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Overview of Alzheimer's disease and its management

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 REVIEW

Overview of Alzheimer’s disease and its

management
Johanna C Meyer, Pamela Harirari, Natalie Schellack
Department of Pharmacy, Faculty of Health Sciences, Sefako Makgatho Health Sciences University

Correspondence to: Hannelie Meyer, e-mail: hannelie.meyer@smu.ac.za

Keywords: Alzheimer’s, dementia, risks, prevention, care, pharmacotherapy, non-pharmacological

Abstract
Alzheimer’s disease is a degenerative disease of the brain, the most common cause of dementia in the geriatric population, and a major cause of death.
Alzheimer’s disease places a heavy burden on families, communities and society, in terms of care and costs. This is compounded by the fact that populations
across the world are having a longer life expectancy. An overview of Alzheimer’s as a disease state and its pharmacological and non-pharmacological
management is provided in the paper. Caring for the person diagnosed with Alzheimer’s may be taxing and thus caring for the carer is also described.

© Medpharm S Afr Pharm J 2016;83(9):48-56

Introduction increased care costs for governments, communities, families and

Alzheimer’s disease (AD) was identified more than 100 years ago.1
It is a degenerative disease of the brain and the most common
cause of dementia in older people, accounting for 60% to 80%
of cases of late-life cognitive dysfunction.1,2,3 There is a common
misconception that dementia is merely a natural consequence
of aging. Yet, dementia is a condition that impairs the cognitive
brain functions of memory, language, perception and thought,
significantly interfering with the ability to maintain activities
of daily living.4,5,6 The risk of developing dementia increases
significantly with age; however, it is not a predictable consequence
of aging.7
Alzheimer’s disease/dementia is contributing to the global non-
communicable disease burden, and it is a leading source of
morbidity and mortality in the aging population.4 According to
the latest statistics, Alzheimer’s disease/dementia is amongst the
top 50 causes of death in South Africa, ranking 27th with an age
adjusted death rate of 7.67 per 100 000 and accounting for 2 664
annual deaths (0.48%). South Africa is ranked 31st in the world in
terms of Alzheimer’s as the cause of death.8
Dementia, including AD, is considered one of the major health
challenges of current times and a global public health priority.4,9
It affects individuals, families and communities and is a growing
cause of disability. Often dementia is hidden, misunderstood and
underreported.4,9
Dementia has a major negative effect on people’s functioning,
independence, and the need for care. This in turn is placing a heavy
burden on families, communities and society, with the cost of care
often paid for out-of-pocket. The personal, social and economic
consequences of dementia are enormous. Dementia leads to
individuals, and to losses in productivity for economies. The cost
of care for dementia, estimated at US$ 604 billion per year in 2010,
is growing at a faster rate than the prevalence of the disease.4 In
2015 the cost of care was estimated to be US$ 21.6 billion in the
African region, which was one of the greatest increases observed
since 2010.10
Prevalence and incidence
Worldwide, the overall burden of AD is substantial with an
increasing prevalence in the aging population.2,11,12,13 Globally,
an estimated 47.5 million people are living with dementia, with
62% of the disease burden in low and middle-income countries,
where access to social protection, services, support and care are
very limited.9 In future, the number of dementia cases is expected
to nearly double every 20 years with the increasing aging
population.4,6
In 2016, an estimated 5.4 million people of all ages in the United
States were living with AD. This figure includes an estimated
5.2 million people ≥ 65 years and 200 000 people < 65 years, who
have younger-onset Alzheimer’s.14 According to the latest evidence
from the ongoing Framingham Heart Study in Massachusetts,
with more than 5 200 participants, cases of Alzheimer’s are still
increasing at an alarming rate, however the rate of increase seems
to be declining.15
The incidence of dementia is age-dependent, varies across
countries and in general doubles every 10 years after age
60 years.6,12 In Africa, an estimated 818 106 people are developing
dementia each year, currently affecting more than 4 million
people. This figure is expected to be more than 7 million by
2013 and double to 14 million by 2050. The ageing population

