Alzheimer’s Disease – Causes, Symptoms, and Treatments

By | October 1, 2019
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Introduction

Alzheimer’s disease, known to be a progressive and neurodegenerative disease is one of the most discussed and researched diseases in elderly citizens which results in fatal dementia and affects normal life drastically causing memory loss and impairment of other cognitive abilities. The patient’s behavior and attitude regarding decision making are disturbed and start forgetting recent events or talk. Patients older than 65y are prone to this disease. But it can also be found in younger patients called younger-onset Alzheimer’s disease (early-onset Alzheimer’s disease). As it is a progressive disease, its symptoms worsen over time.

Prevalence of Alzheimer’s Disease:

Its prevalence increases with age. About 5% of 65 years old citizens and 90% of 95 years old citizens. Inherited Alzheimer’s cases are less than 1%.

Major Causes of Alzheimer’s Disease:

Several mechanisms are proposed that are likely to initiate Alzheimer’s in patients. The chromosomal mutation is involved in the majority of causes.  The major causes are given below:

  • Amyloid plaque: 

β-amyloid is a protein is present in the brain that aggregates in cortex region resulting in plaque and lesion formation in the brain leading to Alzheimer’s disease.

  •  Neurofibrillary Tangles (NFTs): 

A Phosphorylated form of “tau” protein aggregates alongside neurons in the cortex (a part in brain) and disrupt the transport system of the neuron and cause toxic effects to result in brain cell degeneration.

  • Neuronal Alterations: 

There are a neuronal depletion, excitation and other alteration causing neuronal imbalance:

1.     Mainly cholinergic neuronal degeneration.

2.     Over excitation of Glutamate receptors (NMDA receptors).

3.     Over activation of an enzyme called monoamine oxidase type B.

  • Mitochondrial Dysfunction: 

There is overwhelming evidence of mitochondrial dysfunction involvement in neurodegenerative diseases.

  • Oxidative Stress:

Plays important role in the progression of Alzheimer’s. At higher concentrations and long-term exposure, reactive oxygen species can damage cellular macromolecules such as DNA, proteins, and lipids, which leads to necrotic and apoptotic cell death. Biochemical alterations in these macromolecular components can lead to various pathological conditions and human diseases, especially neurodegenerative diseases.

Diagnosis of Alzheimer’s Disease:

Diagnosis is mainly based on routinely symptoms.

1.     Brain imaging and validated biomarkers of the disease will enable a more sophisticated diagnosis with identified cognitive strengths and weaknesses and neuroanatomic localization of deficits.

2.     Physician should take medication history i.e. use of alcohol or other substance, trauma history. Find medication use of anticholinergics, hypnotics, sedatives, opioids, antipsychotic and anticonvulsant which contribute in dementia symptoms.

Symptoms of Alzheimer’s Disease:

Patient having Alzheimer’s shows vast variety of symptoms that are useful in clinical findings. These given below:

·        Memory:

The earliest symptom of Alzheimer’s is that the patient will forget recent past events and this forgetfulness increases over time.

60% of Alzheimer’s disease is related to memory loss and is considered as the most common cause of dementia.

The severity of memory loss varies from mild stage to a severe stage. They tend to repeat statements, forgetting conversations and recent events. Memory loss can also affect mood. They also have trouble finding the incorrect names for a particular object.

·        Decision making:

It’s one of the main symptoms along with memory loss. They tend to have difficulty in making decisions i.e. in wearing clothes, in social interaction and any king of judgments.

·        Depression:

Depression in Alzheimer’s is considered as a symptom but sometimes it can be a cause of dementia. People with depression are likely to forget things due to overthinking on a specific event.

·        Psychotic Problems:

They may face sleep disturbance, suspicions, delusions, hallucinations.

·        Combativeness:

·        Patients with Alzeihmer’s are more likely to be in aggressive behavior. They can lose control over themselves over an insignificant argument.

·        Uncooperative:

They have difficulty in cooperating with others. They don’t like to have help from anyone.

·        Motor hyperactivity:

The motor responses of Alzheimer patients are hyper-activated means, they respond to an external stimulus at once.

Severity and no. of symptoms of above-mentioned symptoms may vary from patient to patient. 

Stages of Alzheimer’s Disease:

On the basis of severity, Alzheimer’s disease has three stages Mild, Moderate and Severe that are scored with the help of mini-mental status examination (MMSE score).

1)Mild Stage:

As name indicates it is the early stage of Alzheimer’s. Its MMSE score ranges between 26-18. The patient faces difficulty in remembering recent events, difficulty in preparing food and contributing to other household activities. He may get lost during driving. He is also less likely to contribute to difficult tasks and can’t take an interest in his/her habits.

