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CPD 66: UNDERSTANDING ALZHEIMER’S DISEASE Biography - Amy Louise Oates. I qualified from the Robert Gordon University Aberdeen with a Master in Phamacy in 2011. I then undertook my pre-registration year with Gordons Chemists in Edinburgh. After registration I moved back home, where I am now working for Johnstons Pharmacy in Longford Town, Lanesborough and Ballygar, Co. Galway. I also recently completed a Cardiology in Clinical Pharmacy Practice module with Trinity College Dublin.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice. 2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN - If I have identified a knowledge gap

- will this article satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs?

Published by IPN. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published in CPD and the Pharmacy is copyright and no part of this can be used within any other publication without the permission of the publishers and author.

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Understanding Alzheimer’s Disease

60 Second Summary

Alzheimer’s disease is the most common cause of dementia among older adults. Dementia is a term describing a range of different conditions which cause damage to the brain. Dementia is a chronic progressive mental disorder that adversely affects higher cortical functions including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. Alzheimer's disease is the most common form of dementia. It is a degenerative cerebral disease with characteristic neuropathological and neurochemical features.1 It is this damage that affects memory, thinking, language and the ability to perform everyday tasks.2 AD is an irreversible, progressive brain disorder, and although treatment can help to manage symptoms, there is no cure for the disease.3 The disease is named after Dr. Alois Alzheimer. In 1906, Dr. Alzheimer examined the brain of a patient who died of an unusual mental illness. Her symptoms included memory loss, language problems and unpredictable behaviour. Dr. Alzheimer’s examination found many abnormal clumps – now referred to as amyloid plaques, and tangled bundles of fibres – now referred to as neurofibrillary tangles. These plaques and tangles are the main features of Alzheimer’s Disease, as well as the loss of neurons – connections between nerve cells – in the brain. AD is a slow disease that progresses in three stages – an early stage with no symptoms, a middle stage with mild cognitive impairment, and a final stage Alzheimer’s Diseases. The brain of a patient with AD usually shows marked atrophy. In most cases every part of the cerebral cortex

There are three recognised stage of the disease - preclinical, mild cognitive impairment, and severe cognitive impairment. The presence of amyloid plaques and neurofibrillary tangles in the brain are used to diagnose AD. There is no cure for AD, treatment is aimed at alleviating the symptoms. Acetylcholinesterase inhibitors such as Donepezil, Rivastigmine and Galantamine are used in the treatment of AD, and also the glutamate receptor agonist Memantine.

is involved.4 The cortical ribbon may be also be narrowed and ventricular dilation present in AD, due to atrophy of both the amygdala and hippocampus. The median survival for people with Alzheimer's Disease from the time of onset has been estimated at seven years. Survival figures can vary however and depend on how they are measured, comorbidities, age (median survival decreases with increasing age) and sex.1 ANATOMY Healthy neurons have an internal structure made of microtubules that guide nutrients and molecules from the body of the cell, down the end of the axon and back. A protein called Tau binds to the microtubules and stabilises them.5 In Alzheimer's Disease, tau is chemically changed. It starts to pair with other threads of tau and they become tangled together. These neurofibrillary tangles (NFTs) cause a breakdown in communication between neurons and later can cause cell death The hippocampus and medial temporal lobe are the initial sites of tangle depositions and atrophy. In Alzheimer's Disease there is also the presence of plaques. Plaques are dense, insoluble deposits of protein and cellular material outside and around the neurons. Beta-amyloids is the protein that makes up these plaques. In AD these amyloid plaques develop in the hippocamus, an important structure in the brain that helps to encode memory, and also in other areas of the cerebral cortex that are used in thinking and making decisions. Neurofibrillary tangles and amyloid plaques are characteristic of

Alzheimer’s Disease is a degenerative brain disorder that usually develops in midlate adulthood. Azheimer’s is characterised by a progressive and irreversible decline in memory and a deterioration of various other cognitive abilities. Signs and symptoms vary between patients, however the same stages of the disease exist.

Alzheimer's Disease is initially associated with memory impairment that progressively worsens over time. Patients with AD also display additional symptoms of anxiety, depression, insomnia, paranoia and agitations. As the disease worsens patients will required assistance with basic activities of daily living, including dressing and bathing.


