Alzheimer Disease Project PDF

Running head: ALZEIHMER’S DISEASE
ALZEIHMER’S DISEASE
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Abstract
The paper aims to focus on the pathophysiology of the Alzheimer’s disease and its linkage with
the signs and the symptoms. The generation of the Aβ can be recognized as the first step if the
amyloid cascade initiation that progresses with excitotoxicity, hyperphosphorylation of the tau,
inflammation. Each of these procedures contribute to the neuronal loss due to the death of the
nerve cells and neurotransmitter abnormalities. All these can be manifested as behavioral or
cognitive abnormalities. The Β-amyloid hypothesis, the cholinergic hypothesis, the reactive
oxygen species hypothesis, the glutamate hypothesis, the chronic inflammation have been found
to be playing the basic role in the pathogenesis of AD. The treatment of AD involves proper
pharmacological symptoms and providing cognitive behavioral therapy to the AD patients.

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Table of Contents
Introduction......................................................................................................................................3
Pathophysiology..............................................................................................................................3
Stages of AD................................................................................................................................4
Degenerative processes occurring in Alzheimer’s disease..........................................................5
Amyloid plaque hypothesis.........................................................................................................5
Reactive oxygen species..............................................................................................................6
Neurotransmitter deficiencies......................................................................................................7
The glutamatergic theory.............................................................................................................7
The chronic inflammation in the brain........................................................................................8
Effect of cholesterol.....................................................................................................................8
Diagnosis.....................................................................................................................................9
Treatments...................................................................................................................................9
Conclusion.....................................................................................................................................10
References......................................................................................................................................11

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ALZEIHMER’S DISEASE
Introduction
Alzheimer's disease is the most common type of brain dementia that causes in ageing and
that causes cognitive damage. Initially the Alzheimer’s disease may notice only a mild confusion
or difficulties in remembering. AD is distinctively different from that of some common forms of
dementia. The AD subspecialists are able to distinguish the steps of the cognitive decline by
recognizing the histopathological features of the brain.
Pathophysiology
The defined histopathological feature defining AD are the extracellular amyloid plaques
and the presence of the intracellular neurofibrillary tangles. Recently the recognized
histopathologic feature included synaptic degradation, aneuploidy and the hippocampal neuronal
loss. The diagnosis of the AD is associated with the tallying of the plaques and the tangles with
the histopathologic diagnostic standards.
Some of the early symptoms of the disease is short term memory loss with confusion
with space and time, impairment of the judgment, difficulty in planning, disturbances in the
personality and hence social withdrawal and some neurologic difficulties such as impairment of
speech, sensory problems, or problems related to expression of thoughts.
The progression of the Alzheimer’s disease takes place slowly in five stages- the
preclinical stages, the mild cognitive impairment (MCI), moderate dementia due to AD, and
severe dementia.

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Stages of AD
The preclinical stage- AD develops long before the manifestation of the symptoms. In the
preclinical stage there would be no symptoms. This stage can last for years and may for even
decades. Although no symptoms can be observed but the new imaging techniques can identify
the deposits of the amyloid beta proteins in the brain cells. The preclinical AD begins at the
entorhinal cortex, that connects the hippocampus which is responsible for the formation of the
memory (Morrison & Lyketsos, 2005). Several studies have shown that neuronal loss may begin
earlier than the onset of the clinical symptoms. With the atrophy of the brain, the cerebrospinal
fluid fills in the space previously filled by the neurons.
Mild cognitive impairment (MCI) is a special type of memory loss that does not
necessarily impair the daily functioning of the person but can cause short term memory loss.
In mild to moderate AD, the patients face more loss in memory (such as challenges in
recalling the names or confusion regarding a particular place), reduction in the ability to process
the complex thoughts (such as difficulties in calculation or preparing a meal) and in some cases
mild personality or change in the mood. In this stage the brain atropy spreads to the other parts of
the cerebral cortex (Jacobs et al., 2012). The severe AD is characterized by the total memory loss,
severe cognitive impairment, blurred speech, severe behavioral symptoms (Morrison &
Lyketsos, 2005).
The parts of the brain that are responsible for the control of the speech, reasoning and
processing of the conscious thoughts are gradually affected. With time and severity of the
condition there occurs more neuronal loss leading to the memory loss, seizures, weight loss,
incontinence, non-recognition of the peers and the loved ones.