S Afr Pharm J 48 2016 Vol 83 No 9


is considered to be a major contributing factor to the increased
prevalence.10
The incidence and prevalence of AD or dementia is not associated
with a particular gender. Although in terms of numbers,
particularly over the age of 85 years, more females than males
have the disease. This is explained by the better life expectancy
amongst women.8,16
There is a paucity of published epidemiological data on the
prevalence of dementia and AD in South Africa and in other low-
and middle-income countries.17,18 According to estimates in the
World Alzheimer Report 2015 there were almost 186 000 people
living with dementia in South Africa, of whom nearly 75% were
women. This number is expected to rise to nearly 275 000 by
2030.6 A pilot study conducted in a rural black community of 2000
households in Bloemfontein, South Africa, showed a prevalence of
6.4% for dementia diagnosed by DSM-IV criteria.18
Disorders associated with neurodegeneration such as traumatic
brain injury, alcohol dependence and HIV infection are increasingly
affecting adults in South Africa. HIV-associated dementia (HAD) is
prevalent in 15–30% of untreated adults with late-stage disease.
Older adults, who already have an increased risk of non-AIDS-
related dementias, are most likely to have untreated HIV. This
might further impact the numbers of people with dementia.17
Risk factors for Alzheimer’s disease
Bearing in mind the projected increase in the number of people
who will be affected with AD and dementia within the next
20–30 years, there is an urgent need to identify opportunities for
effective prevention to mitigate this.9
Genetic risk factors
Apart from age as the major risk factor for AD, the most clearly
established risk factors, although not fully understood yet, are a
family history of dementia, rare dominantly-inherited mutations
in genes that impact amyloid in the brain, and the apolipoprotein
E (APOE) epsilon 4 (e4) allele.19 Evidence has shown that family
history of dementia as a risk factor for the development of AD
varies with the type of family relationship, the age of onset of
disease and the race. The risk of developing AD increases with
10-30% if an individual has a first degree relative with dementia.
Compared to the general population, where two or more siblings
are affected with late-onset AD, the risk of AD increases three-
fold.19 With late-onset AD, APOE is the main genetic risk factor
involved. Compared to non-carriers, people who are carriers of
one or two e4 allele are respectively at a 2- to 3-fold and 8- to
12-fold increased risk of developing AD.19 The strength of the
association is further modified by factors such as gender, race and
vascular risk factors.19
Acquired risk factors
There are a number of acquired factors that may influence the risk
for Alzheimer's disease.15,19,20,21 Risk factors include hypertension,
S Afr Pharm J 49
REVIEW
lipoproteins, cerebrovascular disease, altered glucose metabolism,
and brain trauma, of which many appear to be most relevant
when present in midlife.19 Hence, a key strategy to reduce the risk,
progression and severity of AD would be to manage these factors
during midlife.19,20
Published evidence from various studies suggested an association
between certain pharmacological classes (e.g. benzodiazepines,
anticholinergics, antihistamines, opioids) and cognitive
impairment in older adults. The relationship, however, is not fully
understood yet. In most cases the effects have been recognised
to be temporary and reversible, while in other studies, especially
in the case of long-term exposure, cognitive effects may not be
reversible in some patients.19,22
Environmental risk factors
Apart from apolipoprotein E (APOE) epsilon 4 (e4), genetic
studies showed limited predictive effects on Alzheimer’s onset.
This sparked renewed interest in directing resources towards
investigating environmental and toxic exposures as potential
risk factors for AD.23 Potential environmental risk factors being
investigated include second hand smoke, air pollution and
pesticides.19
Protective factors and prevention
While treatments to prevent or cure AD are urgently needed,
evidence has shown that steps can be taken to delay the onset
of AD.15 Recent epidemiological data from the Framingham Heart
Study in the United States, suggest that the onset of dementia
might be prevented, or at least delayed, by higher levels of
education and heart-healthy lifestyle measures.15 A decline in the
risk for developing dementia was observed amongst those who
had at least a high-school education.15 Higher levels of education
together with intellectual or cognitive stimulation assist in
building a robust connection of brain cells or cognitive reserve.5
In the case of degeneration of brain cells, there will be sufficient
brain cells remaining to keep memory and thinking intact and
help to limit the onset of AD. This also explains why previous
studies recommend activities such as crossword puzzles, reading
books, learning a new language or playing a musical instrument,
which may help to curb Alzheimer’s in old age.15 Evidently,
higher levels of education alongside cognitive activity produce a
cognitive reserve that decreases the impact of neurodegeneration
on cognitive function.5
Three components of lifestyle, i.e., social, mental, and physical
activity, are evidently inversely associated with the risk for
dementia and AD.15,23-25 Although more data and robust studies
are needed to confirm this relationship, lifestyle activities play a
role in other preventative strategies such as cognitive function
and healthy-heart lifestyle.15
Many of the risk factors for chronic diseases such as heart disease,
cancer, and diabetes can also increase the risk of dementia.
Suggestive evidence for other causative factors is not conclusive
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yet.4 The Framingham Heart Study also observed risk factors for
heart disease like smoking, high blood pressure and obesity.
Evidently, the risk of developing dementia was also decreased
where cardiovascular factors were better controlled. Regular
physical activity is known to improve blood vessel health,
including in the brain, and may stimulate levels of nerve growth
factors in the brain. Furthermore, regular exercise controls obesity
and diabetes, which both are associated with an increased risk for
developing AD.15
Pathophysiology
Alzheimer’s disease is a degenerative brain disorder characterised
by the destruction of nerve cells and neural connections in
the cerebral cortex of the brain.26 It is also characterised by
aggregation of amyloid β (Aβ) in extracellular senile plaques,
and formation of intraneuronal neurofibrillary tangles consisting
of hyperphosphorylated tau protein. This results in progressive
and irreversible memory deterioration, as well as deterioration
