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Anejo Health Communications Anejo Health Communications
Margaret Bray
ISBN: 978-950-9647-78-7
Margaret Bray
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// Pocket Guide to Alzheimers Disease
Table of Contents
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Introduction
Diagnosis
. Ten Warning Signs
New Diagnostic Criteria and Guidelines for Alzheimer's
Disease
. Summary of New Diagnostic Criteria and Guidelines for
Alzheimers Disease
. Dementia due to Alzheimer's disease
. Mild cognitive impairment (MCI) due to Alzheimer's disease
. Preclinical Alzheimer's disease
. Biomarkers
. Neuropathologic Assessment of Alzheimer's
Risk Factors for Alzheimers Disease
. Cardiovascular Disease
. Cerebrovascular Disease
. Physical Frailty
. Exercise
. Good and Bad Cholesterol
. High Energy Diets, Diabetes and Obesity
. Vitamin D
. Spouse and Carers Stress and Cognitive Health
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Treating Alzheimers Disease
. Cholinesterase Inhibitors
. NMDA Receptor Antagonist, Memantine
Treatment of Associated Conditions
. Treatments for Behavioral Symptoms
. Treating Sleep Problems
. Alternative Therapies
. Ginkgo Biloba
. Vitamin E
. Fatty Acids and Lipids
. Omega-3 fatty acids
. Caprylic Acid and Coconut oil
. Phosphatidylserine
. Coenzyme Q10
. Coral Calcium
. Huperzine A
. Tramiprosate
Etiology of Alzheimers Disease: Biology, Genetics and
Scientific Advances
. Advances in Genetics of Alzheimers Disease
. Predicting Onset of Familial Alzheimers Disease
. Biology of Alzheimers Disease
. Beta-Amyloid
. Presenilin Mutations
. Tau
Contacts and Links
References
Clinical Pearls
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Introduction
Alzheimer disease (AD) is the most common cause of dementia in
the elderly and accounts for 50 to 80% of dementia cases (Alzheimers
Association, www.alz.org). It is a degenerative neurologic disease with
progressive cognitive, behavioral and motor impairment manifested
as increased deficits regarding attention, executive function, language,
memory, and visuo-spatial skills, and in the ability to function in the
home, social and work settings.
Alzheimers disease is predominantly observed in people over the age
of 65 years (late-onset Alzheimers disease), and tends to be more prevalent
in women (2 out of 3 cases) than men. Currently there are estimates
of up to 5.4 million people in the US that may have Alzheimers. This
equates to approximately 1 in 8 Americans over 65 years old, and 50%
of over 85 year-olds. In 2006, the worldwide prevalence of Alzheimers
disease was 26.6 million. By 2050, the prevalence of Alzheimers is expected
to have quadrupled, to an anticipated 1 in 85 persons worldwide (Brookmeyer
et al, 2007).
Additionally, it is estimated that approximately 5% of people with
Alzheimers disease (200,000 people in the US) have the early onset
familial form of the disease, which most commonly occurs in 40 to
50 year olds. The amyloid precursor protein (APP) gene associated
with rare, inherited forms of Alzheimer's disease has been identified
on chromosome 21, which codes for amyloid precursor protein, the
parent molecule from which beta-amyloid is formed. Chromosome 21
is also the chromosome of which people with Downs Syndrome have
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three copies rather than two. Indeed, many individuals with Downs
syndrome develop Alzheimer's disease, often as young as their 30s and 40s.
It has also been shown that people with the apolipoprotein E4
(ApoE4) gene (approximately 1 in 7 of the population in the US) are
at higher risk for developing Alzheimer's disease. It is believed ApoE4
attaches itself to a brain cell receptor, that in turn attaches to APP, and
is carried into the brain cell, where proteases breakdown APP producing
protein fragments (beta-amyloid) that are believed to be the start of
the cause of degeneration and death of neurological tissue, and the
manifestation of the characteristics of Alzheimers disease. Research
is ongoing to identify further possible routes and causes of the disease.
