July 2013 | Volume 23 | Number 6 PRIMARY HEALTH CARE 32

Continuing professional development

Aims and intended learning outcomes
This article explores the reasons Alzheimers disease
(AD) challenges scientists, current medical thinking
on pathogenesis and, most importantly, patients and
their families, and why effective treatments or a cure
remain elusive. This article will describe and classify
AD, and will examine the current evidence and theories on
its pathogenesis.
After reading the article you should be able to:
Classify the different types of AD and describe the
pathological profile of the disease.
Identify the theories on causes and pathogenesis of
AD, including risk factors.
Outline the reasons why there is a lack of progress in
a cure for AD.
Describe the strategies for new drug treatment
approaches for AD.
Discuss the social and moral dilemmas that face
families of patients with AD and how they can
be addressed.
Identify personal learning needs on understanding
AD in your professional role.
Now do time out 1
Introduction
More than a century ago Alois Alzheimer characterised
a disease in a patient who had died from an unusual
mental illness (Alzheimer 1907). It is surprising how
little is still known and understood about the aetiology,
pathogenesis, treatment, management and prevention of
AD (Goedert 2009). Diagnosis is difficult, particularly in
the early stages, with confirmed diagnosis only possible
once dementia has manifested to the point where the
distinction between mild cognitive impairment (MCI),
arguably a normal part of the ageing process, and AD
is not so subtle, precluding any confusion or overlap
in symptoms.
So, why has there been such little progress in
advancing our understanding of this devastating
and incurable disease? The answers may lie in the
complexity of human beings and assumptions about
normal ageing compared with what constitutes AD and
the differences between the two. Experiments on mice
have demonstrated significant success in possible drug
treatment strategies based on current understanding
of pathophysiological mechanisms, yet have failed in
clinical trials. Bapineuzumab, for example, demonstrated
clear benefits in mice but failed to improve cognition
and daily function compared with placebo in patients
(Castillo 2012).
Now do time out 2.
1
Understanding of the condition
T
i
m
e

o
u
tBefore reading the account of AD, write down
a paragraph summary of the condition, such
as you might use to teach a nursing student.
Refer to this as you read on, identifying
where your understanding is challenged or
supplemented. Reflect on where your ideas
on the disease come from.
Correspondence
info@yaso-shan.co.uk
Yaso Shan is a medical writer
and health consultant at
Vinings Natural Health Centre
in West Sussex
Keywords
Alzheimers disease,
dementia, mental illness,
ageing
These keywords are based on
the subject headings from
the British Nursing Index.
For related articles visit our
online archive and search
using the keywords
Peer review
This article has been subject
to double-blind review and
has been checked using
antiplagiarism software
Conflict of interest
None declared
Author guidelines
www.primaryhealthcare.net
Abstract
Alzheimers disease was first identified more than 100 years ago but still relatively little is known and understood
about the aetiology, pathogenesis, treatment, management and prevention of the disease. Diagnosis is difficult,
particularly in the early stages, and effective treatments remain elusive. This article reviews the evidence and
theories on the pathogenesis of the disease, outlines risk factors and treatment options and examines some of the
ethical dilemmas that nurses and patients face.
PHC788 Shan Y (2013) Treatment of Alzheimers disease. Primary Health Care. 23, 6, 32-38.
Date of submission: August 24 2012. Date of acceptance: December 12 2012.
Treatment of Alzheimers disease
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Continuing professional development