of various cognitive functions, leaving the patient dependent on
other people and requiring full-time medical care.27
Epidemiological studies have shown AD to be the leading cause
of dementia.27 According to Dumanski et al. (2016),28 AD is
complex and may have a number of pathways contributing to its
pathology. The majority of early-onset AD patients do not illustrate
a clear autosomal pattern of inheritance. However, rare autosomal
dominant forms of AD exist, predominantly manifesting as early-
onset AD.26 Although the pathogenesis of AD remains unclear, all
forms of AD appear to have overproduction and/or decreased
clearance of amyloid β peptides in common.19 Mutations in three
genes – amyloid precursor protein (APP), presenilin 1 (PSEN1) and
presenilin 2 (PSEN2) – were identified to cause AD, even though
they are accountable for less than 1% of AD cases.29
Although late-onset AD is regarded as multifactorial, it involves
a strong genetic predisposition.26 The genetic component
itself is complex and heterogeneous (i.e. more common but
less penetrant), because there is no single model that explains
the mode of disease transmission, and gene mutations
or polymorphisms may interact with each other and with
environmental and other non-genetic influences, such as,
hypertension, cerebrovascular disease and brain trauma.19,29 The
common genetic risk factor associated with late-onset AD is
apolipoprotein E (APOE). The genetic predisposition of the non-
Mendelian form of AD is quite substantial, even for late-onset AD
patients, with a heritability estimate of 60–80%. Family history can
be considered as a risk factor for the development of AD.19 The
translation of genetic findings into functional mechanisms that
are biologically important in disease pathogenesis and treatment
design has proven to be difficult as the genetic contribution to AD
risk remains poorly understood.26
Prospective clinical and biomarker studies have shown that AD
pathology (asymptomatic phase) usually presents decades before
clinical symptoms appear.30 Clinical diagnosis of AD focuses on
the development of dementia rather than on the underlying
S Afr Pharm J
neuropathological changes.31 Usually, early cognitive changes
may be subtle or non-existent. This makes it difficult for early
diagnosis, and thus requires highly sensitive tests targeting
specific brain regions affected in the early disease progression.
The data regarding structural brain changes in preclinical AD
remain unclear. Cortical thinning or hippocampal atrophy has
been associated with brain amyloidosis, in some studies, whereas
other studies have found no relationship or have reported
increased cortical thickness.30 According to Pegueroles et al.
(2016),30 another challenge in diagnosing subjects is the fact that
brain structure is highly dynamic and evolves with age, making it
difficult to distinguish whether effects on brain structure are age-
related or disease-specific.
Evidence from previous studies indicates that cognitive decline
can be associated with extensive changes across the brain
regions responsible for temporally correlated activity at rest
and suppression of activity during task-related behaviours, i.e.
posterior cingulate and temporoparietal regions, also known as
the default mode network (DMN).31 The dysfunction of the DMN
may be used as a neuroimaging marker of cognitive decline in
preclinical populations. These subjects may present with lack of
verbal fluency and sound reasoning, low processing speed and
poor function of episodic memory.31
Clinical features, diagnosis and care
There is a long asymptomatic period between the onset of
biochemical changes in the brain and the presentation of clinical
symptoms of AD.19 A decline in amyloid β 1-42 in cerebrospinal
fluid (CSF) has been perceived to precede disease onset by
25 years, whereas cognitive impairment seems to manifest only
5 years prior to clinical diagnosis.19
The most common hallmark of AD is memory impairment.32
Deterioration of other cognitive functions is usually accompanied
by, or appears after, memory decline. Development of symptoms
occurs gradually. Early symptoms of the disease include
visuospatial abnormalities and executive dysfunction. Language
deficits and behavioural changes are usually noticeable in the
later stages of the disease.32
According to the Diagnostic and Statistical Manual (DSM), patient
history and clinical assessment of patients with dementia indicate
significant cognitive impairment in one or more of the following
cognitive areas; learning and memory, language, executive
function, complex attention, perceptual-motor function and
social cognition.25
Declarative episodic memory is usually affected in the early stages
of AD, whereas, semantic memory tends to be affected at a later
stage.32 Diagnosis is usually conducted by testing memory by
asking patients to recall series of words or objects immediately,
and then after a 5-10 minute delay. Patients may present with the
inability to retain new information.25
Executive function impairment may be subtle or prominent.32
50 2016 Vol 83 No 9
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Diagnosis is done by interviewing the patient’s family, friends or
colleagues. The patient may seem to have become disorganised
or demotivated, with loss of insight over time. Spatial ability and
orientation may be impaired such that patients get lost in familiar
places.25
Alzheimer's disease patients may present with neuropsychiatric
symptoms such as, apathy, irritability and social disengagement,
especially in the later stages of disease.32 It can be difficult
to distinguish between apathy and depression, therefore
diagnosis should be thorough to rule out depression. Patients
with depression tend to visit a physician on their own and may
complain of memory loss, whereas patients with AD are usually
brought to physicians by family, friends or colleagues, and are
unaware of their memory loss.25
Other signs and symptoms are difficulty to handle complex tasks,
inability to cope with unexpected events and sleep disturbances,
which manifest in the early stages of AD, whereas seizures and
apraxia, which can be assessed by asking the patient to perform
ideomotor tasks, usually present in the later stages.25,32 The
progression of AD is inevitable; however, the progress of disease
can be measured using the Mini-Mental State Examination
(MMSE), the Clinical Dementia Rating Scale and the Montreal
Cognitive Assessment (MoCA).25,32
A detailed clinical assessment can provide an accurate diagnosis
of AD, but it lacks sensitivity and specificity.32 It is therefore
imperative to carry out a detailed cognitive and general
neurologic examination. Other diagnostic modes that can be
beneficial in identifying AD are neuropsychological assessments,

