Alzheimer's disease - A detailed case study

ALZHEIMER’S DISEASE – THE
CASE STUDY
By Uzair Ahmed

School of pharmacy- GNITC, Ibrahimpatnam
ALZHEIMER’S DISEASE – THE CASE STUDY
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S. No CONTENTS PAGE NO
1 Introduction to Alzheimer’s disease
2 Epidemiology & Aetiology
3 Diagnosis & Course
4 (i) Case study :
Case study of 65 year old lady with AD
(ii) Case study :
Case study of 63 year old with AD and a novel
presenilin 2 mutation
̄
5 Treatment
i. Psycho-social treatment
ii. pharmacotherapy
Treatment of cognitive disturbance
i. cholinesterase inhibitors
ii. Estrogen replacement therapy
iii. Anti inflammatory agents
iv. Antioxidant agents: selegiline and vitamin E
6 conclusion
7 Referance

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Abstract
Alzheimer's disease is one of the most devastating brain disorders of elderly humans. It is an
undertreated and under-recognized disease that is becoming a major public health problem.
The last decade has witnessed a steadily increasing effort directed at discovering the etiology
of the disease and developing pharmacological treatment. Recent developments include
improved clinical diagnostic guidelines and improved treatment of both cognitive disturbance
and behavioral problems. Cholinesterase inhibitors, including donepezil, tacrine, rivastigmine,
and galantamine are the recommended treatment of cognitive disturbance in patients with
alzheimer's disease. The role of estrogen replacement, anti-inflammatory agents, and
antioxidants is controversial and needs further study. Antidepressants, antipsychotics, mood
stabilizers, anxiolytics, and hypnotics are used for the treatment of behavioral disturbance.
Future directions in the research and treatment of patients with alzheimer's disease include:
applying functional brain imaging techniques in early diagnosis and evaluation of treatment
efficacy; development of new classes of medications working on different neurotransmitter
systems (cholinergic, glutamatergic, etc), both for the treatment of the cognitive deficit and the
treatment of the behavioral disturbances;and developing preventive methods (amyloid p-
peptide immunizations and inhibitors of β-secretase and γ-secretase). Hence alzheimers disease
is considered to be the most concerning and untreated ascpect in the medical fraternity.

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INTRODUCTION
Alzheimer’s disease is a brain disorder that slowly destroys memory and thinking skills and,
eventually, the ability to carry out the simplest tasks. In most people with the disease — those
with the late-onset type symptoms first appear in their mid-60s. Early-onset Alzheimer’s occurs
between a person’s 30s and mid-60s and is very rare. Alzheimer’s disease is the most common
cause of dementia among older adults.
The disease is named after Dr. Alois Alzheimer. In 1906, Dr. Alzheimer noticed changes in the
brain tissue of a woman who had died of an unusual mental illness. Her symptoms included
memory loss, language problems, and unpredictable behavior. After she died, he examined her
brain and found many abnormal clumps (now called amyloid plaques) and tangled bundles of
fibers (now called neurofibrillary, or tau, tangles).
These plaques and tangles in the brain are still considered some of the main features of
Alzheimer’s disease. Another feature is the loss of connections between nerve cells (neurons)
in the brain. Neurons transmit messages between different parts of the brain, and from the brain
to muscles and organs in the body. Many other complex brain changes are thought to play a
role in Alzheimer’s, too.
This damage initially takes place in parts of the brain involved in memory, including the
entorhinal cortex and hippocampus. It later affects areas in the cerebral cortex, such as those
responsible for language, reasoning, and social behavior. Eventually, many other areas of the
brain are damaged. This leads to beginning of the dementia /AD condition.

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AIM : A detailed case study on patient suffering from Alzheimer’s disease
EPIDEMIOLOGY
AD can be divided into a familial type and a sporadic type, and also into an early-onset type
(younger than 65) and a late-onset type (older than 65). The 6-month prevalence of AD in the
general population appears to be 5.5% to 9%. There prevalence of the disease doubles every
10 years. AD currently afflicts nearly half of the people aged 85 years and older.
Individuals with cognitive deficit that do not meet the generally accepted clinical criteria for
AD, but have a noticeable decrease from prior levels of cognitive performance with problems
in new learning, may have mild cognitive impairment. Recent studies show that 40% of these
individuals will develop AD within 3 years.

