Pharmacology of drugs used to treat Alzheimer's disease

1. Alzheimer's disease
Pharmacotherapy
KRVS Chaitanya

2. Dementia
• Dementia describes a clinical syndrome that is characterised
by a significant deterioration in mental function that leads to
impairment of normal function.
• In healthcare, we measure ‘normal function’ by activities of
daily living (ADLs).
• These are a series of routine activities that people should be
able to do without assistance. They can be broadly divided into
personal tasks and domestic tasks.
– Personal: washing, dressing, toileting, continence, transferring (e.g.
bed to chair)
– Domestic: cooking, cleaning, shopping, managing finances, taking
medication

3. • Dementia can be caused by several conditions, which all manifest with
poor mental performance and impaired normal functioning.
• The clinical manifestations of dementia can reflect the underlying
aetiology.
– Alzheimer’s disease (AD): 50-75%
– Vascular dementia (VD): 20%
– Dementia with Lewy-body (DLB): 15-20%
– Front temporal dementia (FTD): 2%
– Rare causes: Parkinson’s disease dementia (PDD), Huntington’s disease
(HD), Prion disease, others.

4. Alzheimer's disease
• Alzheimer's disease (AD) is a progressive neurodegenerative
disorder that causes significant deterioration in mental
performance.
• This leads to impairment in normal social and occupational
function.
• It is the most common cause of dementia and unfortunately an
incurable condition that has a variable clinical course

5. Epidemiology
• Dementia is primarily a disease of older adults.
• The World Health Organisation (WHO) estimates that almost 50 million
people have a diagnosis of dementia worldwide.
• In the UK, it is estimated that > 500,000 people have a diagnosis of AD.
• The prevalence of dementia increases with age. The estimated prevalence
at 60-64 years is 0.9% compared to 41.1% in those aged 95 years and over.
• A significant proportion of patients with dementia remain undiagnosed and
up to 54% of patients with dementia require care home placement.

6. Aetiology
• The exact cause of AD remains unknown.
• The overarching theory involves environmental and genetic
risk factors that increase the chance of developing pathological
processes, which lead to dementia.

7. Causes
• Like all types of dementia, Alzheimer’s develops due to the death of brain
cells. It is a neurodegenerative condition, which means that the brain cell
death happens over time.
• In a person with Alzheimer’s, the brain tissue has fewer and fewer nerve
cells and connections, and tiny deposits, known as plaques and tangles,
build up on the nerve tissue.
• Plaques develop between the dying brain cells. They are made from a
protein known as beta-amyloid. The tangles, meanwhile, occur within the
nerve cells. They are made from another protein, called tau.
• The Alzheimer’s Association have produced a visual guide to show what
happens in the process of developing Alzheimer’s disease

8. Risk factors
• Unavoidable risk factors for Alzheimer’s disease include:
– Aging
– Having a family history of Alzheimer's disease
– Carrying certain genes
• Other factors that increase the risk of Alzheimer’s include Trusted
Source severe or repeated traumatic brain injuries and having
exposure to some environmental contaminants, such as toxic metals,
pesticides, and industrial chemicals.

9. • Modifiable factors that may help prevent Alzheimer’s
include:
– Getting regular exercise
– Following a varied and healthful diet
– Maintaining a healthy cardiovascular system
– Managing the risk of cardiovascular disease, diabetes, obesity,
and high blood pressure
– Keeping the brain active throughout life

10. Commonly recognised risk factors
– Age: older age is a major risk for AD
– Genetics: most cases of AD are sporadic. Small number of inherited
causes exist (<5%, autosomal dominant inheritance).
– Cardiovascular disease: smoking and diabetes increase
risk. Exercise decreases risk.
– Depression
– Low educational attainment
– Low social engagement and support
– Others: head trauma, learning difficulties.

11. Pathophysiology
• The neurodegeneration in AD is hypothesised secondary to altered
amyloid and tau protein metabolism.
• The brain is composed of billions of neurons.
• The normal functioning of theses neurons is dependent on
surrounding supportive structures such as microtubules and the
protein tau, which stabilise these microtubules.
• Pathological changes that occur in AD leads to interruption of key
neuronal process including communication, metabolism and repair.

12. • The two key pathological changes in AD are senile plaques
and neurofibrillary tangles:
1. Senile plaques (SP): deposits of beta-amyloid (aggregation of protein
with a beta-sheet secondary structure). Dense, insoluble. Occur
outside of neurons (i.e. extracellular).
2. Neurofibrillary tangles (NFT): aggregations of
hyperphosphorylated tau proteins. Typically occur in areas of the
brain involved in memory. Promote neuronal cell death. Form inside
neurons (i.e. intracellular)

13. • Both SP and NFT are characteristic of AD but no path
gnomonic.
• They can be seen in other neurodegenerative conditions. SP is
also seen in normal ageing.
• Therefore, it is the amount of these pathological changes and
the topographic location within the brain (e.g. hippocampus
and medial temporal lobes) which is characteristic of AD.