WARNING SIGNS FOR ALZHEIMER’S DISEASE

 Memory problem NOT caused by alcohol abuse / head injury; worsening over time
 Language problems i.e. difficulty naming objects, finding right word to use
 Difficulty in fastening zips and buttons or to dress themselves
 Personal hygiene not important; may not want to bath; do not care about image
 Extreme mood swings; change in mood for no reason e.g. being calm then suddenly
scared or angry and aggressive, within minutes
 Impaired judgement; strange behaviour e.g. wearing underclothes over top clothes or
taking clothes off in public
 Get lost in familiar places such as their own neighbourhood
 Even recognition of their own family and friends becomes difficult
 Recalls memories of childhood at times; cannot remember what happened the same
day

EARLY/MILD STAGE MODERATE/MIDDLE LATE/SEVERE STAGE

(MMSE 18-26) STAGE (MMSE 10-17) (MMSE 0-9)
Symptoms might only be Problems are more People are more disabled
apparent in retrospect apparent and disabling and need a great deal of help

Progresses to total
Problems with Needs help with basic dependence on
Activities of
daily living

routine tasks activities of daily caregiver e.g. feeding,

Inability to living e.g. feeding, toileting, walking
manage finances dressing, bathing Requires care 24 hours a
day, 7 days a week

Anxiety, suspicion,
Behaviour

Changes Crying, screaming,

pacing, insomnia,
in personality groaning
agitation, wandering,
paranoid, delusional

Confusion & memory loss  Difficulty recognising  Loss of speech

 Misplacing objects family and friends  Misidentifies or is
Cognition

 Forgetting names and  Chronic loss of recent unable to recognise

recent events memory of events familiar people
 Disorientation  Severe impairment of  Urine and faecal
 Denial of memory loss recall for recent events incontinence

Figure 1: Warning signs and stages of Alzheimer’s disease 1,33

MMSE: Mini-Mental State Examination
MMSE: Mini-Mental StateFigure 1: Warning signs and stages of Alzheimer’s disease 1,33
Examination