Definition and prevalence
AD is the most common form of dementia. It is a
degenerative, incurable and terminal disease. It is the
most common form of senile dementia and, along with
cerebrovascular disorders, the leading cause of dementia in
our population (Alzheimers Society 2012). On a biological
level, AD is described as a clinicopathological state
literally meaning the loss of the ability to think (Gandy
2005). Clinically, patients exhibit progressive cognitive
failure including loss of the ability to form and retrieve
new memories, changes in personality and a loss of the
ability to navigate even the most familiar environments.
Ultimately, all cortical function is lost and death occurs
as a complication of the terminally bed-bound state, for
example, with pneumonia or sepsis (Lublin and Gandy
2010). There is also a decline in reasoning, which involves
establishing connections, forming judgements and making
decisions. However, there is disagreement about the
extent of some of these symptoms prior to diagnosis and
about the basic nature of the disease itself even among
AD specialists. That controversy is no better illustrated
than in contemplation of how the disease is initiated at the
molecular level (Gandy 2005).
Ageing populations have increased the prevalence
of AD. The disease constitutes 62 per cent of all cases
of dementia and there were 800,000 people in the UK
with a form of dementia in 2012 (more than 17,000 of
whom were under 65) (Alzheimers Society 2012); the
number of cases is expected to rise to more than 1.7
million by 2051.
Now do time out 3.
Pathology
AD is defined by a characteristic loss of hippocampal and
cerebrocortical neurons (Lublin and Gandy 2010). These
regions control memory, thought, language, attention,
perception and consciousness. The structural changes in
this neurodegenerative process involve the accumulation
of a protein called amyloid (which deposits outside the
neurones) and neurofibrillary tangles (NFTs), which
accumulate inside the neurones. The cerebral amyloid in
AD is deposited as military structures known as plaques,
which primarily consist of the amyloid-beta (A) peptide
(Lublin and Gandy 2010).
A peptide was identified in 1984 as the major
constituent that characterises AD (Lublin and Gandy
2010). These amyloid plaques and NFTs have long been
regarded as the signature pathological lesions of AD
(Armstrong 2011). The discovery of A (Glenner and Wong
1984) as the most important molecular constituent of
these plaques resulted in the formulation of the Amyloid
Cascade Hypothesis or ACH (Hardy and Higgins 1992),
the most important model of the molecular pathology of
AD developed over the last 20 years. Essentially, the ACH
proposes that the deposition of A is the initial pathological
event in the disease leading to the formation of NFTs, cell
death and, ultimately, dementia (Armstrong 2009).
ACH has a number of limitations that arise from a
lack of understanding of the association between plaques
and NFTs (if one exists at all). Of the two original cases
described by Alzheimer, both had numerous plaques
but only one of them had significant numbers of NFTs
(Graeber et al 1997), thus creating a controversy that
persists to this day as to the relative significance of the
two lesions. Armstrong (2011) challenges the ACH with
questions on the relationship between the pathogenesis
of amyloid plaques and NFTs, and the relationship and
significance of these lesions to disease pathogenesis, and
suggests limitations to the hypothesis:
Amyloid plaques and NFTs may be reactive products
resulting from neurodegeneration in AD rather than
being its cause.
There is no generally accepted mechanism to explain
how the deposition of A leads to the formation of NFTs.
Classification
AD does not develop in a characteristic pattern for all those
affected, notably in its onset. Therefore, the disease is
classified according to the following (Armstrong 2011):
Early onset (<65 years)
Late onset/sporadic AD (SAD)
Familial AD (FAD)
2
Normal ageing or Alzheimers?
T
i
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e

o
u
tWith a colleague discuss normal ageing and
its effects on reasoning and memory. The
purpose of your conversation is to establish
your individual ideas on what constitutes
expected deterioration in aspects of cognitive
ability as people age. Did you find that you
both shared norms of disability? If you found
that your ideas differed, could this help
explain why it is harder to agree what counts
as AD and to agree when to intervene?
3
Statistical evidence
T
i
m
e

o
u
tThinking beyond the statistics, what in your
practice has demonstrated a growth in the
incidence and the care demands associated
with AD recently? Is the profile of your work
or the percentage of your time that you spend
with this group of patients changing? If
AD-related work is not on the increase locally,
determine why you think that is. Make notes
you can use to discuss care requirements and
best use of resources with colleagues.

