During the course of the normal aging process, concentrations of ACh tend to decrease, resulting in the sporadic lapses of short-term memory that many elderly individuals tend to experience from time to time. This normal, non-debilitating decline in memory, referred to as Age-Associated Memory Impairment, or benign senescent forgetfulness, should not be confused with Alzheimer's Disease, a serious brain disorder, in which levels of ACh can drop by up to 90 percent. The gradual death of cholinergic brain cells results in a progressive and significant loss of cognitive and behavioral function.
Research in the last two decades has revealed that Alzheimer's Disease begins in the entorhinal cortex and proceeds to the hippocampus. As hippocampal cells lose their connection to other neurons and die, short-term memory falters and, as a result, individuals may become easily confused. Once competent individuals may lose the ability to remember simple facts like where they live, what year it is, or what they had for breakfast. Next, neurons in the cerebral cortex begin to degenerate, leading to a greater difficulty with language and judgement. Appetite may decline and individuals may also begin to lose control over bladder and bowel function. As the disease progresses even further, many patients cannot recognize even close members of their family and become unable to perform simple tasks such as bathing or eating. Many suffer from anxiety, suspiciousness, and may wander or pace. The disease finally leads to a complete loss of mental function and an inability to communicate in any way.
Significant loss of cholinergic neurons is not the only biological explanation for this devastating condition. Autopsies of those who have died from Alzheimer's reveal an abnormal presence of intracellular neurofibrillary tangles and extracellular beta amyloid patches, called neuritic plaques, in the cholinergic pathways of the brain. It is thought that neurofibrillary tangles are the result of a mutated protein normally involved in the healthy functioning of microtubules. In affected cells, these tangles interfere with axonal transport of enzymes, nutrients, and other materials essential to the cell. The exact role of neuritic plaques in the progression of Alzheimer's disease is, however, somewhat less clear. Excess concentrations of beta amyloid are associated with neuron death, yet the mechanism by which this occurs is still not known.
Though there is no cure for Alzheimer's, there are two drugs presently on the market which can help to ease some of the symptoms of the disease. Both of these drugs work to inhibit acetylcholinesterase, the enzyme which inactivates ACh at the synapse. Inhibiting this enzyme prevents the normal breakdown of ACh and is a way of compensating for the lowered concentrations of ACh characteristic of Alzheimer's disease. Tetrohydroaminoacridine (THA), marketed in 1993 under the name Tacrine or Cognex, was the first Alzheimer's drug to be approved by the U.S. FDA and has been shown to improve memory and language deficits in early stages of the disease. The drug is less effective in later stages when the total number of cholinergic neurons has been reduced even further. THA is not helpful in alleviating the paranoia, hallucinations, and aggressive behavior that many patients exhibit and has many side effects including nausea, liver dysfunction, vomiting, diarrhea, anorexia, and dizziness. The wide range of side effects produced by THA are due to a lack of the drug's substrate specificity. Though it can successfully target and prevent the breakdown of ACh in cholinergic pathways, it also reacts with additional, unrelated chemicals in the body, thus producing the undesired symptoms. A second drug, one with more substrate specificity, was approved by the FDA in 1996. Donepezil, marketed under the name Aricept, targets only ACh in the brain and allows for the same improvements in cognitive function as THA, yet without as many side effects.
Neither of these drugs, however, is a cure and neither can slow the progression of the disease. The difficulty in finding a cure for Alzheimer's Disease reflects the immense complexity of the condition. A deficit in ACh is only one of the many factors contributing to this devastating brain disorder. To learn more about Alzheimer's a helpful list of informative links can be reached at http://www.alzweb.org.