14. • The amyloid deposition hypothesis is supported by
identification of genetic mutations in the amyloid precursor
gene APP leading to early-onset AD, and evidence of neuronal
apoptosis on treatment of cells with beta-amyloid.
• However, some patients with severe AD do not have evidence
of amyloid deposition on autopsy, and other patients who had
no evidence of dementia have amyloid deposition.

15. • Several additional mechanisms are part of the pathological
processes in AD.
• Alongside SP and NFT, these result in neuronal cell death that
leads to memory failure, personality changes and problems
with activities of daily living (hallmarks of dementia).

16. Clinical features
• Dementia can be difficult to identify due to the insidious and non-specific
symptoms.
• Many clinical features are attributable to dementia. Some are characteristic
of all dementias whereas others are typical of a particular type, like AD.
• There is usually a slow onset of symptoms and lack of insight with
accommodation to cognitive or functional changes.
• It is best to consider clinical features in the following domains: cognitive
impairment, behavioural and psychological symptoms of dementia (BPSD),
disease-specific features and activities of daily living.

17. – Cognitive impairment
– Poor memory
– Language problems: receptive and expressive dysphasia
– Problems with executive functioning: planning and problem solving
– Disorientation
– BPSD
– Agitation and emotional lability
– Depression and anxiety
– Sleep cycle disturbance
– Disinhibition: social or sexually inappropriate behaviour
– Withdrawal/apathy
– Motor disturbance: wandering is a typical feature of dementia
– Psychosis

18. Disease-specific features
– AD: early impairment of memory. Manifests as short-term memory loss
and difficulty learning new information.
– VD: typically a ‘stepwise’ decline in function. Predominant gait,
attention and personality changes. May have focal neurological signs
(e.g. previous stroke)
– DLB: parkinsonism (tremor, rigidity, Bradykinesia, postural
instability). Fall, syncope and hallucinations predominant feature
– FTD: marked personality change and behavioural disturbances.
Memory and perception relatively preserved.

19. Activities of daily living
– Loss of independence: increasing reliance on others for
assistance with personal and domestic activities
– Early stages: problems with higher level function (e.g.
managing finances, difficulties at work)
– Later stages: problems with basic personal care (e.g.
washing, eating, toileting) and motor function (e.g.
walking, transferring)

20. Cognitive assessment
• A formal mental status examination should be completed using
a recognised cognitive assessment tool.
• There are multiple cognitive assessment tools, which are
designed to test different areas of higher cortical functioning.
• Cognitive domains assessed include:
• Attention and concentration
• Recent and remote memory
• Language
• Praxis: planned motor movement (e.g. perform a task)
• Executive function
• Visuospatial function

21. • There are a variety of different cognitive assessment tools that range
from basic screening tools, to in-depth assessments of each
cognitive domain.
• Here we summarise some of the main tools.
1. Mini-cog
– Overview: a three item word memory and clock drawing. Screening tool
in general practice.
– Time: 2-4 minutes
– Setting: General practice
– Cut-off for dementia: 5/8

22. 2. Abbreviated mental test score (AMTS)
• Overview: a ten item scoring tool predominantly used in hospital settings
(e.g. hospital ward).
• Time: < 5 minutes
• Setting: hospital ward and General practice
• Cut-off for dementia: 6-8/10
3. Mini-mental state examination (MMSE)
• Overview: an eleven item tool. Measures cognitive function. Extensively
studied and well-validated. Copyrighted.
• Time: ≤ 10 minutes
• Setting: Memory clinic, hospital-setting
• Cut-off for dementia: 24/30

23. 4. Montreal cognitive assessment scale (MoCA)
• Overview: test several domains including executive function, attention, some
language, memory and Visuospatial skills.
• Time: 10 minutes
• Setting: memory clinic, hospital-setting
• Cut-off for dementia: 26/30
5. Addenbrookes cognitive examination - III
• Overview: longer cognitive assessment tool that assess five domains: attention,
memory, verbal fluency, language and Visuospatial abilities. Based on the ACE-R,
which was originally designed to classify different kinds of dementia
• Time: 15-20 minutes
• Setting: memory clinic
• Cut-off for dementia: 82-88/100

24. Diagnosis
• It is essential to exclude all alternative causes before making a diagnosis of
dementia.
• Patients with suspected dementia are usually referred to a memory clinic.
• At memory clinic, patients undergo a formal history and examination
(including medication review), full complement of baseline investigations
including bloods and neuroimaging to exclude an underlying cause, and
formal cognitive assessment.
• In AD, this may be reflected by the lack of other neurological symptoms,
absence of major cardiovascular risk factors and predominant impairment
in memory, thinking and behaviour.