2)Moderate stage:

Its MMSE score ranges between 17-10. The patient needs assistance with activities of daily living. The patient has difficulty with regard to understanding time (date, year, and season). He cannot recall recent events and have severely impaired. May forget some details of past life and the names of family and friends. Functioning may fluctuate from day to day. The patient generally denies problems. May become suspicious or tearful. Loses the ability to drive safely. Agitation, paranoia, and delusions, hallucinations are common.

3)Severe stage:

Its MMSE score ranges between 9-0. The patient reaches a most severe level, cannot speak, eat and walk and lacks control over urination and defecation. The patient needs care 24/7 a week.

Treatment of Alzheimer’s Disease:

  • Goal of treatment:

The goal of treatment in Alzheimer’s is to maintain the function and prevent the severity as long as possible. Medicine is given according to stages. If the patient is in a mild to moderate stage, cholinesterase inhibitor is given and the dose is maintained and if the patient is in moderate to the mild stage then add memantine is preferred. But therapy can be changed by a physician. Alternatively, alone cholinesterase inhibitor or memantine can be used. Behavior symptoms are mostly treated by support.

  1. Non-medicinal treatment:   

This includes behavioral and environmental management. Urination, defecation, sleep disturbance can be maintained through this. At the initial stage of Alzheimer’s, the patient and caregiver is advised to change the lifestyle of the patient which can help in the decrease in disease progression.

  1. Medicinal Treatment:

Medicinal treatment is further classified to:

·        Cognitive Therapy

·        Non-cognitive Therapy

Cognitive Therapy:

These drugs are used to treat or prevent cognitive symptoms. Some studies suggest that managing blood pressure, cholesterol and blood glucose reduce the risk of progression in Alzheimer’s.

1.Cholinesterase enzyme Inhibitors:

These inhibitors prevent the destruction of acetylcholine in nerve endings resulting in increased concentration of Ach at neuronal synapse. They can either selective (blocking only acetylcholinesterase enzyme) or non-selective (also blocking butyryl cholinesterase enzyme).

Tacrine was 1st drug to show significant benefit in Alzheimer’s but due to severe hepatotoxicity, it is replaced by newer drugs such as Donepezil, Rivastigmine and Galantamine.

Cholinesterase inhibitors are 1st line treatment for Alzheimer’s and has shown a significant effect in mild to moderate stage. Donepezil, rivastigmine and galantamine are prescribed in mild to moderate stage. Donepezil is also used in severe stage.

If transfer from one cholinesterase to another is needed, at least for the 1-week patient is required to stop that medication.

Rivastigmine and galantamine are short-acting, so the patient is advised not to discontinue these medicines for several days or longer, otherwise, it should be restarted at lowest dose.

These drugs should not be used with ketoconazole and quinidine.

Associated Side Effects:

  • GI symptoms
  • Headache
  • Urinary incontinence
  • Dizziness
  • Syncope
  • Bradycardia
  • Muscle weakness
  • Salivation
  • Sweating

Abrupt discontinue of these medicines can worsen the cognitive symptoms in some patients.

Doses of cholinesterase inhibitors:

  • In a mild to moderate stage, donepezil is given 5mg in the evening (range is 5-10 mg), but in the severe stage, it is given between 10-23mg. The patient should be warned about weight loss if he/she is taking 23mg dose. Drug-food interactions not found and can be used with or without a meal.
  • Rivastigmine is given 1.5mg twice day (usual dose 3-6mg) in capsule and oral solution and 4.6mg (usual dose is 9.5-13.3mg) once a day in a transdermal patch. Mild to moderate renal and hepatic impairment is reported. Patients with body weight less than 50kg are considered to have a maximum dose of 4.6mg once daily in a transdermal patch. The medicine should be taken with a meal. Multiple patches at once should be avoided as it results in hospitalization and eventually death due to cholinomimetic toxicity.
  • Galantamine 4mg is given twice daily (usual dose 8-12mg), it can cause moderate renal and hepatic impairment, the dose should not exceed 16mg (maximum daily dose. Galantamine 8mg once daily is given in the extended-release form (usual dose 16-24mg), it can cause severe renal and hepatic impairment so it is not recommended in actual practice. The medicine should be taken with a meal.

2.Other Medicines for Alzheimer:

Memantine:

Only FDA-approved NMDAantagonists used in Alzheimer’s Disease, which results in a reduction in neuronal excitation. It can be used alone or in combination with cholinesterase inhibitors. It is preferred in the severe stage of Alzheimer’s. Dose adjustment should be done in renal impairment. Constipation, confusion, headache, dizziness are common adverse effects. It is given 5mg, the maintenance dose is 5mg twice daily. Extended-release is given 7mg daily with a maintenance dose of 14mg daily.