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Early onset AD (<65 years) is usually caused by
autosomal dominant mutations in the genes for amyloid
precursor protein (APP), presenilin 1 (PS1 or PSE1)
and presenilin 2 (PS2 or PSE2). This form of AD
accounts for approximately 2-5 per cent of all AD cases
(Blennow et al 2006). First degree relatives of patients
with AD are at higher lifetime risk of developing the
disease than the rest of the population (Green et al
2002). The risk may be partly due to the presence
of the allele Apo4 (apolipoprotein 4), which is the
only proven genetic factor of risk so far identified in
the development of both the early- and late-onset
forms of AD (Corder et al 1994). The factor increases
susceptibility to AD but it is neither necessary nor
sufficient for the development of the disease.
Now do time out 4.
Late onset AD or sporadic AD (SAD) is the
most common form of AD, accounting for more than
90 per cent of cases and usually occurs after 65 years
of age. SAD affects almost 50 per cent of people
over the age of 85 and may or may not be hereditary
(Alzheimers Disease Health Center 2012).
Familial AD (FAD) is a rare form of AD that is known to
be entirely inherited. In affected families, members of at
least two generations have had AD, with a much earlier
onset (often in the 40s) (Alzheimers Disease Health Center
2012). Some sources categorise this along with early-onset
AD (Alzheimers Society 2013). The total known number
of cases of FAD worldwide is about 200 people with
mutations in three genes shown to be causative of FAD
(alzheimersillness.com 2013). The three genes involved
account for 30-50 per cent of all autosomal dominant
early-onset cases, or around 10 per cent of familial early
onset cases (Binetti 2009). The genetic link in some late
onset cases of AD (in people aged 65 and over) is more
complex than the link for younger people. The presence of a
positive family history in the late onset cases is considered
as a risk factor, but a clear autosomal dominant pattern of
inheritance is rare (Binetti 2009). Recent experiments in
mice have added weight to the idea that AD is driven by an
infection-like spread of protein aggregates in the brain, as
the history of theories in Table 1 (Schnabel 2012) shows.
Now do time out 5
Table 1 History of theories about Alzheimers disease (1970s to present)
Date/Theory Comment
1970s-1980s: Alzheimers disease is
a suspected prion disease
Researchers noted similarities between AD and transmissible spongiform encephalopathies such as
scrapie and CreutzfeldtJakob disease.
1980s-1990s:
Plaques cause AD
Alzheimers plaque proteins were successfully isolated in 1984 and referred to as amyloid beta (A).
It was shown to be quite different to scrapie amyloids. A was determined as a fragment of a larger
neuronal membrane protein called amyloid precursor protein (APP) coded by a gene on chromosome 21.
Early 1990s-early 2000s:
Confusion and debate
Many of the transgenic mice that over-expressed APP developed the typical brain plaques associated with
AD but they did not develop the other major AD amyloid (NFTs), which are made of tau protein, found
inside the neurones. These mice also failed to show the profound neuronal losses and memory failures seen
in human AD. The NFTs correlated better with dementia.
Late 1990s-present:
The oligomeric prion hypothesis
Early experiments showed that A, besides forming plaques can also cluster into soluble oligomers
made of comparatively few copies of A. Oligomers were thought to exist only fleetingly as intermediate
aggregates on the way to form complex plaques.
Circumstantial evidence suggests that build-up of A aggregation occurs over decades; it is this which
represents the last, lethal stage of disease.
4
Genetic predisposition
T
i
m
e

o
u
tLook back to your time out 1 description of
AD and note whether genetic predisposition
featured. What is the significance of this
if you discuss the disease with anxious
members of the public?
5
Slow scientific progress
T
i
m
e