CPD 66: UNDERSTANDING ALZHEIMER’S DISEASE

HEALTHY BRAIN

SEVERE ALZHEIMER'S

Alzheimer’s, genetic mutation is the most probable cause. In early-onset Alzheimer’s, symptoms occur in people aged 30-60 years. Mutations in the following genes unequivocally cause early-onset AD:5 • Amyloid precursor protein (APP) gene on chromosome 21 • Presenilin-1 (PS1) Gene on chromosome 14 • Presenilin-2 (PS2) gene on chromosome 1 SYMPTOMS

National Institute on Aging, Alzheimer’s Disease Fact Sheet. Available online from: https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet

AD, however they can be found in other neurodegenerative diseases and may also occur in normal aging. NEUROPATHOLOGY The presence of amyloid plaques and neurofibrillary tangles in the brain are used to diagnose Alzheimer’s Disease. The plaques consist of deteriorating neuronal material surrounding deposits of a sticky protein called beta-amyloid. The neurofibrillary tangles are twisted protein fibres located in the nerve cells. These fibres are made of a protein, tau. When incorrectly processed, tau molecules clump together and form tangles. These plaques and tangles however are not unique to AD, they can be found in other neurodegenerative disorders and also in healthy elderly patients, but in smaller amounts. A deficiency in the neurotransmitter Acetylcholine has also been linked to Alzheimer’s Disease. The cholinergic system is involved in memory function, and a cholinergic deficiency impacts on cognitive decline and behavioural changes in AD.5 Activity of both choline acetyltransferase (CAT) and the catabolic enzyme acetylcholinesterase are significantly reduced in the cerebral cortex, hippocamus and amygdala in patients with AD.5

ETIOLOGY The actual cause of Alzheimer's Disease is unknown, however several risk factors for AD have been identified:

The symptoms of Alzheimer’s Disease varies between patients, but do seem to develop over the same general stages.3 AD is characterised by deterioration in cognition (E.g.: thinking, conceiving and reasoning), functional ability (E.g.: activities of daily living such as dressing, personal hygiene and handling money), behaviour (E.g.: agitation, wandering and uncharacteristic aggression) and non-cognitive symptoms including depression, delusions and hallucinations. Patients with AD might have difficulty performing everyday activities, such as shopping, socialising and recognising people and places. Communication becomes a problem as patients find it more difficult to find words and remember names. Alzheimer's disease can also be associated with a loss of confidence and feelings of fear, confusion, apathy, stigma and depression.1

• Obesity

The severity of Alzheimer's disease is assessed using several methods. Clinical practice uses a variety of measures, often along with clinically based assessments such as biographical interview. Severity is frequently defined by Mini Mental State Examination (MMSE) score:1

• insulin resistance

• Mild Alzheimer's disease: MMSE 21–26

• vascular disease

• Moderate Alzheimer's disease: MMSE 10–20

• Advancing age • Family history

• hypertension • dyslipidaemia CAUSES The cause of Alzheimer’s Disease is still not fully understood. Most people with AD have late-onset Alzheimer’s, with symptoms becoming apparent in their mid-60s. Research suggests that there can be a relationship between cognitive decline and vascular conditions such as heart disease, stroke, and high blood pressure, and also a link with metabolic conditions such as diabetes and obesity.3 In early-onset

• Moderately severe Alzheimer's disease: MMSE 10–14 • Severe Alzheimer's disease: MMSE less than 10. MILD STAGE Early, preclinical stage Alzheimer’s Disease has virtually no symptoms. Memory problems may signal the very early stages of AD. Examples of these initial signs of cognitive impairment include problems with word-finding, impaired reasoning or judgement and vision issues.


CPD 66: UNDERSTANDING ALZHEIMER’S DISEASE

APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron’s membrane, partly inside and partly outside the cell. ANDERSON, H.S. et al, Alzheimer’s Disease Treatment and Management, 2016. Available online from: http://emedicine.medscape.com/ article/1134817-overvieW

Enzymes act on APP and cut it into fragments of protein, one of which is called beta-amyloid. ANDERSON, H.S. et al, Alzheimer’s Disease Treatment and Management, 2016. Available online from: http://emedicine.medscape.com/ article/1134817-overvieW

MODERATE STAGE

• Weight loss

Middle stage Alzheimer’s Disease is characterised by mild cognitive impairment (MCI). Patients can experience problems such as:

• Seizures

• taking longer to complete normal daily tasks • repeating questions • losing things

• Difficulty swallowing • Increased sleeping • Groaning, moaning • Lack of control of bladder or bowel DIAGNOSIS

• Hallucinations, delusions and paranoia

Alzheimer's Disease is usually diagnosed following a clinical examination and an autopsy or brain biopsy. Patients are usually diagnosed during the mild stage showing the above symptoms. Lumbar punctures are used in research settings, as levels of tau in the cerebrospinal fluid are elevated in AD, and amyloid levels are usually low.5 Early and accurate diagnosis can be beneficial for a number of reasons. If treatment is commenced early in the disease process it may help preserve daily functioning for some time, even though the underlying Alzheimer’s process cannot be stopped or reversed.3 An early diagnosis can help patients and their families as then can plan for the future, take care of financial and legal matters, take care of living arrangements and develop support networks.