25. Diagnostic criteria
• There is a diagnostic criteria for dementia based on the Diagnostic and
Statistical Manual of Mental Disorders (DSM-V).
• We have simplified this into three key components:
– Functional ability: inability to carry out normal functions.
Represents a decline from previous functional level
– Cognitive domains: impairment involving ≥2 cognitive domains
(see chapter on cognitive assessment)
– Differentials excluded: clinical features cannot be explained by
another cause (esp. psychiatric disorders and delirium)

26. Mild cognitive impairment
• This describes cognitive deficits in one or more of the major
cognitive domains, but the deficit is insufficient to interfere
with independence in daily activities.
• Mild cognitive impairment is an increasingly important term
because it helps identify patients at risk of progression
to dementia.
• Patients should have regular follow-up and be advised to
undertake healthy brain activities (e.g. exercise, socialising).

27. Differential diagnosis
• Dementia is a clinical syndrome that reflects deterioration
from an underlying cause, the most common being AD.
• The main differentials to exclude in a patient with features of
dementia are the three ‘D’s’:
– Depression (and other psychiatric disorders): psychosis can be a feature of
dementia.
– Drugs: consider drugs with anti-cholinergic effects (e.g. anti-histamines,
anti-psychotics, anti-epileptics)
– Delirium: acute confusional state. May be prolonged recovery following
episode.

28. Severity
• The severity of dementia can be determined based on the level of
functional inability.
• Severity of dementia is determined using cognitive assessment tools
(e.g. MMSE/MoCA) or rating/assessment tools (e.g. clinical
dementia rating - CDR).
• In general, dementia can be divided into mild, moderate or severe.
• Mild: MMSE 21-26, MoCA 18-25, CDR 1
• Moderate: MMSE 10-20, MoCA 10-17, CDR 2
• Severe: MMSE <10, MoCA <10, CDR 3

29. Investigations
• Baseline investigations are essential to exclude an
alternative diagnosis.
• Typical baseline investigations involve a routine set of
blood tests and neuroimaging.
• Bloods
– Full Blood Count
– Erythrocyte Sedimentation Rate (ESR)
– Urea And Electrolytes
– Bone Profile
– Hba1c
– Liver Function Tests
– Thyroid Function Tests
– Serum B12 And Folate Levels

30. • Other
– ECG
– Virology (e.g. HIV)
– Syphilis testing
– CXR
• Neuroimaging
– Typically magnetic resonance imaging (MRI) but CT may be used if
MRI not available or unsuitable. Important to exclude an alternative
diagnosis (e.g. brain tumour) and can be used to help characterise the
type of dementia (e.g. small vessel disease in VD).

31. Management
• Pharmacological therapy can be used in patients with AD, but it is
only a small part of overall management.
• The management of AD, and dementia as a whole, should involve a
full assessment of the biological, psychological and social needs of
the patient.
• With significant deterioration in normal activities of daily living,
patients will become dependent on others.
• This means help from families, organisation of carers, and with
more advancing symptoms, need for care home placement.

32. TREATMENTS
• There is no known cure for Alzheimer’s disease. It is not
possible to reverse the death of brain cells.
• Treatments can, however, relieve its symptoms and improve
quality of life for the person and their family and caregivers.
• The following are important elements of dementia care:
– Effective management of any conditions occurring alongside
Alzheimer's
– Activities and daycares programs
– Involvement of support groups and services

33. Medications for cognitive symptoms
• No disease-modifying drugs are available for Alzheimer’s
disease, but some options may reduce the symptoms and help
improve quality of life.
• Drugs called cholinesterase inhibitors can ease cognitive
symptoms, including memory loss, confusion, altered thought
processes, and judgment problems.
• They improve neural communication across the brain and slow
the progress of these symptoms.

34. • Three common drugs with Food and Drug Administration (FDA)
approval to treat these symptoms of Alzheimer’s disease are:
– Donepezil (Aricept), to treat all stages
– Galantamine (razadyne), to treat mild-to-moderate stages
– Rivastigmine (Exelon), to treat mild-to-moderate stages
• Another drug, called memantine (Namenda), has approval to treat
moderate-to-severe Alzheimer’s disease.
• A combination of memantine and donepezil (Namzaric) is also
available

35. Emotion and behaviour treatments
• The emotional and behavioural changes linked with Alzheimer’s disease
can be challenging to manage.
• People may increasingly experience irritability, anxiety, depression,
restlessness, sleep problems, and other difficulties.
• Treating the underlying causes of these changes can be helpful. Some may
be side effects of medications, discomfort from other medical conditions, or
problems with hearing or vision.
• Identifying what triggered these behaviors and avoiding or changing these
things can help people deal with the changes.
• Triggers may include changing environments, new caregivers, or being
asked to bathe or change clothes.