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neuroimaging, biomarkers and genetic testing. The most common
disorders considered in the differential diagnosis of AD are other
neurodegenerative dementias, and vascular dementia, which is
caused by ischaemic or haemorrhagic strokes.32
Stages of Alzheimer’s disease
The progression of AD is divided into three main stages namely
the mild (early-stage), moderate (middle-stage), and severe (late-
stage) (see Figure 1).1,33 Symptoms of AD can be divided into
cognitive symptoms, non-cognitive (behavioural) symptoms and
activities of daily living.1 Cognitive symptoms present throughout
the illness, while behavioural symptoms and activities of daily
living are less predictable and depend on the individual patient.1
Understanding what these stages entail, can assist with the
personal treatment plan for the patient.1,33
Caring for a person with Alzheimer’s disease
A critical component of an AD patient’s treatment plan is to
ensure the patient and the caregiver/s are involved in the care
and related decision-making process. Hence, education on the
course of illness, prognosis, available treatments, legal decisions,
and quality-of-life issues, upon initial diagnosis, is essential.1 The
caregiver should also understand how AD changes people, what
are the challenges as a result of these changes and how to cope
with the subsequent challenges.
Basic principles of care for the patient with AD1,33
• Help family members, friends and others understand the disease.
• Find the optimal level of autonomy and adjust expectations for
patient performance over time.
• Changes in communication skills
◦◦ Consider vision, hearing, or other sensory impairments to
adapt.
• Changes in personality and behaviour
◦◦ Avoid confrontation.
◦◦ Remain calm, firm, and supportive, if the patient becomes
upset.
◦◦ Keep the person with AD safe: In the home, when going out
and when driving.
◦◦ Reduce choices, keep requests and demands of the patient
simple, and avoid complex tasks that lead to frustration.
◦◦ Identify the symptom and causative factors, and adapt the
caregiving environment to remedy the situation.
◦◦ Personal discomfort may trigger behaviours: Monitor for
pain, hunger, thirst, constipation, full bladder, fatigue,
infections, skin irritation, comfortable temperature, fears, and
frustrations.
◦◦ Environmental triggers: Noise, glare, an insecure space, and
too much background distraction, including television.
• Changes in activities of daily living
◦◦ Provide everyday care: Activity and exercise, healthy diet,
personal hygiene, dressing and grooming.
S Afr Pharm J
◦◦ Adapt daily activities: Daily household chores, going out,
music, eating out, travel, spiritual activities, holidays, visitors.
◦◦ Provide frequent reminders, explanations, and orientation
cues.
◦◦ Employ guiding, demonstration, and reinforcement.
◦◦ Maintain a consistent, structured environment with
stimulation level appropriate to the individual patient.
◦◦ Interventions should redirect the patient’s attention rather
than be confrontational and should specifically address
known triggers. Creating a calm environment and removing
stressors and triggers is key.
• Attend to medical problems
◦◦ Commonly include falls, incontinence, constipation, flu,
pneumonia, dehydration.
◦◦ Bring sudden declines in function and the emergence of new
symptoms to professional attention.
• Changes in intimacy and sexuality
◦◦ Address or adapt to changes in intimacy and sexuality.
◦◦ Reassure the person of love and safety.
• End-of-life care: Moving the person, prevent hurting themselves,
swallowing problems, skin problems, foot care.
• Future planning: Plan ahead in terms of health, legal and
financial issues.
Caring for the caregiver
Caregivers must be prepared, and able to, face the challenges that
will occur as the patient is progressing through the degenerative
stages of the disease.1,33 One of the most important aspects of
the AD patient’s care is to ensure that the caregiver is taking care
of himself/herself.1,33 A number of actions that the caregiver can
take, which could potentially bring some relief, improve his/her
quality of life and prevent physical and mental illness, are shown
in Figure 2.1,33
Management of Alzheimer’s disease
Treating the symptoms of cognitive impairment and maintaining
the patient’s functionality for as long as possible are the primary
goal of AD treatment.1 This can assist in preserving the patient’s
independence and dignity for a longer period of time, as well
as assist and encourage caregivers.1,33 Secondary goals include
treating psychiatric and behavioural sequelae.1 Presently, there
is no cure for AD, neither evidence of available pharmacological
treatment to prolong life, nor halt or reverse the pathophysiological
processes of the disease.1
In the past, a considerable amount of research on developing
disease-modifying treatments for AD was conducted.34 Despite
many promising preclinical research results, the human clinical
trials were unsuccessful. Subsequently, the focus shifted to
preventative measures to delay the onset of AD rather than
treating the disease. However, it remains imperative to identify
strategies that may slow down the progression of AD. Currently,
52 2016 Vol 83 No 9
Caregivers must be prepared, and able to, face the challenges that will occur as the patient is
progressing through the degenerative stages of the disease.1,33 One of the most important aspects
of the AD patient’s care is to ensure that the caregiver is taking care of himself/herself.1,33 A number
of actions that the caregiver can take, which could potentially bring some relief, improve his/her REVIEW
quality of life and prevent physical and mental illness, are shown in Figure 2.1,33