• Impulsive behaviour

TREATMENT

• Problems coping with new situations

The final stage of Alzheimer’s disease is severe Alzheimer’s Disease. At this stage patients are unable to communicate and are totally dependent on others for their care. At this sever stage the body shuts down with the following symptoms:

There is no cure for Alzheimer’s Disease, however there are many therapeutic agents used to help slow disease progression or alleviate symptoms. The aims of treatment are to promote independence, maintain function and treat both cognitive, noncognitive (hallucinations, delusions, anxiety, marked agitation and associated aggressive behaviour), behavioural and psychological symptoms.1

• Complete inability to communicate

Treatment for Alzheimer’s Disease should

• personality or behaviour changes • wandering MODERATELY SEVERE STAGE In Moderate Alzheimer’s Disease damage occurs in the brain that controls language, reasoning, sensory processing and conscious thought. Symptoms of this stage of AD include: • Increases memory loss • Confusion • Problems recognising family and friends

SEVERE STAGE

The beta-amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluble plaques. ANDERSON, H.S. et al, Alzheimer’s Disease Treatment and Management, 2016. Available online from: http://emedicine.medscape.com/ article/1134817-overvieW

only be initiated under the following conditions:1 •

Only specialists in the care of patients with dementia (psychiatrists, neurologists, and physicians specialising in the care of older people) should initiate treatment.

Treatment should be continued only when it is considered to be demonstrating an effect on cognitive, global, functional or behavioural symptoms.

Patients continuing on treatment should be reviewed regularly using cognitive, global, functional and behavioural assessment. Treatment should be reviewed by an appropriate specialist team and carers' views on the patient's condition at follow-up should be sought.

Most of the medication used in the treatment of Alzheimer's Disease are symptomatic therapies that modulate neurotransmitters, either acetylcholine or glutamate.5 Acetylcholinesterase inhibitors – such as Donepezil and Galantamine – are used in the treatment of mild to moderate Alzheimer’s Disease.6 Treatment should only be initiated and supervised by a specialist in the management of dementia. The benefit of these medications is assessed after 3 months by repeating the cognitive assessment. It can be a good indicator of the patient’s response to the treatment. Medication should be discontinued if there the patients is not responding. If the patient shows significant deterioration after discontinuation, the treatment may be re-started. Other psychotropic medications are used to treat secondary symptoms of Alzheimer's Disease, such as depression, agitation, aggression, hallucinations, delusions and sleep disorders:


CPD 66: UNDERSTANDING ALZHEIMER’S DISEASE • Anti-depressants • Anxiolytics • Anti-parkinsonian agents • Beta-blockers • Anti-epileptic drugs • Neuroleptics The most successful AD medications to date are the acetylcholinesterase inhibitors, which work to enhance the brain’s cholinergic system.4 Cholinergic treatment does not alter the progressions of neurodegeneration however. Treatment works to reduce the metabolism of acetylcholine, which is deficient in the brain in AD, and thereby prolonging its action at cholinergic synapses. Three cholinesterase inhibitors – Donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), are all indicated for the treatment of mild to moderate Alzheimer's Disease.6 As a class, these agents have all demonstrated measurable effects on cognition, behaviour and activities of daily living. The main adverse effects are gastrointestinal – nausea, vomiting, diarrhoea, anorexia, weight loss. The medication is better tolerated if taken on a full stomach, Insomnia and vivid dreams have also been reported. The differences between the three drugs appear to be their side effect profile, titration schedules and dosing regimens. Memantine is also indicated for mild to moderate AD in patients who are unable to take acetylcholinesterase inhibitors and in severe disease. One of the actions of memantine is to non-competitively block the NMDA receptor and thereby protecting against excitotoxic destruction of cholinergic neurons. Studies have shown benefits on cognition, daily living activities and behaviour in moderate to severe AD. The use of memantine is generally limited to at least moderately impaired patients. Side effects of memantine treatment can include hallucinations, confusions, dizziness and headache. The combination of both memantine and acetylcholinesterase inhibitors is not recommended. Donepezil is a reversible inhibitor of acetylcholinesterase indicated for the treatment of mild to moderate Alzheimer's Disease. Acetylcholinesterase inhibitors can cause un-wanted dose dependent side effects. For this reason donepezil should be started at a low dose and the dose increased according to response and tolerability. The maximum daily dose of donepezil is 10mg, taken at night. Common side effects of Donepezil treatment include abnormal dreams, agitation, aggression, anorexia, dizziness and fatigue. Galantamine is also a reversible inhibitor of acetylcholinesterase and also has nicotinic