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Degenerative processes occurring in Alzheimer’s disease
AD is featured by 3 neuropathologic hall marks, such as the extracellular plaques
consisting of the β-amyloid proteins or the plaques, the neurofibrillary tangles (NFTs) and
degeneration of the neuronal cells (Morrison & Lyketsos, 2005). As stated by Swerdlow, (2007)
neurofibrillary plaques are present in other forms of dementia but in AD the NFTs and the
plaques are localized within some particular regions of the brain that is associated with the
clinical symptoms. According to the researches the Beta amyloid plaques plays the crucial role in
the progression of the AD.
Amyloid plaque hypothesis
Amyloid plaques are lumps of insoluble proteins that are generated by the normal
cleavage of the amyloid precursor proteins (APP). The APP is normally cleaved by the secretase
family of enzymes. In AD the γ-secretase cleaves the peptide at a wrong site resulting in the 42
amino acid peptide known as amyloid beta that is not soluble and are capable of forming clumps.
Jacobs et al., (2012) have stated that three genes have been found to be linked with the
pathogenesis of the AD, the APP, PS1 [presenilin 1], and PS2, located in the chromosome 21,
has been found to be linked with the formation of the amyloid plaques. Interestingly it has been
found that people suffering from Down’s syndrome possess these 21-3 copies of the
chromosome (Morrison & Lyketsos, 2005). This results in the death of the neuronal cells. After
the formation of the plaque occurs the hyper-phosphorylation of the tau proteins. Another
important pathology related to AD is the loss of the cholinergic neurons. PS1 and the PS2 are
the genes that codes for the catalytic subunit of γ-secretase. In the histological staining of the
human brain neurofibrillary tangles are seen. As opposed by Nelson et al., (2012), the NFTs and
no the amyloid-b plaques correlates with the degree of cognitive impairment in the AD. Other

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clinic-pathological studies have discovered that it is not the density and but the extent of the
NFTs linked with the ante-mortem cognitive status. It has been found that the NFTs in the
temporal lobe is associated with low episodic memory. The NFTs are generated from the
destruction of the neuronal microtubules caused by the alteration of the support proteins tau
(Swerdlow, 2007). In general the microtubules are the main components of the neuronal cells as
they help in the transmission of the neuronal messages. In AD the phosphorylation of the tau
proteins occur destroying the bonds of the microtubules and disrupting their normal structure.
Neuropathological survey and in vivo studies have shown linkage between the tau pathology and
the cognitive impairment. However it is also related to the pathophysiology of the amyloid
plaques and neuronal loss. The growing evidences have suggested that along with the
accumulation of the fibrillar amyloid-β peptides, the tau proteins also form aggregates (Bejanin
et al., 2013). The spatial distribution of the Tau protein has been associated with the cognition.
Reactive oxygen species
Lushchak, (2014), have emphasized on the oxidative stress hypothesis behind the
progression of AD. The Aβ protein causes the lipid peroxidation in the neurons generating
reactive oxygen species that reacts with the other macromolecules for achieving a stable
conformation. The reactive oxygen species forms a molecular bond throwing a high energy
electron (Lushchak, 2014). This reactive thrown of molecule (free radical) damages the neuronal
cells. It affects the macromolecules such as the nucleic acids, carbohydrates, proteins and the
lipids (Morrison & Lyketsos, 2005). Due to the high consumption rate of the brain, and high
lipid content and paucity of the antioxidant enzymes, the brain experiences high oxidative stress.
High rate of oxidative stress have been found to play a main role in the progression of the AD.
According to Revel et al., (2015), the mitochondrial derived ROS are involved with the initial

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development of the amyloid plaques in AD along with the alterations in the glutathione (GSH),
glutathione peroxidase (GPx) and the malondialdehyde (MDA) levels. The presence of these
biomarkers are involved in the protection against the ROS attacks on the lipids (Bejanin et al.,
2013). Presence of the MDA reflects the radical attacks on the lipids due to the lipid
peroxidation. In a cross sectional study by Gustaw‐Rothenberg, Kowalczuk & Stryjecka‐
Zimmer, (2010) patients suffering with mild cognitive impairment has found to possess higher
levels of MDA.
Neurotransmitter deficiencies
In AD the portions of the brain where the serotonin, acetyl choline and norepinephrine
are prominent are changed impacting a large area of the cerebral cortex. Serotonin is normally
considered to be effective in treating depression and anxiety. The serotonin receptors are altered
in case of AD that affects the cognitive function of the patients. Depression has been fpund to be
one of the common comorbities in AD. The reduction in the levels of the norepinephrine in case
of AD can be linked with the psychological symptoms observed in AD ( agitation, psychosis,
memory loss). Vazey & Aston-Jones, 2012) have stated the emerging role of the norepinephrine
in the cognitive dysfunction in AD due to the loss of the locus coeruleus norepinephrine (LC-
NE) neurons (Vazey & Aston-Jones, 2012). LC is the sole source of the NE throughout the
cerebral cortex and are highly involve in the cognitive functions.
The glutamatergic theory
Glutamate is an important excitatory neurotransmitter of the brain and has been found to
be in 66% of the brain synapses. The glutamatergic neurons are also important because they form
projections in other areas of the brain influencing the cognitive status (Swerdlow, 2007).
Normally three types of postsynaptic glutamate receptors, are associated with cognition but in