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ETIOLOGY
The main neuropathological features of AD appear to be senile plaques and neurofibrillary
tangles. The senile plaques seem to develop first in brain areas associated with cognition, and
spread to other cortical areas as the disease progresses. The senile plaques consist, among other
components, of insoluble deposits of amyloid p-peptide (Aβ), a fragment of the amyloid
precursor protein (APP). Aβ peptide is generated from APP by two consecutive cleavage
events: proteolytic activity by β-secretase generates one end of the Ap peptide, while γ-
secretase generates the other end, also by proteolysis. There appear to be two types of Aβ: a
longer species, Aβ42, and a shorter species, Aβ40. Aβ42 seems to be deposited initially and
may have a role in initiating the events that ultimately lead to amyloid deposition. It is still not
clear if the senile plaques are the cause or a by-product of AD, although there are increasing
data that dysfunction in the metabolism of APP with subsequent increase in the insoluble Aβ
is responsible for AD. Aβ seems toxic to the neuron either directly, or indirectly by causing
inflammation or increasing the production of free radicals.
The accumulation of neurofibrillary tangles in neurons is a second distinguishing feature of
AD. Neurofibrillary tangles are mostly formed by chemically altered (abnormally folded and
phosphorylaled) tau protein, a protein involved in microtubule formation. Tangle formation is
related to the severity of disease; the more advanced the stage of disease, the more tau tangles
in the brain. Despite the presence of neurofibrillary tangles in AD, no cases of AD secondary
to mutations in the tau gene on chromosome 17 have been reported, although frontotemporal
dementias with parkinsonism were found in some families with that mutation. The finding that
the tau alteration follows Aβ accumulation in patients with AD is supported by recent data.

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DIAGNOSIS AND COURSE
The clinical manifestations of AD include disturbances in the areas of memory and language,
visuospatial orientation, and higher executive function. Noncognitive changes include
personality changes, decreased judgment ability, wandering, psychosis, mood disturbance,
agitation, and sleep abnormalities.
The diagnostic evaluation of patients suspected of having AD comprises
(i) A history from a reliable informant (containing general
medical history, neurological history, neuropsychiatrie
history, family history)
(ii) Physical and neurological examination
(iii) Routine laboratory examinations (complete blood count, sequential multiple analysis-21
, thyroid function tests, vitamin B12, folate, rapid plasma reagin); optional laboratory
examinations (erythrocyte sedimentation rate, human immunodeficiency virus (HIV) serology,
serology for Lyme's disease, urinalysis, urine drug screen, lumbar puncture,
electroencephalography); and (iv) neuroimaging (computed tomography or magnetic
resonance imaging).
Symptoms
1.visuospatial
orientation
2.judgement
disability
3.sleep
abnormalitiess

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Neuropathological examination (looking for the hallmark senile plaques and neurofibrillary
tangles) from autopsy studies suggest a 90% accuracy rate in the clinical detection of AD - if
it is done by using standardized criteria such as those of the Diagnostic and Statistical Manual
of Mental Disorders, 4th edition (DSM TV) criteria and the National Institute of Neurological
and Communicative Diseases and Stroke - Alzheimer's Disease and Related Disorders
Association. (NINCDS-ADRDA)
The Fazekas-scale provides an overall impression of the presence of WMH in the entire brain.
It is best scored on transverse FLAIR or T2-weighted images.

