Summary of Drug Targets in Alzheimer's Disease Treatment
Alzheimer's disease (AD) or senile dementia of the Alzheimer type (SDAT) is the most common form of dementia, for which currently there is no cure. Alzheimer's disease is prevalent in older populations, and at least half of all new cases of dementia in a year are AD. Although no drugs have an indication for delaying or halting the progression of Alzheimer's, four drugs have been approved by regulatory agencies such as the U.S. FDA to treat the cognitive affects of AD.
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Causes
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MRIs may be used to aid in diagnosis of Alzheimer's disease, by eliminating other subtypes of dementia and other cerebral pathologies. There are three hypothesis about the cause of AD. The oldest hypothesis suggests that AD is caused by reduced synthesis of the neurotransmitter acetylcholine, but this theory is not supported widely because medications to treat acetylcholine deficiency have not been very effective in treatment of Alzheimer's. The amyloid hypothesis suggests that amyloid beta deposits are the cause of the disease, while the latest theory suggests that a close relative of the beta-amyloid protein rather than the protein itself may be the major cause.
Features
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Alzheimer's disease is characterized by a loss of neurons and synapses in the cerebral cortex. The loss in brain structure is especially degenerative in the temporal lobe and parietal lobe (the part of the brain responsible for speech, vision and the integration of sensory information) as well as parts of the frontal cortex (the part of the brain responsible for attention, long-term memory, conscious planning and other dopamine-sensitive neurons). Further, the brains of AD patients have a higher incidence of amyloid plaques and neurofibrillary tangles, which may be related to the disease and its progression.
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Biochemistry
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Alzheimer's Disease is associated with fragmentation of the protein APP (amyloid precursor protein) in the brain, as well as neurofibrillary tangles. The exact cause of AD is unknown, although a number of clinical trials have helped doctors to understand the biochemistry of the disease. Two problems in brain function have been identified as possible causes for AD. First, the amyloid precursor protein (APP), which is critical to neuron growth and survival as well as post-injury repair, seems to be somehow fragmented in Alzheimer's patients into smaller pieces, which form clumps called senile plaques that seem to be associated with AD. Secondly, the break-up of the protein tau leads to neurofibrillary tangles and disintegrates established neuron's transport systems; these neurofibrillary tangles are also associated with AD.
Pharmaceutical Treatments: ACh and Cholinergic Neurons
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A variety of drugs can be prescribed to treat cognitive effects of Alzheimer's disease, although no drugs currently have the ability to prolong the progression of the disease. Four medications are currently approved to treat the cognitive manifestations of AD; three are acetylcholinesterase inhibitors and one is an NMDA receptor antagonist. Acetylcholinesterase inhibitors (like donepexil, galantamine and rivastigmine---brand names Aricept, Razadyne, and Exelon, respectively) try to reduce the rate at which acetylcholine (ACh) is broken down, combating the loss of ACh and the death of neurons that use ACh. However, the use of these acetylcholinesterase inhibitors has not shown any significant effect in delaying the onset of advanced AD and severe dementia.
Pharamceutial Treatments: Memantine and NDMA Receptors
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Metamine, a type of NMDA receptor antagonist, may be moderately effective in the treatment of the effects of Alzheimer's. The fourth drug used to combat AD is memantine (brand names Akatinol, Axura, Ebixa, Memox and Namenda), a NMDA receptor antagonist. Excess levels of the neurotransmitter glutamate can lead to cell death through over-activity, through a process called excitotoxicity. Memantine blocks NMDA receptors and inhibits their overstimulation by glutamate and has been shown to be moderately effective in the treatment of moderate to severe AD. Use of both memantine and donepezil (above) has been shown to be at least marginally effective at treating the cognitive manifestations of AD.
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References
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