Alzhiemers Disease A Neurodegenerative Disease Biology Essay


In 1906, German physician, Dr.Alois Alzheimer's performed a brain autopsy in one of his patients died due to severe memory problems, confusion and difficulty in understanding questions. He noted highly dense aggregated structures around the nerve cells (neuritic plaques) and twisted bands of structures inside the nerve cells (neurofibrillary tangles). Hence the name of this degenerative disorder bears his name (Alzheimer's disease research association, 2010)

Scientific discovery of this degenerative disorder was founded out 100 years ago. During 1960s, scientists found out the relation between the decline in cognition and presence of plaques and neurofibrillary tangles in the brain. Scientists recognized this (Alzheimer's) as a disease and it is not a part of aging.

In 1990's the research on molecular level study of neuronal degeneration and susceptibility genes. Scientists worked on finding out genetic, environmental, and other risk factors responsible for the formation of amyloid plaques and neurofibrillary tangles.

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FDA approved drugs were currently used to treat only the cognitive symptoms of the AD, and these drugs only slows the progressive decline in cognition.

Progressive changes in molecular environment of neurons and neurodegeneration has its implication in psychological functioning. Degenerative diseases are the diseases of grey matter characterized by the progressive loss of neurons which is associated with secondary changes in white matter of brain. The pattern of neuronal loss is selective, affecting one or more group of neurons leaving others intact. They arise without any clear inciting event in a patient without previous neurologic deficits.

The major critical degenerative diseases are Alzheimer's disease and Pick disease. Their clinical manifestation is seemed to be "dementia".

Dementia is the progressive loss of cognition independent of the state of attention resulting from diseases of the brain (Gilroy, 1985).It may be due to,

Therapeutic drug use (e.g. Atropine, Phenytoin,etc.,)

Metabolic systemic disorders (e.g. Acid-base disorders, hypo - ,hyperglycemia , haematological disorders ,Pulmonary insufficiency, Hypopituitarism, Cardiac dysfunction, Hepatolenticular degeneration)

Intracranial disorders(e.g. cerebrovascular insufficiency, chronic meningitis or encephalitis, neurosyphilis, HIV, Epilepsy,tumor,abscess,subdural hematomas, multiple sclerosis, normal pressure hydrocephalus)

Deficiency states (e.g. vitamin B 12 deficiency, folate deficiency, niacin or pellagra)

Collagen - vascular disorders : Systemic lupus erythematosus, temporal arteritis, sarcoidosis, Behcet's syndrome)

Exogenous intoxication: (e.g. Alcohol, Carbon monoxide, organophosphates, toluene, trichloroethylene , carbon disulfide, lead, mercury, arsenic, thallium, manganese)

Dementia is not part of normal aging and always represents a pathologic process. The present study investigates on the Alzheimer's disease where dementia is one of the clinical manifestations.

Alzheimer's disease - the most common form of dementia caused by progressive neuronal degeneration with pathological features showing the presence of amyloid plaques and neurofibrillary tangles, primarily affecting middle-aged and elderly individuals in whom it is cause of 70 percent of cases of dementia.(Perry et al.,2003)


The accurate etiology of Alzheimer's disease is unknown. The salient pathological features are the presence of amyloid plaques and neurofibrillary tangles. The "amyloid cascade hypothesis"(Hardy, 1991) is mainly investigated by the researchers and there is still the search for cause of Alzheimer's disease. The amyloid cascade hypothesis is supported by the study of early-onset inherited (genetic) Alzheimer's disease. In early-onset disease, Mutations associated with Alzheimer's disease have been found in about half of the patients. The mutation leads to increased formation in the brain of a particular form of a small protein fragment called A-Beta (Aβ). In the majority of sporadic (for example, non-inherited) cases of Alzheimer's disease (these make up the vast majority of all cases of Alzheimer's disease) there is too little removal of Aβ protein rather than its increased production. The past and ongoing researches are focusing on the ways to prevent or slow down Alzheimer's disease to decrease the amount of Aβ in the brain, where one of the probable causative known.