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CASE STUDY - 01
A Case Report of a 65-Year-Old Alzheimer's Disease Patient
GENERAL DETAILS
NAME : Mrs. saanvi
AGE: 65
GENDER : Female
OCCUPATION : Red Staff Nurse
ADDRESS : Bangalore
INFORMANT: Self
HISTORY OF PRESENTING ILLNESS
Pre-morbid : Patient wakes up at 6 am, prepares breakfast,
goes to hospital by 7 am, comes back by 3 pm, prepares
lunch & eats, sleeps for 1-2 hours, goes to temple ,prepares
dinner by 8pm and sleeps by 10pm.
In-Hospital : Attends rounds, prepares duty roster, indents
medications, supervises work.
Patient was apparently normal till 3 years ago
Performing her daily activities when she initially noticed difficulty in putting the badge on her
dress.
She was able to identify the badge, hold it tightly, insert pin into the dress but difficulty in
pinning, unpinning and stopped wearing the badge.
•Difficulty in putting paste over the brush-Squeeze amount of paste, brushes only front part of
the teeth.
•Difficulty in opening and closing jar lid, holds it tightly and keeps moving the lid clockwise
and anticlockwise
Clumpsly
•Difficulty in opening the pen cap, change in pattern
Of holding pen cap ,initially used to hold with 2 fingers,
Now uses all the fingers and posteriorly.

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AFTER FEW MONTHS
Over next few months Disturbed sleep - increased sleep latency - initially 5 min, now 1-2 hours.
No nocturnal awakening, excessive day time sleepiness, snoring.
H/o 11kg weight loss with reduced appetite since 2 years.
No h/o early satiety, palpiations, sweating, heat or cold intolerance, visual disturbances,
osmotic symptoms
PAST HISTORY
HTN since last 5 years on amlodipine 5mg OD
No previous admissions to the hospital.
PERSONAL HISTORY
• Predominant vegetarian diet
• Appetite - reduced
• Bowel and bladder – regular
• Sleep - increased latency
SUMMARY
A 65-year-old lady presented with progressive difficulty in using various objects in the past 3
years with significant weight loss.
Neurodeficit: Limb apraxia, oro-buccal apraxia
Anatomical localization: Left parietal lobe, frontal lobe
Pathology: 1. Degenerative 2. Paraneoplastic

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GENERAL EXAMINATION
Elderly female, conscious, cooperative, lying supine on the bed, well oriented to time place
person.
No cyanosis & lymphadenopathy edema
BMI - 18kg/m2
BP: 140/80mmhg Right , Left arm supine posture
PR: 78 /min regular normal volume, character, peripheral pulses were well felt with no
radial/femoral delays
NERVOUS SYSTEM EXAMINATION
1. Spontaneous speech - fluency, grammar : normal
No paraphasia, neologism, perseveration, circumloculation
2. Comprehension - normal
3. Naming - Abnormal or disturbed
4. Reading - Disturbed
Memory:
Recent - Difficulty to remember daily activities
Remote - normal
Visual memory - Visuospatial, constructional apraxia Clock drawing, copying figures - not
done.
Dressing apraxia: Had difficulty
Activity
• Real object use : Slightly disturb
• Acalculia - Not able to identify numbers and arrhythmic symbols
• Agraphia - present( unable to write on paper/air, hold pen)
• Identification on self - impaired.

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TABULATION

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FINAL DIAGNOSIS
Diagnosis: Biparietal variant of PCA of Alzheimer’s disease
Pathology- Degenerative
Functional deficit: Graphesthesia, dressing apraxia,
Anatomical localization: Biparietal, frontal
CBD- No asymmetry/parkinonism