Progress of Tau
Disintegrating
Microtubules
Disintegrating
Microtubules
Tangled Clumps
of Tau Proteins
Microtubule Subunits
Fall Apart
Healthy Neuron
Diseased Neuron
Microtubules
Stabilizing
Tau Molecules
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// Pocket Guide to Alzheimers Disease
A Nissl-stained tissue section
(left) and a Bielschowsky-stained
section from Auguste D's brain
(right) Plaques and tangles by
Alois Alzheimer (c1901)
In 1901 Alois Alzheimer described what we now believe to be
Alzheimers disease in a 51-year-old woman named Auguste Deter.
Alzheimer diagnosed Deter with presenile dementia, which today
would be diagnosed as early-onset Alzheimer's Disease. On Deters
death in 1906, Alzheimer performed histopathology on the brain
tissue and described small miliary fociin the superior layers
what is today characteristic of plaques and tangles.
A diagram of neurofibrillary
tangles found in August Deter's
brain, from a 1911 research
paper by Alois Alzheimer (1911)
It was in 1906 that a German physician, Alois Alzheimer, recorded
brain cell abnormalities while performing an autopsy on a patient who
had died after years of severe memory problems, confusion and difficulty
understanding questions. While performing a brain autopsy, Alzheimer
noted dense deposits surrounding the nerve cells (neuritic plaques)
and inside the nerve cells he observed twisted bands of fibers (neurofibrillary
tangles). Today, when these plaques and tangles are found during autopsy
there is certain diagnosis of Alzheimer's disease. Despite knowledge
of the underlying pathology, treatments that directly target the underlying
molecular pathways and halt the brain degeneration, specifically the formation
of plaques and tangles, have still to be identified, although progress has
been made in this field (2010 Progress Report on Alzheimers Disease).
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More recent tissue section showing plaques and tangles
Electron micrograph showing healthy areas of the brain and diseased
areas
Tangles are forming Healthy area
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Today the only approved treatments for Alzheimers are those that
have an indirect effect through the slowing of cognitive decline by aiding
neurotransmission. These drugs include the cholinesterase inhibitors
(donepezil, galantamine and rivastigmine), whose mode of action is
to make more acetylcholine available for neural communication processes
in otherwise deteriorating cells, and the N-methyl-D-aspartate
(NMDA) receptor antagonist, memantine. These drugs do not delay
or halt progression of the disease, but help to maintain neurotransmission
across brain cells, provide temporary symptomatic relief and may slow
symptoms of cognitive decline in mainly in the earlier stages of
Alzheimers disease.
In this book we describe as much as possible that is known about
Alzheimers disease today, from the possible causes and risk factors,
through diagnosis, treatments and advances in the understanding of
the disease.
Finally, there is a wealth of information available about Alzheimers
that is in the public domain, particularly on the internet. The most
valuable of these are the web pages of the Alzheimers charities, for
instance the Alzheimers Association www.alz.org in the US, which has
detailed comprehensive information on all aspects of Alzheimers, with
pages targeting all stakeholders: patients, carers, physicians as well as
researchers.
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There is no single test that can show whether a person has Alzheimer's.
Furthermore, it has become increasingly evident that the signs and
symptoms of Alzheimers are unique to each individual, and diagnosis
is complicated by several presenting characteristics being the same as
other diseases. While physicians can almost always determine if a person
has dementia, it may be difficult to determine the exact cause (Santacruz
and Swagerty, 2001). For example a person having trouble with memory
does not mean they necessarily have Alzheimer's, since many other
conditions can cause problems with memory and thinking. Diagnosing
Alzheimer's requires careful medical evaluation, including medical history,
mental status testing, physical and neurological examination, blood
tests and brain imaging (although not all these measures are fully validated
as yet; see New Diagnostic Criteria and Guidelines for Alzheimer's Disease)
to assess whether a person has Alzheimer's, and to rule out other causes
of dementia-like symptoms.
Signs that may be indicative of Alzheimers include progressive and
disruptive memory loss, depression, anhedonia, apathy, intellectual decline,
difficulty with calculations, multiple missed appointments, loss of interest,
social withdrawal, date or time confusion, occupational dysfunction
or personality change, restlessness and sleep disturbances . Traditionally,
physical and neurological assessments are done using the Folstein Mini
Mental Status Exam (MMSE) (Folstein, Folstein and McHugh, 1975;
Cockrell and Folstein, 1988). The MMSE is made up of a range of
different questions and tests. Below are four sample questions that
give an indication of the style of the MMSE.
