Alzheimer's Disease


Alzheimer's disease (AD) involves irreversible neuronal degeneration, and is the most common cause of dementia in middle-aged and aged people. AD accounts for almost three-quarters of cases of dementia, with the remainder accounted for by vascular dementia (VaD), mixed Alzheimer's and VaD, dementia with Lewy bodies, and frontotemporal dementia. The medical community has been attempting to find ways to diagnose and cure the disease ever since Alzheimer's discovery of the disease in 1907.

It is already known that Alzheimer's disease is a multi-factorial neurodegenerative disorder. Among these factors, age is arguably the most important one, followed by genetic factors and the presence of trace elements including aluminum, iron, zinc, selenium and others. In addition, brain injury, poisoning, metabolic and endocrine diseases, vitamin deficiency, and ischemia and hypoxia in the brain can also lead to Alzheimer's disease. There are numerous hypotheses regarding Alzheimer's disease's pathogenesis including formation and metabolic disorders of Aβ, cholinergic hypothesis, abnormal Tau protein phosphorylation, the metal ions hypothesis, the involvement of oxidative stress, and others. Thus the specific mechanism causing the Alzheimer's disease is still not understood. Pathologically, Alzheimer's disease is characterized by three hallmark elements: numerous senile plaques (SPs) composed of β-amyloid (Aβ) peptides, abundant neurofibrillary tangles (NFTs) formed by filaments of highly phosphorylated tau proteins, and apparent loss of neurons in the brain. All these process happens primarily on the hippocampus and cerebral cortex area of the brain, which are associated with learning and memory function, and, as a result, the major symptoms patients showed clinically progressive memory loss and cognitive impairment. As the disease advances, symptoms can include disorientation, loss of motivation, not managing self care, problem with language, mood swings and behavioural issues.

According to the research, acetylcholine (ACh) plays a key role in learning and memory, and the cholinergic changes observed in patients with AD led to the “cholinergic hypothesis” to explain the symptom pattern of the disease. The cholinergic system is one of many transmitter systems in the central nervous system (CNS). Its neurotransmitter, i.e., that substance which chemically transmits the neuronal impulse, is acetylcholine (ACh). The involvement of ACh in synaptic transmission of peripheral nerve impulses has been well established. In the CNS, the function of ACh as a neurotransmitter has been established only in terms of the Renshaw cells. However, it is believed that ACh is one of the major CNS transmitters and that it functions in the CNS in the same general way that it does in the peripheral nervous system where, in the autonomic system, all preganglionic autonomic fibers, all postganglionic para-sympathetic fibers have ACh as their neurohumoral transmitter. ACh is also the neurotransmitter at motor end plates in the somatic motor system.

The cholinergic system is believed to operate by a release of ACh from the vesicles in the axon terminals of the presynaptic neuron when the presynaptic axon is depolarized. The ACh diffuses across the synaptic space and combines with ACh receptors which induce a change in the permeability of the postsynaptic membrane. ACh in the synaptic space is hydrolyzed by the enzyme acetylcholinesterase (AChE) and, therefore, inactivated so the depolarized cells can recover and function again in the normal cycle of activity. The entire cycle, including release, diffusion, depolarization, and destruction must be completed in about 1 msec for normal neuronal functioning to continue. Successful synaptic conduction is dependent upon regulation of the amount of ACh in the synapse, sensitivity of the postsynaptic membrane, and the rapid destruction of ACh by AChE.

The level of ACh in the synapse is of critical importance. When the amount of ACh is too high, the postsynaptic receptors are continually occupied, and the neural impulse is blocked. When ACh falls below a functional minimum, the amount of ACh will not be sufficient to cause depolarization, and the permeability of the postsynaptic membrane will not be affected. Once again, the impulse will be blocked. Under nondrug conditions, the ACh concentration in the synapse is not believed to exceed the maximum level for normal synaptic function. However, a normal fluctuation within a certain range, and possibly below the functional range, may be expected. That is why cholinesterase inhibitors (ChEIs) have been the cornerstone of treatment for patients with AD. The acetylcholinesterase inhibitors bind to AChE so that ACh is not hydrolyzed. Therefore, the concentration of ACh at the synapse increases because of continued release of ACh from the presynaptic cell and continual leakage of ACh during the resting stage of the neuron.

Alzheimer's disease has a very long incubation period. If it can be diagnosed at a very early stage, followed by treatment at the early stage, the Alzheimer's patient's quality of life and rate of survival might be significantly improved. Tacrine was the first-generation cholinesterase inhibitor but was limited by hepatotoxic side effects. Donepezil, rivastigmine, brasofensine, idebenone, and galantamine then followed, with the former probably the most widely used agent. Efficacy appears similar between these different agents so choice should be based on cost, individual patient tolerance and physician experience. Huperzine A and ipidacrine are also acetylcholine esterase inhibitors. So the two agents can be used to treat Alzheimer's disease.

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