o
u
tStudy Table 1 and decide what investigative
process is under way here. You might refer
to it as a process of elimination or the search
for causes of the condition. Summarise how
you might explain this scientific endeavour to
family members who feel impatient with the
progress of science and why it takes so long.
(Adapted from Schnabel 2012)
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Current evidence and theories
Those working on AD research study not only the
oligomer theory (Table 1) but also other aspects that
may influence the disease profile:
Oxidative stress.
Mitochondrial dysfunction.
Prion/transmission.
Genetics.
Inflammation and immune mechanisms.
Amyloid proteins (A, tau, oligomers).
Cerebrovascular events and other risk factors.
Oxidative stress
Free radicals formation can occur as part of normal
metabolism. Sometimes, the immune system
purposefully creates them to neutralise pathogens
(Knight 2000). Normally, the body can handle free
radicals, but if antioxidants are unavailable, or if the free
radical production becomes excessive, damage can occur
(Christen 2000). Of particular importance to AD is that
free radical damage accumulates with age. The oxidative
stress (OS) hypothesis proposes that the ageing process
in the brain is associated with a progressive imbalance
between the anti-oxidant defences and the pro-oxidative
species. This imbalance can occur as a result of either
an increase in free radical production or a decrease in
antioxidant defence (Gella and Bolea 2011).
Mitochondrial dysfunction
Mitochondria are regulators of both energy metabolism
and cell death pathways. Extensive literature exists
supporting a role for mitochondrial dysfunction
and oxidative damage in the pathogenesis of AD
(Moreira et al 2010).
Prion/transmission
There is the possibility that some of the SAD cases may
arise from an infectious process which occurs with other
neurological diseases caused by prions such as CJD.
Recent studies (Morales et al 2012) on intracellular
and extracellular protein aggregation suggest that those
aggregates are capable of crossing cellular membranes
and can directly contribute to the pathogenesis including
AD. Once initiated, neuropathological changes might
spread in a prion-like manner and disease progression
is associated with intracellular transfer of pathogenic
protein (Brundin et al 2010).
Genetics
Most AD lacks a predictable, autosomal dominant
mode of inheritance (Gandy 2005). While APP and the
presenilins (PS1 and PS2) constitute the only known
AD genes, at least one important generic risk factor is
known for about 25 per cent of the population with AD,
and that is the Apo4 genotype (Mayeux et al 1993).
However, efforts to link Apo4 with A accumulation
have produced mixed results (Gandy 2005).
Inflammation and immune mechanisms
Evidence for the involvement of inflammatory processes
in the pathogenesis of AD has been documented for
some time (Zotova et al 2010). However, it is only
recently that inflammation itself has been hypothesised
in AD pathology. Much of the data relates to outcomes
of two major inflammation-relevant treatment strategies
in AD: the use of anti-inflammatory drugs and
immunisation against A (Zotova et al 2010). For any
inflammatory response, there has to be a challenge;
the immune systems inflammatory response is after all
the bodys defence mechanism to a challenge, insult or
injury. The type of inflammation in the AD brain is not
well defined; it could be a consequence of the disease
with the production of A as a direct immune response
to a challenge (unknown at present), pointing to an
inability of microglia (the brains immune cells) to clear
away ever-growing neuronal debris due to extensive
neurodegeneration and synaptic loss. Mixed and often
contradictory findings with respect to inflammation in AD
indicate the complexity and multifunctional role of the