Physicians keenly observe the following signs for complete evaluation

Loss of memory

Difficulty in familiar tasks performance.

Language problem

Disorientation in time and place

Decreased judgment

Abstract thinking problem

Misplacing things

Mood or behaviour changes

Personality changes

Loss of initiative.


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Early stage:

Memory problems initially dismiss as "a normal part of aging" are to be the first stages of Alzheimer's disease. Short-term memory is common, early in the course of Alzheimer's disease.

Mild personality changes, such as less spontaneity, apathy, and a tendency to withdraw from social interactions, may occur early in the illness.

As the disease progresses:

Problems in intellectual functions develop.

Disturbances in behaviour and appearance e.g. agitation, irritability, quarrelsomeness, and a diminishing ability to dress appropriately.

Later in the course of the disorder:

Affected individuals may become confused or disoriented

Unable to define their place where they live or to name a place

Patients may wander

Unable to engage in conversation


Lose bladder and bowel control (Gilroy et al ,1995).

Final stages of the disease:

Patient may become totally incapable of caring for themselves. Death can then follow, perhaps from pneumonia or some other problem that occurs in very severe deteriorated conditions. Persons in their later age in life more often die from other illnesses (e.g. heart disease) rather than due to Alzheimer's disease.


Early onset AD

Late onset AD

Familial AD

Early onset Alzheimer's: (EOAD)

It is a rare form of AD affecting the people before age 65. This type is seen in less than 10% of all AD patients. (Alzheimer's association, 2007) They experiences premature aging, so those people with Down syndrome are specifically at risk of this type. It is linked with a genetic defect on chromosome 14, where this is not the case in late onset AD. These chromosomal defects can undergo mutation of three genes namely presenilin1, presenilin2, and amyloid precursor protein (Selkoe, 2001).Certain conditions were prevalent in AD. Such a condition called myoclonus which causes muscle twitching and spasms is much more common in people with early onset AD.

Late onset:

It is the most common type affecting about 90% of all those with Alzheimer's. Persons with over the age of 65 may also prone to Alzheimer's. Late-onset Alzheimer's doubles every five years after the age of 65 and not hereditary. It is also known as "sporadic Alzheimer's" because it can affect any elderly person. On average people live roughly eight to ten years after diagnosis. Sometimes patients with sporadic Alzheimer are if they are associated with other diseases their life time reduces and lead to death.E4 type of gene is responsible for producing the apo lipoprotein. (Robin et al, 1999)

Familial Alzheimer's:

Familial Alzheimer's is entirely inherited. The affected families may show their inheritance to their off springs at least of two generations. It is rare, less than 1% of cases of Alzheimer's disease have FAD. Histological examination shows familial AD is indistinguishable from other forms of the disease. Amyloid deposits can be seen in the sections of brain tissue. Amyloid protein forms plaques and neurofibrillary tangles that progress through the memory centers of the brain. The uniqueness of plaque is rare or uncharacteristic of AD. This occurs when the mutation in one of the genes that creates a functional, but malformed protein instead of the ineffective gene products that usually results from mutations. Mutation in different genes like the amyloid precursor protein (APP) gene and the presenilin 1 and 2 (PSEN1 and PSEN2) genes have been discovered in families with early-onset familial disease.(Selkoe,2001)The products of these genes interact with the proteins in molecular level and involve in signalling process within and between cells.


The present management for the treatment of Alzheimer's is symptomatic. The acetylcholine esterase inhibitors were gaining importance in the management. Increasing the muscarinic function of the brain was clinical approach (Johnston, 1992).

The inhibition of AchE increases the Ach at the vicinity of neuronal Ach receptor.

Among the inhibitors physostigmine improved response in animal models of learning and causes mild transitory improvement in memory of patients with AD. Due to its short half -life and tendency of generating the symptoms of systemic cholinergic excess at therapeutic doses its use limited. Tacrine, donepzil, Rivastigmine, and Galantamine was approved by FDA in the treatment of AD (Mayeux, 1999).

