemplified by failure to arrange words in proper order (dysphasia). Ultimately, with pro-gression of the disease, motor function is impaired and the patient may fall into a vegetative state. Death is usu-ally associated with complications of immobility (e.g., pneumonia or pulmonary embolism).


The pathological features of Alzheimer’s disease include the presence of -amyloid plaques, -enriched neurofib-rillary tangles, neuronal loss, and alterations in many neu-rotransmitter systems. Affected brain regions include the entorhinal cortex; hippocampus; amygdala; association cortices of the frontal, temporal and parietal lobes; and subcortical nuclei that project to these regions. Characteristically, the brains of Alzheimer’s disease pa-tients contain two distinct types of insoluble materials that are hallmarks of the brain lesions associated with the disorder: extracellular neuritic plaques containing - amyloid (A ) and intracellular -enriched neurofibrillary tangles. As with Lewy bodies in Parkinson’s disease, it is unclear whether the tangles and plaques are causal or byproducts of degenerative processes. However, consid-erable evidence suggests that alterations in A process-ing may be necessary components of cell destruction.

One theory of the pathogenesis of Alzheimer’s dis-ease proposes that increased production or decreased secretion of the A peptides leads to accumulation of these peptides. A second theory proposes that an abnor-mal -protein causes the formation of intracellular neu-rofibrillary tangles. -Proteins are important in the main-tenance of cytoskeleton function and axonal transport of proteins. Another theory is that A accumulation is a precipitating factor that is followed by the development of the -enriched tangles in the dying neurons.

Therapy of Alzheimer’s Disease

The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer’s disease pa-tients led to the use of drugs that would enhance the ac-tions of acetylcholine in the brain. Therapeutic agents approved for the treatment of Alzheimer’s disease are the cholinesterase inhibitors, drugs that block the break-down of acetylcholine and increase the availability of the neurotransmitter in synapses . These drugs are palliative only and do not cure or pre-vent neurodegeneration.

Available drugs are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galanthamine (Reminyl). The drugs have a significant but modest ef-fect on the cognitive status of patients, possibly because the drugs do not correct for changes that occur in other neuronal systems.

Adverse effects produced by the drugs include nau-sea, diarrhea, vomiting, and insomnia. These symptoms are most frequent and severe with tacrine. Hepatotoxicity is associated with tacrine therapy. Because of these signif-icant side effects, tacrine is not widely used.

Future Directions in the Treatment of Alzheimer’s Disease

It is becoming clear that Alzheimer’s disease is a multi-factorial syndrome and that unraveling its causes may be difficult. However, as knowledge of the mechanisms of degeneration are elucidated, this knowledge can be applied to the development of therapies to alleviate the symptoms and hopefully to prevent the disease or in-hibit its progression.

Several new directions in therapeutic approaches are being investigated. One is to lower A peptide lev-els and thus reduce A deposits through the use of mol-ecules that prevent the proteolytic cleavage of amyloid precursor protein or through a novel immunization technique that would use antibodies to remove the A peptides from the cells and brain. Other approaches be-ing examined are targeted at blocking the more down-stream effects, such as the use of antiinflammatory agents and antioxidants.

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