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CASE STUDY - 02
Case study of 63 year old patient with Alzheimer’s disease and a novel
presenilin 2 mutation
General details
Name – ms. Ross
Age - 63
Gender - female
Occupation - manager
Address - london
CASE REPORT
The patient was referred to our specialty memory clinic at the age of 58 with a 2-year history
of repetitiveness, memory loss, and executive function loss.
Magnetic resonance imaging scan at age 58 revealed mild generalized cortical atrophy. She is
white with 2 years of postsecondary education. Retirement at age 48 from employment as a
manager in telecommunications company was because family finances allowed and not
because of cognitive challenges with work.
Progressive cognitive decline was evident by the report of deficits in instrumental activities of
daily living performance over the past 9 months before her initial consultation in the memory
clinic. Word finding and literacy skills were noted to have deteriorated in the preceding 6
months according to her spouse. Examples of functional losses were being slower in processing
and carrying out instructions, not knowing how to turn off the stove, and becoming unable to
assist in boat docking which was the couple’s pastime.
She stopped driving a motor vehicle about 6 months before her memory clinic consultation.
Her past medical history was relevant for hypercholesterolemia and vitamin d deficiency. She
had no surgical history. She had no history of smoking, alcohol, or other drug misuse.
Laboratory screening was normal. There was no first-degree family history of presenile
dementia. Neurocognitive assessment at the first clinic visit revealed a mini mental state
examination (mmse) score of 14/30; poor verbal fluency (patient was able to produce only 5
animal names and 1 f-word in 1 min) as well as poor visuospatial and executive skills (fig. 1).
She had fluent speech without semantic deficits. Her neurological examination was pertinent
for normal muscle tone and power, mild ideomotor apraxia on performing commands for motor
tasks with no suggestion of cerebellar dysfunction, normal gait, no frontal release signs. Her
speech was fluent with obvious word finding difficulties but with no phonemic or semantic
paraphrasic errors.

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Her general physical examination was unremarkable without evidence of presenile cataracts.
She had normal hearing. There was no evidence of depression or psychotic symptoms.
Figure 01 - visuospatial and executive function testing
As visuospatial challenges were marked at her first visit and poor depth perception developing
over time, posterior cortical variant of ad was also on the differential as was atypical presentation
of frontotemporal dementias. Without fluctuations, parkinsonism, falls, hallucinations, or altered
attention, lewy body dementia was deemed unlikely.
After treatment with a cholinesterase inhibitor, her MMSE improved to 18/30, tested 15 months
later with stability in function. Verbal fluency improved marginally with 7 animals and 3 F-
words. After an additional 18 months, function and cognition declined (MMSE=13/30) so
memantine was added.
It was challenging to know if what was described was misinterpretation of objects in view or a
true hallucination. During this time, she developed muscle rigidity, motor apraxias, worsening
perceptual, and language skills and became dependent for all activities of daily livings.
At the fourth year of treatment, occasional myoclonus was noted. She was a 1 person assist for
walking because of increased risk of falls. After 1 year in the care home, she was admitted to the
acute care hospital in respiratory distress. CT brain imaging during that admission revealed
marked genialized cortical atrophy and hippocampal atrophy (fig-02)

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FIGURE 2: Coronal view, computed tomographic image, patient age 63, showing significant
generalized atrophy and dramatic hippocampal atrophy.
She died at age 63 of pneumonia. An autopsy was performed confirming the cause of death
and her diagnosis of AD, showing numerous plaques and tangles with congophilic amyloid
angiopathy.
In addition, there was prominent Lewy Body pathology noted in the amygdala.

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TREATMENT
The goals of treatment are to achieve improvement in cognition and to minimize behavioral
disturbances (depression, psychosis, agitation, and insomnia).
PSYCHOSOCIAL TREATMENT
Environmental manipulation,13
family support,14
and prevention of other medical
comorbidities can improve functioning of AD patients. In attempting to maintain patients with
AD in their homes for as long as possible, some adjustment of a patient's environment is
important. Written daily reminders can be helpful in the performance of daily activities.
Prominent clocks, calendars, and windows are important. Patient activities should have
minimal changes. Maintaining adequate hydration, nutrition, exercise and cleanliness, is
important. Family support is essential, since members are at risk for depression, anxiety
syndromes, and insomnia.
PHARMACOTHERAPY
Current pharmacological choices available to clinicians treating AD include cognitive
enhancers for the treatment of the cognitive deficit and mood stabilizers, antipsychotics,
antidepressants, and hypnotics for the treatment of behavioral disturbance.
TREATMENT OF COGNITIVE DISTURBANCE
CHOLINESTERASE INHIBITORS
The use of cholinesterase inhibitors in AD is based on the cholinergic deficiency observed in
the disease. Only cholinesterase inhibitors have shown clinically meaningful responses for
patients with AD. By using these compounds, there is an increase in the acetylcholine
concentration available for synaptic transmission by inhibiting enzymes responsible for its
hydrolysis (ie, acetylcholinesterase). These drugs appear to be useful throughout the disease,
but particularly in the middle stage.
The cholinesterase inhibitors (Table III) available now worldwide for clinical use are
donepezil, tacrine, galantamine, and rivastigmine. Physicians and families may not necessarily
see an acute improvement in symptoms, but patients on the medications will have the
appearance of less loss in cognition compared with controls.