Diagnostic Tests
Diagnosis
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Sample MMSE questions
1. Orientation to time: 'What is the date?'
2. Registration: 'Listen carefully. I am going to say three words. You
say them back after I stop. Ready? Here they are... apple [pause], penny
[pause], table [pause]. Now repeat those words back to me.' [Repeat
up to 5 times, but score only the first trial.]
3. Naming: 'What is this?' [Point to a pencil or pen.]
4. Reading: 'Please read this and do what it says.' [Show examinee the
following words on the stimulus form]: Close your eyes
As well as routine laboratory tests, biomarkers can be measured help
rule out other causes of dementia, for example, ApoE4 testing, but
these tests are not routine. Genetic testing for ApoE4 or for familial
Alzheimers Disease types may have to be discussed with a genetic
counsellor (see also New Diagnostic Criteria and Guidelines
for Alzheimer's Disease).
Brain imaging can be done, but controversy still exists over this
approach, and several imaging methods still have to be validated (see
New Diagnostic Criteria and Guidelines for Alzheimer's Disease).
Brain imaging tends to be done on a case by case basis, and also to
rule out other causes of signs and symptoms. Magnetic resonance imaging
(MRI) or computed tomography (CT) scans can be performed if cognitive
decline is recent and rapid; the age is less than 60 years, there is a history
of stroke, gait disturbance or focal neurologic signs, also if there is
cancer, urinary incontinence, bleeding disorder, or current use of
anticoagulants. Further scans such as SPECT and Pecan can be done
if there is diagnostic uncertainty after performing CT or MRI.
Ten Warning Signs
With the advances in the understanding of Alzheimer's disease, has
also come the realization of the importance to potential patients, their
partners, families and carers to know the warning signs of the disease.
To help with this process the Alzheimers Association has developed
a list of 10 warning signs to help people and their carers to help early
detection, shown below.
(source: http://alzheimers.org.uk)
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1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Memory loss that disrupts daily life
Challenges in planning or solving problems
Difficulty completing familiar tasks at home, at work or at leisure
Confusion with time or place
Trouble understanding visual images and spatial relationships
New problems with words in speaking or writing
Misplacing things and losing the ability to retrace steps
Decreased or poor judgment
Withdrawal from work or social activities
Changes in mood and personality
Memory and language centers comparison of normal and
diseased brain
Brain Cross-Sections
Normal Alzheimers
The Alzheimers Association (2009)
10 warning signs of Alzheimers disease
Language
Memory
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New Diagnostic Criteria
and Guidelines for
Alzheimer's Disease
The original clinical criteria for diagnosing Alzheimer's disease were
developed nearly 30 years ago (McKhann et al, 1984). The 1984 criteria,
which reflected the limited knowledge of the day, described only the
later stages of the disease, when symptoms of dementia are evident.
Alzheimers diagnosis was based solely on the clinical symptoms of
dementia and was defined as having a single stage. Furthermore, it
was assumed that people free of dementia symptoms were disease-free.
Diagnosis was confirmed only at autopsy - when the hallmarks of the
disease, abnormal amounts of amyloid proteins forming plaques and
tau proteins forming tangles - were found in the brain. (NIH News,
19 April 2011).
The original National Institute of Neurological and Communicative
Disorders and Stroke and the Alzheimers Disease and Related Disorders
Association (NINCDSADRDA) criteria for diagnosis was based on
the assumption that people who met the clinical criteria would have
Alzheimers pathology when they presented for autopsy after death
(Jack et al, 2010). It was believed that for Alzheimers, like many other
brain diseases, there was a close relationship between clinical
symptoms and the underlying pathology, such that (a) Alzheimers
pathology and clinical symptoms were synonymous, and (b) individuals
either had fully developed Alzheimers pathology, in which case they
were demented, or they were free of Alzheimers pathology, in which
case they were not demented (at least not because of Alzheimers) (Jack
et al, 2010).