Non-pharmacological therapy

Get Help Get Exercise Non-pharmacological therapies have become more important
with the and Eat over the last number of years, as evidence of the role of certain
Caregiving Healthy Food
protective factors against the progression of dementia have
Join a Support Build a Support become available, e.g. physical activity, life style factors and
Group for AD Team educational stimuli.15 Since there is no current cure for AD – a
Caregivers degenerative disease that negatively affects the quality of life of
Keep Up with
Hobbies and the patient as well as of the family or carer – non-pharmacological
Take Breaks and Interests treatment interventions should be considered.
Spend Time with
Friends Non-pharmacological strategies to slow disease progression
Keep Own
Health, Legal
Consider In view of the slow onset of AD, early intervention has potential
and Financial
Nursing Home
Information Up benefits for patients. Research evidence has shown that there
or Hospice
Get Counselling to to Date are non-pharmacological strategies, which may help slow the
Services
Deal with Stress, progression of AD. However, more research is needed in patients
Own Feelings and to with AD. A summary of these strategies appears in Table I.34
Plan for Unexpected
Events A multi-factorial approach to the non-pharmacological
strategies in Table 1 is recommended as no one cause has been
Figure 2:Strategies
Figure 2: Strategies for
for caregivers
caregivers to
to take
take care
care of
of themselves
themselves 33
33 identified as exclusively contributing to neurodegeneration.34
Many of these strategies are modifiable life-style factors which
Management
clinical trials and of Alzheimer’s
further research aredisease
being conducted to find a can be implemented by patients themselves, with support from
treatment that targets the gene responsible for AD progression. 35 their caregivers as well as the multi-disciplinary health care
Treating the symptoms of cognitive impairment and maintaining the patient’s team. functionality
34 for as in this field of AD management is showing
Evidence
A recent study showed that manipulating an early trafficking
long as possible are the primary goal of AD treatment.1 This can assist in preserving the patient’s
promise, hence further research should be encouraged, especially
protein pathway
independence (COPI) for
and dignity which affects
a longer APPof–time,
period a protein
as wellthat causes
as assist and encourage caregivers.1,33
1 considering that disease modifying pharmacological treatment is
Secondary
the goals include
development treating psychiatric
of Alzheimer’s, amyloidand behavioural
plaques sequelae.
responsible forPresently, there is no34 cure
for AD, neither evidence of available pharmacological treatment to prolong life,still nor evasive.
halt or reverse
memory loss and other symptoms of Alzheimer’s 1
can be decreased
the pathophysiological processes of the disease.
significantly. The decrease of COPI resulted in some improvement Non-pharmacological interventions to improve cognition and
In the
of past, aimpairment,
memory considerable showing
amount ofpromise
researchfor
on the
developing disease-modifying
development of autonomy
treatments for AD
was conducted.34 Despite many promising preclinical research results, the human clinical trials were
future Alzheimer’s treatments that will slow the progression of the
unsuccessful. Subsequently, the focus shifted to preventative measures to delay Evidence
the onsetfrom the literature over the last 10 years identified
of AD
disease. 36,37
various
rather than treating the disease. However, it remains imperative to identify strategies thatinterventional
may slow tools, which could be used as part of

Table I: Non-pharmacological strategies to slow disease progression34

Strategy Role in slowing disease progression
• Blood pressure monitoring may have direct benefit on patient’s physical and cognitive health.
Blood pressure • Anti-hypertensive medications which manipulate the RAS may be neuroprotective.

• Adherence to a healthy diet should be advised and supported.

• Lower rate of mortality in those who follow a Mediterranean diet.
Diet
• Personalised supplementation to address specific dietary deficiencies, e.g. vit D, vit B12 and folate, may be useful.
• Sunlight exposure for improving vit D intake.
• Almost any physical activity maintained by AD patients may have a role in slowing the progression of cognitive and
Exercise functional symptoms.
• Exercise helps to protect from consequences of frailty.
• Improvements in MMSE.
Cognitive stimulation therapy
• Improvement in quality of life.
(CST)
• See Table II
• Maintaining social networks help maintain independence and quality of life.
Social networks
• Social engagement can reduce agitation - encourage ways to improve social interaction.
• Medicines used for behavioural and psychological symptoms have limited effect in AD population. Non-
pharmacological interventions for symptoms of agitation, depression and psychosis need to be investigated further.
Behavioural and Psychological • Social engagement and steps taken to improve quality of life via diet, physical activity and pain management to protect
Symptoms of Dementia (BPSD) from distressing symptoms.