36. • It is often possible to change the environment to resolve obstacles
and boost the person’s comfort, security, and peace of mind.
• The Alzheimer’s Association offer a list of helpful coping tips for
caregivers.
• In some cases, a doctor may recommend medications for these
symptoms, such as:
– Antidepressants, for low mood
– Antianxiety drugs
– Antipsychotic drugs, for hallucinations, delusions, or aggression

37. There are multiple facets to management.
1. Assess capacity and advanced care planning: ideally completed when
patients still retain capacity. Consideration of advance statements/decisions
and appointment of lasting power of attorney.
2. Physical and mental health: consider co-existing anxiety and depression.
Manage physical health needs as normal. Consider delirium if any acute
deterioration.
3. Driving: must inform the DVLA. Check website for guidance.

38. 4. Non-pharmacological: programmes to improve/maintain cognitive
function (e.g. structured group cognitive stimulation programmes).
Also exercise, aromatherapy, therapeutic use of music/dancing,
massage.
5. Managing BPSD: non-pharmacological interventions. Consider
referral to old-age psychiatry if difficult to control.
Pharmacological therapy should be used on specialist advice.
6. Care plans: people with dementia require a care manager and care
plan. This includes details on diagnosis, treatment, environmental
modifications and review plans.

39. 7. End-of-life care: focus on physical, psychological, social
and spiritual needs. Oral nutrition encouraged as long as
possible. Long-term feeding (i.e. NG feeding, gastrostomy
tube) inappropriate in severe dementia. No evidence for
increased survival or reduced complications. Resuscitation
discussions.

40. Pharmacological therapy
• Medical therapy for the treatment of dementia should be
initiated by a specialist in treating patients with dementia.
• The two main drugs are acetyl cholinesterase inhibitors and N-
methyl-D-aspartic acid receptor antagonists.
• Pharmacological agents are primarily indicated in patients with
AD.
• They should not be used in patients with mild cognitive
impairment.

41. Cognitive enhancers
• These are a heterogeneous group of drugs developed for use in
dementia and other cerebral disorders.
• They do elicit pharmacological effects, but widely different
mechanisms of action are claimed.
• Therapeutic benefits are limited, and at the best, short-lasting.

42. The indications of cognition enhancers include:
1. Alzheimer’s disease (AD) and multi-infarct dementia (MID).
2. Mild cognitive impairment (MCI) or‘ common symptoms’ of the elderly;
dizziness and episodic memory lapses.
3. Mental retardation in children, learning defects, attention deficit disorder.
4. Transient ischaemic attacks (TIAs), cerebrovascular accidents, stroke.
5. Organic psycho syndromes and sequelae of head injury, ECT, brain surgery.

43. • A variety of drugs have been briskly promoted by
manufacturers and wishfully prescribed by physicians.
• The mechanism by which they are believed to act are:
1. Increasing global/regional cerebral blood flow
2. Direct support of neuronal metabolism.
3. Enhancement of neurotransmission.
4. Improvement of discrete cerebral functions, e.g. Memory.

44. Cerebroactive drugs
1. Cholinergic activators:
Tacrine, Rivastigmine, Donepezil,
Galantamine
2. Glutamate (NMDA) antagonist:
Memantine
3. Miscellaneous cerebroactive drugs:
Piracetam, Pyritinol (Pyrithioxine), Dihydroergotoxine
(Codergocrine), Citicoline,
Piribedil, Ginkgo biloba.

45. Choice of therapy depends on severity:
– Mild-to-moderate AD: acetyl cholinesterase inhibitors (e.g. donepezil,
Rivastigmine).
– Moderate-to-severe AD: N-methyl-D-aspartic acid receptor antagonist
(e.g. memantine). May be used in combination with acetyl
cholinesterase inhibitors.

46. • Acetyl cholinesterase inhibitors are associated with small
improvements in cognition, neuropsychiatric symptoms, and
ADLs in patients with mild-to-moderate AD. However, there is
conflicting evidence on there impact on long-term outcomes
(e.g. need for care home, effect on critical ADLs).
• Memantine has modest effects in patients with moderate-to-
severe AD in terms of reducing functional decline.

47. PROGNOSIS
• There is no cure for dementia and it is considered a life-limiting condition.
• It is estimated that one in three people over the age of 65 will die with
dementia and the estimated median survival after diagnosis is 3-9 years
(variable).
• Progression of dementia has been estimated by WHO, which is based on
each stage of severity.
• Development of delirium on a background of dementia is associated with
more rapid progression.
– Mild: first 2 years
– Moderate: next 2-4 years
– Severe: 4-5 years onwards

48. Thank you