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Now for the first time in nearly 30 years, the clinical diagnostic criteria
for Alzheimer's disease dementia have been revised.
Expert international workgroups convened by the Alzheimer's Association
and the National Institute of Aging (NIA) have jointly issued four new
criteria and guidelines to diagnose Alzheimer's disease. These new criteria
update, refine and broaden previous widely used guidelines jointly issued
by the Alzheimer's Association and the National Institute of Health
(NIH) over the past 30 years (Jack et al, 2011).The final versions of
the guidelines, revised to reflect input from the professional community
at large, now appear as free-access papers in Alzheimer's and Dementia:
The Journal of the Alzheimer's Association [abbreviated, Alzheimers
Dement] (Albert et al, 2011; Jack et al, 2010; McKhann et al, 2011;
Sperling et al, 2011). The new guidelines aim to improve current diagnosis,
strengthen autopsy reporting of Alzheimer's brain changes, and establish
a research agenda for future progress in earlier detection and even greater
diagnostic accuracy.
The notable differences from the 1984 NINCDS-ADRDA criteria include
formulation of three stages of Alzheimer's disease and inclusion of
measurement of biomarkers (although the use of biomarkers is still
to be validated and standardised before use in routine clinical practice)
(Jack et al, 2011). The three stages of Alzheimer's disease adopted in
the new guidelines are:
The fourth guideline updates criteria for documenting and reporting
Alzheimer's related changes observed during an autopsy.
The aim is to replace the complex 7-stage classification of Alzheimers
used by physicians (Reisberg et al, 1989). In particular in the revised
criteria, a distinction is made between the pathophysiological processes
of Alzheimers and the clinically observable syndromes, whereas this
distinction was not in the 1984 criteria (Jack et al., 2011). The following
diagram shows how the new guidelines relate to Alzheimer's disease
progression over time, and how the clinical stages and markers of the
disease interrelate over time.
(connect to graph "Alzheimer's disease progression)
1.
2.
3.
Dementia due to Alzheimer's disease
Mild cognitive impairment (MCI) due to Alzheimer's disease
Preclinical (presymptomatic) Alzheimer's disease
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Alzheimer's disease progression
EARLIEST ALZHEIMERS
changes may begin years or
more before diagnosis.
MILD TO MODERATE
ALZHEIMERS STAGES
generally last from 2-10 years.
SEVERE ALZHEIMERS
may last from 1-5 years.
Progression through the brain showing earliest Alzheimers through
to severe Alzheimers
Copia de libro Alzheimer:Maquetacin 1 14/08/2012 9:08 Pgina 23
This diagram from the 2010 Progress Report on Alzheimers Disease
shows the changes of markers for Alzheimers disease over time in
relation to the clinical stages of Alzheimers as defined in the new
guidelines
Key
Fxn - ADL: function - activities of daily living; Cog: cognitive
performance; CSF Tau: levels of tau in cerebrospinal fluid; CSF
abeta42: cerebrospinal fluid levels of beta-amyloid protein ending at
amino acid 42; FDG PET: fluorodeoxyglucose positron emission
tomography to indicate amount of glucose metabolism by the brain;
MRI hippocampal volume: magnetic resonance imaging to show
changes in volume of the hippocampus; MCI: mild cognitive
impairment, lMCI: late cognitive impairment.
A
B
N
O
R
M
A
L
N
O
R
M
A
L
TIME
Pre-Symptomatic eMCI lMCI Dementia
CSF abeta 42
CSF A42
Amyloid Imaging
CSF Tau
FDG PET
Function (ADL)
MRI Hippocampal Volume
Cognitive Performance
FDG-PET
Amyloid
imaging
Fxn Cog CSF tau
MRI hipp
Alzheimers Disease Progression
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Summary of New Diagnostic Criteria and
Guidelines for Alzheimers Disease
Dementia due to Alzheimer's Disease
Clinical symptom of dementia due to Alzheimer's disease are impairments
in memory, thinking and behavior decrease a person's ability to function
independently in everyday life (McKhann et al, 2011). The dementia due
to Alzheimer's disease guideline updates and clarifies clinical criteria to
diagnose dementia from all causes and specifically from Alzheimer's
disease (McKhann et al, 2011). In the future, biomarker evidence may
provide additional diagnostic certainty.