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case of the AD pathology only one type of glutamate receptors are associated (Mlyniec, 2015). It
has been found that there is a low activation of the -methyl-D-aspartate (NMDA) receptor in the
AD brains, which results in a low level of neurotransmission in the brain. The low regulation of
the glutamate NMDA receptor causes a vicious cycle of neuronal damage, where the continuous
activation of the receptor causes a huge influx of the calcium that affects the normal signal
transduction in brain (Swerdlow, 2007). It has been noticed that this results in an increased
production of the APP, that is again linked with a higher rate of plaque formation and
hyperphotophosphorylation of the tau proteins in brain (Mohsenzadegan & Mirshafiey, 2012).
The chronic inflammation in the brain
The NFTs, amyloid β plaques and the damaged nerve cells results develops inflammatory
response as a natural response to any kind of cell damage (Heneka et al., 2012). The microglia
of the brain during an AD pathogenesis, releases cytotoxic molecules like the pro-inflammatory
cytokines, reactive oxygen species, complement proteins and the reactive oxygen species
(Swerdlow, 2007). This kind of a response to the cellular damage causes harm than protection.
Programmed cell death of the neurons can be initiated by the cytokines causing damage to the
myelin sheath. The increased inflammatory response augments the prostaglandin levels produced
by the cyclogenases COX-1 and COX-2 in a brain with AD (Heneka et al., 2012).
Effect of cholesterol
Recent researches have been found that the cholesterol levels are involved in the
pathogenesis of the AD. Since brain contains the highest amount of the cholesterol reserve. The
increase in the cholesterol levels helps in the production of the Aβ. As stated by Wood et al.,
(2014) vascular dementia is a common feature that coexist in AD patients. A study was

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conducted that reports that there is a strong association between the high density lipoprotein
cholesterol and the amount of NFTs and plaques in the cerebral cortex (Nelson et al., 2012).
Diagnosis
AD can be measured to some extent by the reflexes of the person, the muscle tone and the
strength, sensory function, balance and coordination. Blood tests can be useful to rule out the
other causes of confusion and memory loss. Braun imaging techniques such as the MRI,
computerized tomography (PET), testing of the cerebrospinal fluid, positron emission
tomography (Frisoni et al., 2013).
Treatments
There is no such treatment to treat the condition but the treatment lies in slowering down
the progression of the disease. Some medicines like donepezil, galantamine, rivastigine and
tacrine can be useful in AD diseases. These medications work by inhibiting the enzyme
acetylcholinesterase that is responsible for the breaking down of acetyl choline. Cholinesterase
inhibitors can also be used as the therapy (Salomone et al., 2012). Memantidine can be used in
case of severe AD. Antidepressant medications can be provided for controlling the behavioral
symptoms (McKhann et al., 2012). Anti-anxiety medications such as Clonazepam and
Lorazepam can be used. Researchers are turning out to be more medically relevant such as
measuring the outcome such as the functional decline i.e the ability to perform the daily
activities. Jacobs et al., (2012) have stated that the loss of the ADLs in AD is a predictor of
institutionalization. The ideal treatment of AD in elderly people involves cognitive behavioral
therapy, constructive activity for the AD patients, helping out the patients to accomplish their
daily chores. Social inclusion of these people is necessary to improve their quality of living.

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Conclusion
In conclusion it can be said that the evolving pathophysiology of the AD can pave the
way for the future of the therapeutics. The amyloid plaques and the neurofibrillary tangles are the
probable hallmarks of AD. The future treatment strategies would probably focus on the multiple
mechanism in AD. A large number of factors such as the oxidative stress , cholesterol, loss of
cholinergic neurons, accumulation of the amyloid and the tau proteins and chronic inflammatory
response can cause the formation of the plaques and the tangles in the brain. Although caring for
a person with AD can be challenging but a pinch of love and care can help in reshaping the life
of these people. Coping and support, calm and a quite environment helps to control the
behavioral problems in the AD patient.

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References
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P. (2017). Tau pathology and neurodegeneration contribute to cognitive impairment in
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