immune system (Zotova et al 2010). Inflammation in the
CNS (as in the periphery) is a mixture of both destructive
and rebuilding processes. It is this balance between the
two processes that determines the overall integrity of
the tissue or the whole organism (Rogers et al 2002).
Therefore inflammation should not be viewed as wholly
detrimental or wholly beneficial in AD.
Amyloid proteins (A, tau, oligomers)
The build-up of amyloid plaques has characterised AD and
has received the bulk of the attention in this pathology.
However, there is a gulf in opinion as to whether these
plaques are toxic, protective or inert. Of great interest
more recently is the significance of the free-floating
oligomers (intermediary amyloid proteins), which is gaining
prominence as the real culprit in the neurotoxicity that is
characteristic of AD (Gandy et al 2010).
Cerebrovascular events
It has been suggested that patients with a clinical
history of stroke have an increased risk of developing
AD particularly in the presence of vascular risk factors
(Honig et al 2003). Furthermore, silent cerebral or
brain infarcts or silent brain ischemia (SBI) (identified
by neuroimaging techniques), even in patients with no
history of transient ischaemic attacks (TIAs) or stroke,
can contribute to the loss of memory and cognitive
function in the elderly. It was found that SBI more than
doubles the risk of dementia including AD (Vermeer et al
2003, 2007) and AD patients with SBI have lower
global cognitive function scores than patients with pure
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AD (Song et al 2007). Other risk factors are identified
in Table 2.
Now do time out 6.
Treatment
There are no drug treatments available that can cure AD
(Table 3). At best, medicines abate or improve symptoms,
temporarily slow down progression and manage the various
symptoms associated with the disease and this may be
unique to each patient. Early detection is always advised to
delay progression as treatments work best in the early stages
of the disease (Hartz et al 2010). Acetylcholine (ACh) is
a key neurotransmitter in the brain signalling short-term
memory and learning. It is broken down by the enzyme
acetylcholinesterase, which is in excess in the AD brain.
Glutamate is the most common neurotransmitter in the
brain and is involved in learning and memory. Dying brain
cells in AD release excess amounts of glutamate that causes
harm to the brain by over-stimulating healthy brain cells.
The choice of drug for any given patient is mostly
determined by the stage of the disease with donepezil,
rivastigmine and galantamine prescribed for mild to
moderate AD and memantine for moderate to severe
AD, who are intolerant to or have a contraindication to
cholinesterase inhibitors (National Institute for Health
and Care Excellence (NICE) Guidelines March 2011).
Now do time out 7.
New approaches
The following list summarises the various treatment
strategies currently being considered in light of recent
advancements in AD research (Lane et al 2012):
Anti-plaque strategies with monoclonal Ab (anti-A42
Ab: oligomeric A42 (for example, Bapineuzumab,
Solanezumab, Crenezumab).
Attack or disrupt the prion-like transmissibility of
protein aggregates.
Target inflammatory pathways/mechanisms on the
basis that inflammation is deleterious not beneficial
as a result of an initial trigger or immune challenge
(if so, identify that challenge).
Treatments that mimic the APP gene variant that
confers protection against AD.
Monoclonal Ab or gene therapy/strategy to target the
Apo4 variant.
Disrupt or inhibit the enzymatic cleavage of APP
into amyloid. For example, to inhibit the secretases,
BACE1, PS1 or PS2 (such as Semagacestat a
-secretase inhibitor).
Correct or target mitochondrial dysfunction.
Antioxidant therapy to tackle oxidative stress.
Table 2 Risk factors associated with Alzheimers disease
7
Drug treatments
T
i
m
e