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TABLE
CHOLINESTERASE INHIBITORS.
Drug name Dosage Side effects
Donepezil 5-10 mg PO qhs nausea, vomiting, diarrhea
Tacrine 20-40 mg PO qid nausea, vomiting, diarrhea, hepatotoxicity
Galantamine 8-12 mg PO bid nausea, vomiting, diarrhea
Rivastigmine 2-6 mg PO bid nausea, vomiting, diarrhea
ESTROGEN REPLACEMENT THERAPY
Considerable evidence has emerged regarding the role of estrogen on brain development,
neuron survival, regeneration, and plasticity. It appears to exert its effect in the brain by
enhancing transcription and mediation of nongenomic events. It has been suggested that the
abrupt decline of estrogen production in postmenopausal women increases the risk for these
women developing AD; men, in contrast, have an intrinsic supply of estrogen by aromatizing
testosterone in the brain. There is increasing evidence that estrogen replacement therapy (ERT)
in postmenopausal women may have a role in delaying AD by improving cognitive function
and reducing the risk for both cognitive impairment and AD, as shown in several open-labeled
clinical trials and at least one double-blind placebo-controlled trial, although a recent major
double-blind controlled study found no effect of estrogen in patients who already had AD.

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At the present time, there are several ongoing investigations regarding primary prevention with
estrogen in patients with AD (Women's Health Initiative - Memory Study; Women's
International Study of Long Duration Oestrogen for Menopause, Preventing Postmenopausal
Memory Loss and Alzheimer's with Replacement Estrogens Study). These studies will
hopefully show whether ERT is helpful in preventing AD, while other studies will show
whether ERT can delay disease progression.
The selective estrogen-receptor modulators are another interesting class of compounds
currently being tested in AD. These act as estrogen agonists in some tissues and antagonists in
other tissues (raloxifene, tamoxifen, droloxifene, and tiboline).
ANTI-INFLAMMATORY AGENTS
The hypothesis that anti-inflammatory therapy can slow the progression of AD has gained
support from some retrospective epidemiologic studies. There are very few prospective double-
blind clinical trials of nonsteroidal anti-inflammatory drugs (NSAIDS) in AD. Nonrandomized
studies with NSAIDS (indomethacin, ibuprofen, diclofenac, naproxen), steroids (low-dose
prednisone), and other anti-inflammatory agents (hydroxychloroquine, colchicine) showed
promising results in modulating the course of the disease.

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Unfortunately, these studies included small sample sizes. Recent studies have not replicated
the previous positive results. Although some previous high-dose prednisone studies showed
improvement, the use of high-dose steroids over a long period of time can cause substantial
health problems.
Another class of anti-inflammatory agents is that of the cyclooxygenase-2 (COX-2) inhibitors
(celecoxib, rofecoxib). By being more specific for the brain than the currently available nsaids,
they are now favored in clinical trial use for patients with AD. A major double lind placebo-
controlled trial comparing rofecoxib with naproxen and placebo has now been completed and
the results were negative.
Fig: Mechanism Of Nsaids In Alzheimers Disease