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Table II: Non-pharmacological interventions for patients with Alzheimer’s disease38

Category Sub-category Approach Benefits

Reality orientation (RO) • Informal RO: Care staff should continuously convey basic information • Temporally and spatially reorient
about who the patient is, where he/she is and what time it is. patients.
• Formal/class RO: Patients meet daily, for 30–40 min sessions in a • Beneficial effects on cognition for
classroom; perform specific tasks, e.g. rehearsal of spatial and temporal mild to moderate AD.
information, discussion of current social events /episodes of their • Enhances the conventional
personal stories with supportive material, such as a whiteboard or pharmacological treatment.
newspapers.
Cognitive stimulation • 5-week programme: Visual imagery, word association and • Beneficial effects for mild to
therapy (CST) categorization tasks. moderate AD patients, stable on
• 14-session programme: Physical games, sounds, childhood, food, cholinesterase inhibitor treatment.
current affairs, scenes, word association, being creative, categorising • Significant cognitive effects and slow
Holistic techniques

objects, orientation, using money, number games, word games and down decline.
team quiz; session ±45 minutes long; starts with warm-up activity and • Preserve implicit memory.
song, choosing a group name; themed sessions that incorporate a RO • Reduce neuropsychiatric
board, reminiscence, multisensory stimulation and implicit learning. disturbances, particularly
depression/dysphoria, apathy.
Reminiscence Two types of individual and group sessions: • Improving global cognition.
• Guided by an individual’s free recall • Reduced depressive symptoms.
◦◦ Group meetings at least once a week. **Additional research necessary.
◦◦ Patients encouraged to talk about past experiences, activities and
events.
• Using a life-review procedure
◦◦ Patients actively search for autobiographical memories and
rebuilding their life story.
◦◦ Construction of a life book with personal materials to serve as
memory aid, e.g. photographs, music.
Spaced retrieval • Association of names with faces, or names with objects. • Increased retention span.
Cognitive
methods

• Patients are trained to recall information over progressively longer • Recall of meaningful items.
intervals of time. • Maintenance effects of spaced
retrieval training.
Music therapy • Benefits of use of sounds: Socialization, communication, coordination • Benefits up to advanced stages of
and expression. AD.
• Music sessions usually consist of listening to songs of different styles in • Reduction in frequency and extent
a passive or a participative manner. of neuropsychiatric symptoms
Alternative strategies

• Helps the recovery of memories by evoking autobiographical events especially anxiety and depression.
together with a sense of personal dignity and self-awareness. • Stimulates memory.
• Stimulates communication skills, impaired due to AD, leading to • Improved communication and
isolation because of inability to speak. personal autonomy.

Bright light therapy • Reduce circadian rhythm deregulation and likelihood of night-time • Indication of changes in: agitation/
disturbances and ‘sundown syndrome’, i.e. confusion/agitation in late aggression; depression/dysphoria;
afternoon/early evening. aberrant motor behaviour; appetite/
• Bright light consists of a set of fluorescent bulbs installed in a box; eating disorders.
patients sit close to the light box, with their eyes open, but not looking **Additional research necessary.
directly at light.

AD patients’ personalised treatment plan, to improve the Pharmacotherapy (PH)

cognition and autonomy of daily living and reduce behavioural
and psychological symptoms.38 A summary of these non-
pharmacological interventions is shown in Table II.38
Non-pharmacological interventions are
techniques which should be tailored to the needs of each specific
patient considering the individual needs; medical condition;
patient’s resilience and adherence to treatment; available
health, social services and professional resources; caregiver care
commitment; and support.38
An important consideration in the treatment of AD patients is
the fact that they are older patients and therefore may be taking
multiple medicines for other acute or chronic conditions. As the
complementary number of medicines increases, the risk for potential adverse
drug effects and non-adherence also increases.1 Aside from
medicines that temporarily relieve symptoms, there is no curative
treatment available for AD.35 This is due to the complex nature of
AD pathogenesis.39 Most of the symptomatic treatment attempts
to improve or maintain cognition.1