The dementia due to Alzheimers as outlined in the new guidelines is
further categorised into three sub-criteria:
1.
2.
3.
Probable Alzheimers dementia (core clinical criteria) includes
meeting the clinical criteria for all cause dementia along with
insidious onset; clear history of worsening of cognition by report
or observation; and initial and most prominent cognitive deficits
include amnestic presentation and/or deficits in language
presentation, visuo-spatial presentation and executive function.
Probable Alzheimers dementia criteria retain the framework
of the 1984 NINCDS-ADRDA criteria and can be used in
the clinical setting.
Possible Alzheimers dementia - diagnosis for patients who
meet core clinical criteria but exhibit an atypical course of
cognitive decline or mixed etiological presentation. Possible
Alzheimers dementia criteria can be used in the clinical setting.
Any patient with previous possible Alzheimers dementia per
the 1984 NINCDS-ADRDA criteria should be re-evaluated
with the updated criteria.
Probable Alzheimers dementia with evidence of Alzheimers
pathophysiology - diagnosis for patients who meet the core
clinical criteria and incorporate biomarkers, advanced imaging
and evaluation of biochemical changes. Currently it is not
recommended to use biomarker tests for routine Alzheimers
diagnosis (see below)
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Mild Cognitive Impairment (MCI) due to
Alzheimer's Disease
Symptoms of MCI due to Alzheimer's disease are noticible mild changes
in memory and thinking that can be measured on mental status tests,
but are not severe enough to disrupt a person's day-to-day life (Albert et
al, 2011).
The new guideline for MCI due to Alzheimer's disease is based on two
sets of criteria:
Preclinical Alzheimer's Disease
Preclinical Alzheimer's disease is a newly defined stage of the disease
in the conceptual phase that reflects current evidence that measureable
biomarker changes in the brain may occur years before clinical
symptoms affecting memory, thinking or behavior are observed (Sperling
et al, 2011). The evidence suggests that brain changes caused by the
disease may begin years or even decades before symptoms such
as memory loss and confusion occur. The strongest biomarker candidates
for Alzheimer's disease include brain imaging studies using MRI or
positron emission tomography (PET), and proteins in cerebrospinal
fluid (CSF). The new guidelines are designed to include people with
pathophysiological changes in the brain but are cognitively normal (no
evidence of dementia or mild cognitive impairment), but while the
guidelines identify these preclinical changes as an Alzheimer's stage,
they do not establish diagnostic criteria that doctors can use right now.
Rather, they propose additional research to establish which biomarkers
Core clinical criteria clinical and cognitive assessments that establish
concern of change in cognition over time; impairment in 1 or more
cognitive domain; preservation of independence in functional abilities;
not demented, and etiology of MCI consistent with Alzheimers,
including where relevant, Alzheimers genetic factors. Core clinical
criteria can be used in clinical settings.
Research criteria incorporates biomarkers, advanced imaging and
evaluation of biochemical changes with probabilistic framework for
levels of certainty for MCI due to Alzheimers. Research criteria
established solely for the purpose of research. Prior to use outside
the research setting, validation and standardization of biomarker
analyses will have to be done (see below).
1.
2.
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may best confirm that Alzheimer's-related changes are underway and
how best to measure them. These preclinical guidelines are also not
meant to imply that all individuals with early Alzheimers pathology
will progress to clinical Alzheimers dementia. Furthermore, although
changes in CSF levels of the three most common known protein markers
(beta-amyloid, tau and phosphorylated tau) may be measured reliably
in the controlled trial setting, individuals vary greatly in the rates at
which they develop signs and symptoms of Alzheimer's; presently,
brain structural changes are a more reliable method that CSF markers
in predicting cognitive decline.
The newly defined preclinical stage of Alzheimer's may also help in
the search for new treatments. Further they could help optimize current
treatment strategies and help define when best to start treatment in
the early course of this deliberating disease.