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ANTIOXIDANT AGENTS: SELEGILINE AND VITAMIN E
Current theories suggest that an increase in free-radical formation may occur in AD and have
a direct toxic effect. The brain may be vulnerable to the damaging effects of oxidative stress
because of an abundance of catecholamines and a relatively low concentration of antioxidative
enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase).
Furthermore, Aβ has been implicated in increased free-radical formation.
Vitamin E in doses of 1000 IU orally twice daily and selegiline (a monoamine oxidase B
inhibitor) in doses of 5 to 10 mg orally every morning, seem to minimize free-radical damage
by acting as free-radical scavengers. A recent major double-blind study comparing the effect
of selegiline alone, vitamin E alone, selegiline and vitamin E with placebo in patients with AD
showed that both delayed nursing home placement and the loss of activities of daily living.
However, neither selegiline nor vitamin E improved cognition compared with placebo. There
was no additive effect in combining vitamin E with selegiline.

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TREATMENT OF BEHAVIORAL DISTURBANCE
A wide range of dementia-associated behavioral disturbances afflict the majority of patients
with AD, with depression and psychosis being the most commonly studied from the point of
view of treatment. Depression in patients with AD should be treated aggressively, with careful
monitoring of cognitive function. With limited clinical trial data, the treatment of depression
in AD remains empirical and consists in starting an antidepressant at a low dose and increasing
it slowly. Sufficient dosage and duration of treatment arc needed for clinical response in
depressed patients without dementia. The depressed elderly may take up to 6 weeks to respond
to antidepressant medication and patients with AD should be expected to take as long.
Reversible monoamine oxidase inhibitors like brofaromine and moclobemide appear to be also
effective in patients with depression and dementia, without the severe potential side effects of
the classic monoamine oxidase inhibitors (phenelzine, tranylcypromine).
Use of tricyclic antidepressants is limited to nortriptyline and desipramine, since they have
fewer anticholinergic properties than their parent compounds amitriptylinc and
imipramine. They were both studied in doubleblind, placebo-controlled trials and were
effective in treating depression in AD patients.
All newer antidepressants, including fluoxetine, sertraline,
paroxetine, fluvoxamine, citalopram, nefazodone, bupropion, mirtazapine, and venlafaxine
appear to have beneficial effects in depression in AD patients, although only fluoxetine,
paroxetine, and fluvoxamine were studied in double-blind, placebo-controlled trials. At the
present time, the selective serotonin reuptake inhibitors (SSRIs) are the standard of care for the
treatment of depression in patients with AD. Depression in these patients can very often be
complicated by psychosis and behavioral disturbances, which can also be an independent
feature of the disease. The incidence of psychosis in patients with AD is 25% to 50%. Multiple
treatments have been proposed, but very few controlled trials are available. Treatment of
psychosis in patients with AD should rely on atypical antipsychotics such as risperidone and
olanzapine, which have been used in double -blind placebo-controlled trials.
Risperidone was studied in a large (625 patients) doubleblind placebo-controlled study
evaluating the efficacy and safety of an atypical antipsychotic in the treatment of psychosis and
behavioral symptoms in patients with AD.

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CONCLUSION
Our cross-sectional models that sought to predict initial diagnosis from baseline predictors
indicates that this task is fairly straightforward if given information about cognitive tests, such
as the Mini-Mental State Examination and the Clinical Dementia Rating, which is intuitive
since doctors and diagnosticians typically rely on these tests in order to make their diagnoses.
Our project model, (1) predicting whether a given patient’s diagnosis would either change from
Cognitively Normal to either Mild Cognitive Impairment or Alzheimer’s Disease illustrate that
Logistic Regression and Support Vector Machines (SVM) have the highest Area Under the
Receiver Operating Curve and the highest Average Precision Recall.
As discussed in the previous study we concluded the following β-amyloid plaque and tau-
tangles may be considered as a the trace of a breakdown of the bilipid layer of the membranes
of the basic structures of a brain and probably in the presence of the excessive pyrrole
breakdown. This leads to the begining of demntia.
Hence the condition of alzheimers disease has been studied

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Alzheimer's disease - A detailed case study

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