o
u
tIdentify the drug treatments that your
patients are using locally. What is their
understanding of the ways in which the drugs
are meant to work?
6
Explanations
T
i
m
e

o
u
tLook at some of the ventured explanations of
why AD occurs. Summarise each, forming an
aide memoire that you might use to discuss
with colleagues or students. At this stage the
explanations are speculative. Anticipating
student questions about this, why is it vital
that scientists speculate regarding the origins
of AD? What can a practitioner add to the
speculation that might help scientists develop
interesting lines of future enquiry?
(Adapted from Povova et al 2012)
Risk factor hypothesis Comment
Smoking Increased risk of Alzheimers disease (AD) (meta-analysis).
Alcohol Increased risk of AD.
Overweight and obesity The higher the BMI, the higher the risk of AD.
BP and management of
hypertension
Increased BP, increased risk (observational studies).
Antihypertensive drugs offer a protective effect.
Hypercholesterlaemia
and statin therapy
Increased risk in middle-aged people 20 years later.
Statins reduce risk.
Nutritional factors Increased antioxidant intake, reduced risk.
Increased saturated fat diet, reduced risk.
Increased omega 3 EFAs, reduced risk.
Diabetes Mellitus Diabetes increased risk of AD.
Also increased risk of vascular dementia.
CVS and cerebrovascular
diseases
Increased risk in stroke patients.
Increased incidence of AD in CVD patients.
Psychosocial factors
Education and
socioeconomic status
Low status increased risk.
Social network and
social engagement
Poor network and engagement leads to reduced cognitive
function & dementia.
Social isolation leads to an increased risk.
Physical activity Physical activity delays onset of dementia and AD
(reduced risk).
Mental activity Protective effect against dementia and AD (reduced risk).
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Table 3 Current drug treatments for Alzheimers disease
8
Multidisciplinary work
T
i
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o
u
tIdentify the different professions involved
locally in managing AD and portraying
this as something that might be managed.
What factors do you think are essential in
conveying the challenge of AD and sustaining
a positive multidisciplinary attitude to work
in this area?
Preventative strategies
Little is known on whether AD can be prevented.
Technological progress is being made on early detection
that can make it possible for those with a family history
of AD to be vigilant about symptoms and take advantage
of assessments early on (McGuire et al 2006). This is
really based on the premise that AD is a response to injury
(Mcguire et al 2006); some go on to be healthy as clearing
away of plaques is at a sufficient rate to prevent deleterious
build-up and some go on to develop dementia and AD.
Predicting risk
The biggest risk factor is age. However, although risk
increases with age, the mechanisms need clarifying so that
measures can be taken to give those at risk a chance to
plan for that eventuality. Genetic counselling is available for
those at risk; given that there is little certainty of how genes
link with disease onset, this may be counterproductive by
creating a sense of worry unnecessarily.
Now do time out 8.
Dilemmas
The task of professionals who come into contact with
patients (psychiatrists, clinical psychologists, community
nurses, mental health nurses, GPs, home helps/
healthcare assistants, social services, solicitors, police
and other authorities) is not an easy one. This condition
has a profound and devastating impact on patients and
their families.
There is the danger of relying on a lay persons prototype
of mental decline where a family member, or carer, has
ulterior motives (such as financial gain). Conversely, there
may be those in the family who are eager to label a relative
showing worrying signs of dementia as being perfectly
normal, delaying any prompt treatment. Professionals
should remember the vulnerability of patients facing a
possible diagnosis of AD and the fear and anxiety that it
invokes, not only in those affected but also family members
who may worry about being at risk. Given the difficulties
in making a diagnosis (especially in the early stages), there
are a number of uncertainties and obstacles that make
treatment and management of AD particularly difficult.
Some of these dilemmas are:
What is the best point at which power of attorney
should be implemented?
If there is a family history of AD and how worthwhile
is genetic counselling? Knowledge can be devastating
so can steps be taken to mitigate the risk. Is there
sufficient progress in treatment strategies for people
diagnosed as being at risk?
What recourse is there for family members who
disagree about the mental capacity of a patient
when AD specialists and professionals cannot agree on
diagnosis or whether the patient retains the ability to
make decisions independent of family influence?
How much emphasis is given to changes in personality
and behaviour, including reasoning abilities, as
a diagnostic tool given that most of the cognitive
assessments focus on memory and recall?
Should society be more sympathetic to those who leave
or divorce their partner/spouse who has AD because
they are no longer the person/personality they once
were or should they stay and honour the in sickness
and in health commitment of all relationships?
How can society, and health and social care in particular,
be better integrated to support the needs of people with
AD so that they are not to be regarded as a burden?
What is the right time to advise admitting someone to
a care home even if they exhibit moments of extreme
lucidity and clarity?
What support services are available to the carers of
AD patients who seek specialist help, counselling or
even psychological intervention in a climate of cuts,
efficiency savings and a recession?
(Adapted from NICE 2011, Alzheimers Society 2012)
Proprietary name
(trade name)
Pharmacological mode of action
Cholinesterase inhibitors
Donepezil
hydrochloride
Rivastigmine
Galantamine

Aricept
Exelon
Reminyl
Inhibits the enzyme
acetylcholinesterase from breaking
down the neurotransmitter
acetylcholine (ACh). ACh is
essential for vital communication
between the nerve cells in the
brain; the loss of communication is
directly linked to the severity of the
symptoms associated with AD.
NMDA receptor antagonists
Memantine Exiba
Memantine blocks glutamate,
another neurotransmitter which
is in excess in AD pathology.
However, unlike ACh, excess
glutamate further damages brain
cells. Therefore, memantine
protects brain cells by blocking
these effects of excess glutamate.
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References
Conclusion
AD presents a unique problem to an ageing society,
not only in terms of cost of care but also in progressing
towards effective treatments that can halt the
advancement of the disease or reverse its damage to
provide a notable quality of life for as long as possible.
Questions on best care options will continue to dominate
until sufficient progress can be made on the very nature
of AD, its pathogenesis and treatments, or even a cure,
which seem a long way off at present.
9
Practice profile
T
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o
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tNow that you have completed the article,
you might like to write a practice profile of
between 750 and 1,000 words. See page 39 or
go to the Primary Health Care website:
www.primaryhealthcare.net and follow the
link to the Learning Zone.
PHC JULY 2013 32-38.indd 38 25/06/2013 10:57