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Tacrine is one of the centrally acting AchE inhibitor (Freeman and Dawson, 1991). Oral Tacrine in combination with lecithin increases the memory performance (Chatellier and Lacombelz, 1990). Clinically tacrine is less in use because of its significant side effects like abdominal cramping, anorexia, nausea, vomiting, diarrhoea , elevation of serum transaminases and thus dose- limiting(Alzheimer's association, 2004).

Memantine, NMDA glutamate-receptor antagonist is an alternative in the management of AD.

The disease management of present scenario focuses on AchE inhibition and formation of new memories (Alzheimer's association, 2007). The existing Ach molecules are prevented from degradation and there by act on intact Ach receptors by the use of AchE inhibitors.


Acetyl choline esterase is one of the neurotransmitter in the peripheral nervous system and central nervous system. It is dominantly present in the somatic nervous system.

Choline and acetyl Co-A in the presence of choline acetyltransferase leads to the formation of Acetylcholine (Ach).

Acetyl choline in presence of acetyl cholinesterase converted into inactive metabolite choline and acetate. More amount of enzyme was found to be present in the synaptic cleft. The clearance of free acetylcholine occurs rapidly at the synaptic cleft for the proper muscle function.

Excess amount of Ach is found at the neuromuscular junction due to the inhibition of AchE by neurotoxins. This leads to paralysis of the respiratory muscles and ceasing of the heart functioning.

Acetylcholine at the synaptic cleft as well at autonomic ganglia involve in the cell signalling through second messengers. Degradation of Ach by acetyl cholinesterase leads to Myasthenia gravis, Alzheimer's disease, and Glaucoma.

The thorough study on the molecular basis, the pathological signs of neuronal degeneration (biomarkers) paves the way for treating AD.


AchE falls into two structural classes namely homomeric oligomers and heteromeric forms. Homomeric oligomers with catalytic subunits are soluble in cell. The presence of hydrophobic amino acids sequence makes it to be associated with the glycophospholipid (outer membrane of the cell).Heterologous type is found in neuronal synapse as a tetramer with catalytic subunits of disulfide- linked to lipid with molecular weight of 20,000 Daltons and they found to be attached to the outer surface of the cell membrane through glycophospholipid.

Fig: I 3-dimensional structural image (ribbon-like) of Acetylcholine esterase

From the 3-dimensional structure of AchE, the active site was found to be present at the centerosymmetric to each subunit and present at the base of the gorge about 20Å in depth (Sussman et al, 1995). Serine 203, Histidine 447, and glutamate 334 were the amino acid residue of catalytic triad lies at the base of the gorge.

The serine hydroxyl group is highly nucleophilic due to the charge relay system involving the carboxyl group from glutamate, the Imidazole on the Histidine; this resembles the catalytic mechanism of hydrolases.

AchE forms a tetrahedral intermediate (acyl enzyme) with the substrate (Ach) and this conjugate concomitantly release the choline part of the substrate followed by the formation of acetate (CH3COO-) and active enzyme (AchE). One AchE molecule hydrolyses 600,000 acetylcholine molecules per minute.


The exact molecular basis of AD is complex but the evidence for possible mechanism of neuronal degeneration is available.

The human brain is the remarkable organ with complex, chemical and electrical process occurs. The various processes like speaking, moving, seeing, remembering, feeling emotions and taking decision were executed by different parts of the brain.

In normal healthy brain, billion of cells called neurons constantly communicate with one and another. The messages from each neurons travel along the axons as the electric charges to the end of neuron. The electrical charges releases chemical messengers called neurotransmitters, they move across the microscopic gapes or synapses between neurons. They find receptors on dendrites on the post synaptic neuron (next neurons) and bind to it. This cellular circuit enables communication within the brain. Healthy neurotransmission is necessary for the proper functioning of the brain.