Alzheimer's disease pharmacotherapy

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: 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). 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. 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. 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 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. 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 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. 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.  Physical and mental health: consider co-existing anxiety and depression. Manage physical health needs as normal. Consider delirium if any acute deterioration.  Driving : must inform the DVLA. Check website for guidance.

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

39. 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 : Alzheimer’s disease (AD) and multi-infarct dementia (MID). Mild cognitive impairment ( MCI ) or‘ common symptoms’ of the elderly; dizziness and episodic memory lapses. Mental retardation in children, learning defects , attention deficit disorder. Transient ischaemic attacks (TIAs), cerebrovascular accidents , stroke. 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 : Increasing global/regional cerebral blood flow Direct support of neuronal metabolism. Enhancement of neurotransmission. Improvement of discrete cerebral functions, e.g. Memory .

44. Cerebroactive drugs Cholinergic activators: Tacrine, Rivastigmine, Donepezil, Galantamine Glutamate (NMDA) antagonist: Memantine 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

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