Other certain drugs are under investigation i.e. Vitamin E.

Non-Cognitive Therapy:

Therapy for non-cognitive symptoms targets psychotic symptoms, inappropriate or disruptive behavior, and depression. Environmental changes are most preferred than medication if needed. The dose should be the lowest and must be increased slowly. Anticholinergic psychotropic drugs should not be used as these can worsen cognition.

 This therapy includes:

  • Cholinesterase inhibitors and memantine.
  • Antipsychotic drugs
  • Antidepressants
  • Miscellaneous therapies
  1. Cholinesterase Inhibitors and Memantine:

Cholinesterase inhibitors and memantine has shown significant improvement of behavioral symptoms.

  1. Antipsychotic Drugs: 

These drugs are traditionally used for behavioural complications but their risks should be in consideration. According to one study, 17% to 18% ofpatients shown significant improvement in behavioural symptoms when treated with nonconventional antipsychotic medication. But its adverse events offset the advantages.

These drugs include aripiprazole, olanzapine, risperidone, quetiapine.

Typical antipsychotics also show improvement but risk of death is associated with these.

Antipsychotic doses:

  • Aripiprazole is started at a 10-15mg dose and maintained at 30mg (maximum) dose per day.
  • Olanzapine is started at 2.5mg following with the maintenance dose of 5 to 10mg per day.
  • Quetiapine has 25mg starting dose following by 100-400mg maintenance dose per day.
  • Risperidone is usually started at 0.25mg following by the maintenance of 0.5-2mg per day. 

Targeted symptoms of Anti-psychotic Drugs:

·        Hallucinations

·        Delusions

·        Suspiciousness

·        Agitation

·        Aggression

  1. Antidepressants:

Depression and dementia share many symptoms. Antidepressants show positive results especially selective serotonin reuptake inhibitors, of which, sertraline and citalopram show significant positive results. Other SSRIs are Fluoxetine, Paroxetine, and Escitalopram.

Tricyclic antidepressants are avoided due to certain complications.

Antidepressant doses:

  • Citalopram is started at 10mg per day followed by 10-20mg maintenance dose per day.
  • Escitalopram is started at 5mg per day followed by 10mg (maximum) maintenance dose per day.
  • Fluoxetine is started at 10mg per day followed by 10-20mg maintenance dose per day.
  • Paroxetine is started at 10mg per day followed by 10-40mg maintenance dose per day.
  • Mirtazapine is started at 15mg per day followed by 15-30mg maintenance dose per day.
  • Sertraline is started at 12.5mg per day followed by 150mg (maximum) maintenance dose per day.
  • Trazodone is started at 25mg per day followed by 75-150mg maintenance dose per day.

Targeted Symptoms 

  • Poor appetite
  • Insomnia
  • Hopelessness
  • Anhedonia
  • Withdrawals
  • Suicidal thoughts
  • Agitation
  • Aggression

4.     Miscellaneous Therapies:

Ani-convulsants such as Benzodiazepines use is not common but are given “as needed” to overcame frequent episodes of agitation.

Carbamazepine, valproic acid, and gabapentin maybe alternatives, but there’s confliction.

Anticonvulsant Doses:

·        Carbamazepine is started at 100mg per day and maintained between 300-600mg per day.

·        Valproic acid is started at 125mg followed by a maintenance dose of 500-1500mg per day.

General Guidelines to Manage Alzheimer

How to Counsel an Alzheimer’s Patient?

Verbal counseling should not be done with these patients as they tend to forget medication-related information.

Two ways of counseling are applied:

  1. Information should be given in the written form to the patient in mild to moderate disease.
  2. Patients with severe Alzheimer have a caregiver with themselves, so the information should be given to them.

What are the stages of Alzheimer on the basis of memory loss?

Memory loss is the key symptom of this condition so it has 7 stages on the basis of memory loss, these stages help in evaluating the severity of memory loss. These are:

  1. No impairment: Disease is undetectable at this stage.
  2. Very mild decline.
  3. Mild decline.
  4. Moderate decline.
  5. Moderately severe decline.
  6. Severe decline.
  7. Very severe decline.

How to provide care to Alzheimer’s Patient?

Patient caregiving plays an essential role in reducing progression and helping the patient with routinely faced problems. Caregivers should be up for 24/7 a week, they face special challenges. They are responsible for administering the medication to patients on time. Proper training can be provided to the caregiver, giving them an awareness of “How to manage challenging behaviors”, when they are trained with caregiving training, caregivers tend to be less stressful.

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