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The discovery that amyloid β protein activates the complement
system has indicated that inflammatory pathways somehow
contribute to the pathogenesis of AD.40 This has resulted in studies
exploring the use of anti-inflammatory agents in preventing and
in slowing down the progression of AD. Studies showed that
patients who were on non-steroidal anti-inflammatory drugs
(NSAIDS) were spared from AD, i.e. had reduced risk of getting
AD. The longer the NSAIDS were used prior to clinical diagnosis,
the greater the sparing effect.40 The mechanism behind this
effect is not fully understood, however, some hypotheses accredit
the regulation of cyclooxygenase-1 (COX-1) and COX-2 as the
driving force behind the effect, since COX-1 and COX-2 levels are
elevated in AD patients.41 Lipid-lowering agents, especially the
3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors,
such as pravastatin and lovastatin (but not simvastatin) have been
associated with lower prevalence of AD, and hence they may also
be used to prevent the onset of AD.1
Medication such as cholinesterase inhibitors and N-methyl-D-
aspartate (NMDA)-receptor antagonists are quite effective in
managing cognitive symptoms, whereas antipsychotics and
antidepressants are more effective in non-cognitive symptoms.
Cholinesterase inhibitors, namely donepezil, rivastigmine
and galantamine, have been shown to improve cognition.1
Donepezil is a piperidine derivative which specifically inhibits
acetylcholinesterase, but not butyrylcholinesterase. Rivastigmine
acts centrally at acetylcholinesterase and butyrylcholinesterase
sites, but has low activity at these sites in the periphery.
Galantamine is a cholinesterase inhibitor that also has activity
as a nicotinic receptor agonist. Memantine is an NMDA-receptor
antagonist which blocks glutamatergic neurotransmission, which
may prevent excitotoxic reactions. It can be used as monotherapy,
or in combination with a cholinesterase inhibitor. Their synergistic
effect has been shown to improve cognition and activities of daily
living.1 Antipsychotics, especially atypical antipsychotics, have
been used to treat disruptive behaviours and psychosis in AD
patients. Antidepressants, especially selective serotonin reuptake
inhibitors, have also been used to treat depression and anxiety in
AD patients.1 Paroxetine, however, causes more anticholinergic
side effects than the other selective serotonin reuptake inhibitors
(SSRIs). Tricyclic antidepressants are usually avoided due to their
severe anticholinergic side effects.1

Table III: Pharmacological management in Alzheimer’s disease1,40-42

Drug class Drug Use Side effects
Cholinesterase Inhibitors Donepezil Mild to moderate AD Mild to moderate gastro-intestinal disturbances
Rivastigmine Donepezil also used for severe including; nausea, vomiting and diarrhoea, urinary
Cognitive Symptoms

AD incontinence, dizziness, headache, syncope, bradycardia,

Galantamine muscle weakness, salivation, and sweating.
Abrupt discontinuation may worsen cognition and
behaviour in some patients.

N-methyl-D-aspartate Memantine Moderate to severe AD Constipation, confusion, dizziness, hallucinations,

(NMDA)-receptor headache, cough and hypertension.
antagonists
Antipsychotics (Atypical) Clozapine Disruptive behaviour and Somnolence, extrapyramidal symptoms, abnormal
Risperidone psychosis in AD gait, worsening cognition, cerebrovascular events,
Non-cognitive symptoms

hypotension and increased risk of death.

Antipsychotics (Typical) Haloperidol Disruptive behaviour and

psychosis in AD

Antidepressants Paroxetine Depression and anxiety in AD Gastro-intestinal disturbances including; nausea,

Venlafaxine vomiting, dyspepsia, abdominal pain, diarrhoea and
constipation, anorexia, anaphylaxis, arthralgia, myalgia,
dry mouth, insomnia, tremor, dizziness, hallucinations,
drowsiness and urinary retention.

Non-steroidal anti- Ibuprofen Patients at risk of developing AD Gastro-intestinal disturbances including; discomfort,
inflammatory drugs Indomethacin (potential preventative option nausea, vomiting, diarrhoea and occasionally bleeding
potential preventative option

(NSAIDS) before cognitive impairment) and ulceration, rashes, angioedema, bronchospasm,

Long-term pre-treatment -

headache, dizziness, drowsiness, nervousness,

depression, insomnia, vertigo, tinnitus, photosensitivity,
haematuria and fluid retention.

3-hydroxy-3- Pravastatin Patients at risk of developing AD Myositis, rhabdomyolysis, gastro-intestinal disturbances,

methylglutaryl coenzyme Lovastatin (potential preventative option pancreatitis, hepatitis, jaundice, sleep disturbance,
A–reductase inhibitors before cognitive impairment) headache, dizziness, depression, paraesthesia, asthenia,
peripheral neuropathy, amnesia, fatigue, sexual
dysfunction, thrombocytopenia, arthralgia, visual
disturbance and alopecia.

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Conclusion
Alzheimer’s disease is the most common form of dementia in
older adults. The disease is extremely complex, with causes
not fully understood. Patients progress through degenerative,
irreversible phases of the disease, while cognitive functioning
(memory, thinking and reasoning) and behavioural abilities
are affected, up to the point where the person must depend
completely on others for basic activities of daily living. Current
pharmacological treatment used in the management of AD may
ease the symptoms for a period of time, but do not stop the
persistent downward progression of the disease. Patients may
benefit from non-pharmacological strategies tailored to the needs
of the individual person. Ongoing research indicated that specific
precautionary measures, i.e. higher education and improved heart
health, are most likely to delay the onset of AD. The urgent need
for drug development is echoed by the words of Margaret Chan,
the Director-General, World Health Organization “I can think of no
other disease where innovation, including breakthrough discoveries
to develop a cure, is so badly needed.” 4
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