receptor agonist properties.6 Galantamine is available in both immediate release and modified release preparations. For the treatment of mild to moderately sever AD, a dose of 4mg twice daily of immediate release preparations is indicated. Dosage can be increased to 8mg twice daily after four weeks. The maintenance dose is 8-12mg twice daily. For the treatment of mild to moderate AD, a dose of 8mg once daily in a modified release formulation is indicated. Dosage can be increased to 16mg after four weeks. Maintenance dose is 16-24mg once daily. The most common side effects of treatment with Galantamine include abdominal pain, bradycardia, decreased appetite, depression, dizziness and fatigue. Rivastigmine is a reversible non-competitive inhibitor of acetylcholinesterase. It is available in both oral and transdermal dosage forms. Orally, dosage us usually started at 1.5mg twice daily, and increased at intervals of at least two weeks according to response and tolerance. Maximum dosage is 6mg twice daily. For transdermal dosage, a patch of 4.6mg /24 hours is applied once daily for at least four weeks. Dosage can be increased to a patch of 9.5mg/24 hours if tolerated, and continued for a further 6 months of treatment. If necessary, dosage can be increased to a patch of 13.3mg/24 hours if well tolerated and cognitive deterioration and functional decline demonstrated. Common side effects of rivastigmine treatment include abdominal pain, agitation, anorexia bradycardia, confusion, dizziness and drowsiness.6

swallowing and may eventually need feeding by a gastrointestinal tube. From the time of diagnosis patients can live between three and ten or more years. With early onset AD, the disease is more aggressive and can have a more rapid course. The primary cause of death in AD is intercurrent illness, such as pneumonia.5 LIFESTYLE FACTORS There are a number of lifestyle factors that benefit cardiovascular health that are associated with a decreased risk of dementia. Such factors include regular exercise, a healthy diet and low stress levels. In patients genetically predisposed to Alzheimer’s Disease, diets high in fat and sugar and suspected to negatively affect the brain by facilitating the development of neuritic plaques. PATIENT COUNSELLING Counselling patients with Alzheimer's Disease should also involve the patient's family and other carers who will provide a supporting role. It is also important to emphasise that it is not only the patient that will be affected by the AD, but also the family and others who give support. Patients generally will have a least one caregiver who has a vital role in management. The caregiver should receive education about the disease and should be routinely screened for fatigue and depressions. Caregivers should also be encouraged to seek out adult day care centres, respite care and home health services.

Memantine is a glutamate receptor antagonist, licensed for the treatment of moderate to severe Alzheimer's Disease. Dosage is usually imitated at 5mg daily, and then increased in steps of 5mg at weekly intervals to a maximum dose of 20mg daily. Common side effects of treatment include constipation, dizziness, drowsiness, dyspnoea, headache and hypertension.

REFERENCES

Non-pharmacological treatment of Alzheimer’s Disease includes social support, increasing assistance with day-to-day activities, information and education, carer support groups, community dementia teams, home nursing and personal care, community services such as meals-on-wheels, befriending services, day centres, respite care and care homes.1

2) The Alzheimer Society of Ireland, Available online from: http://www.alzheimer.ie/ Home.aspx

PROGNOSIS

4) YAARI, R. et al, Alzheimer’s Disease, 2007. Available online from: http://www. medscape.com/viewarticle/553256

Alzheimer's Disease is initially associated with memory impairment and progressively worsens over time. Patients with AD display additional symptoms of anxiety, depression, insomnia, paranoia and agitations. As the disease worsens patients will required assistance with basic activities of daily living, including dressing and bathing. Patients can experience difficulties in walking and

1) NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE, Technology Appraisal Guidance, Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s Disease, 2011. Available online from: http://nice. org.uk/guidance/ta217

3) National Institute on Aging, Alzheimers Disease Education and Referral Centre, About Alzheimer’s Disease. Available from: https://www.nia.nih.gov/alzheimers/topics/ alzheimers-basics

5) ANDERSON, H.S. et al, Alzheimer’s Disease Treatment and Management, 2016. Available online from: http:// emedicine.medscape.com/ article/1134817-overvieW 6) British National Formulary 71

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