Biomarkers
Biomarkers are substances measured in body tissue used to indicate
the presence or absence of a disease, or the likelihood of later developing
a disease. Biomarker tests are usually not measures of clinical
symptoms of a disease, and therefore tests for biomarkers (often
referred to as surrogate) have to be rigorously validated and standardised
for use in clinical practice. Examples are tests for blood glucose levels
in diabetes, and blood cholesterol levels in heart disease. As noted
above for the proposed preclinical guidelines in Alzheimers disease,
the strongest biomarker candidates are brain imaging studies using
MRI or positron emission tomography (PET), and measures of proteins
in cerebrospinal fluid (CSF). The three other guidelines also include
proposals for the use of biomarkers to increase diagnostic accuracy
and treatment optimization.
Neuropathologic Assessment of Alzheimer's
Neuropathologic assessment of Alzheimer's is the reporting of Alzheimer's
-related brain changes during an autopsy. The new guidelines provide
guidance for documenting and reporting Alzheimer's-related brain
changes observed during an autopsy (Hyman, et al 2012). Key
recommendations of the guidelines include: the recognition that
neuropathologic changes may occur in the apparent absence of cognitive
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impairment; an "ABC" score for neuropathologic change that incorporates
histopathologic assessments of amyloid deposits (A), staging of
neurofibrillary tangles (B), and scoring of neuritic plaques (C); and a
more detailed approaches for assessing commonly co-morbid conditions
such as Lewy body disease, vascular brain injury, hippocampal sclerosis,
and TAR DNA binding protein (TDP)-43 immunoreactive inclusions
(Montine et al, 2012). As with the other guidelines, the neuropathologic
guidelines recommend use of biomarker data to complement autopsy
findings to help advance understanding of how closely biomarkers
correlate with the underlying physical processes.
Brain scans help identify Alzheimers
Normal Alzheimers
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MRI Normal AD
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Cell pathways in normal and diseased synapses
-
Secretase
sAPP
N-APP
APP APP
APP
DR6
Pen-2
Aph
Nicastrin
Presenilin
sAPP A40/42
Glc Na Ca
Membrane
Damage
+ 2+
Caspase
3,9
-
Secretase
-
Secretase
-
Secretase
GSK-3/
CDK5
Calpain
Akt
Tau
p25
p35
Glucose
Transporters
NMDAR AMPAR
Acetylcholine
Receptors:
nAChR
mAChR
Glucose
transportes
NMDAR AMPAR nAChR
mAChR
P
P
P
Nuclear translocation
transcriptional regulation
AICD
APP
Intracellular
Domain
Normal Axon
Pruning
Apoptosis
Caspase 6
Destabilized
Microtubules
Neurofibrillary tangles
Apoptosis
Aberrant
Neuronal
Death
Hyperphosphorylation
of Tau
AICD
ROS
Formation
Activation of PKC,
PKA, ERK2
Amyloid Plaques A
Misfolding, Aggregation
Microglia
Activation
Inflammatory
Cytokines
ROS
Formation
Lipid
Peroxidization
p53, Bad,Bax
production and
activation
Apoptosis
Oxidative Stress
Increased Neuronal
Survival, Nautrite
Outgrowth, Sinaptic
sAPP Plasticity, Cell
Adhesin
Alzheimers Disease State Normal State
// Pocket Guide to Alzheimers Disease
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59
Tau
It may also appear that the neurodegeneration seen with tau happens
together with beta-amyloid. In a study by Vossel (2010) in mice it was
shown that transport in axons and neurons was the same in both normal
and tau-deficient neurons until beta-amyloid was added, when the
percentage of cell parts being transported dropped by almost half in
the normal neurons, but was unchanged in the neurons with reduced
tau levels, indicating that tau interacts with beta-amyloid during axonal
transport and may play a role in the toxic effects of Alzheimers.
Copia de libro Alzheimer:Maquetacin 1 14/08/2012 9:08 Pgina 59
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Alzheimers disease signalling pathway
Copia de libro Alzheimer:Maquetacin 1 14/08/2012 9:08 Pgina 60
Copia de libro Alzheimer:Maquetacin 1 14/08/2012 9:08 Pgina 64
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Anejo Health Communications Anejo Health Communications
Margaret Bray
ISBN: 978-950-9647-78-7

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