27 September 2022

Article by Deppo Juneja

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Alzheimer's disease (AD) is the most common cause of dementia. Dementia is the name for a group of symptoms associated with an ongoing decline of brain functioning. AD is a neurodegenerative disorder that usually affects people over the age of 65, with the involvement of language, memory, comprehension, attention, judgment, and reasoning – this is known as late-onset Alzheimer’s. Early-onset Alzheimer’s occurs between the ages of 30 and mid-60s and is very rare (1; 2).

Alzheimer's disease is a complex neurodegenerative disease in which the mechanisms of its pathology are not fully understood. The symptoms display a deceptive onset and progressive impairment of behavioural and cognitive functions such as memory, comprehension, language, and judgment. AD has recently become the leading cause of death in the United Kingdom, where in March 2021 there were 97.2 deaths per 100,000 people (4,616 deaths). Onset before 65 years of age (early onset) is unusual and is seen in less than 10 % of AD patients (1). There is currently no cure for AD, although there are treatments available that may improve some symptoms (3).

Symptoms exhibited in AD patients are dependent on the stage of the disease. Disease classification is divided into preclinical or presymptomatic, mild, and dementia – stage is dependent on the degree of cognitive impairment (4). These stages are different from the Diagnostic and Statistical Manual of Mental Disorder, fifth edition (DSM-5) classification of AD  (5). The initial and most common presenting symptom is episodic short-term memory loss with relative sparing of long-term memory and can be elicited in most patients even when not presenting symptom. Short-term memory impairment is followed by impairment in problem-solving, judgment, executive functioning, lack of motivation and disorganisation, leading to problems with multitasking and abstract thinking. In the early stages, impairment in executive functioning range from subtle to significant. This is followed by language disorder and impairment of visuospatial skills. Neuropsychiatric symptoms such as apathy, social withdrawal, disinhibition, agitation, psychosis, loss of locational awareness and wandering around are also common in the mid to late stages (1; 3; 4). Difficulty performing learned motor tasks (dyspraxia), olfactory dysfunction, sleep disturbances, extrapyramidal motor signs like dystonia, akathisia, and parkinsonian symptoms occur late in the disease (3). This is followed by primitive reflexes, incontinence, and ultimately results in total dependence on caregivers (3).

Alzheimer's disease is a gradual and progressive neurodegenerative disease caused by neuronal cell death. It typically starts in the entorhinal cortex in the hippocampus. There is a genetic role identified for both early and late-onset AD (6). Several risk factors have been associated with AD, with increasing age being the most important risk factor. Traumatic head injury, depression, cardiovascular and cerebrovascular diseases, higher parental age, smoking, family history of dementia, increased homocysteine levels and presence of apolipoprotein E (APOE) e4 allele are known to increase the risk of AD (6; 7). Furthermore, having a first-degree relative with AD increases the risk of developing AD by 10% to 30%. Individuals with 2 or more siblings with late-onset AD have a 3-fold increased risk of developing AD compared to the general population (2; 7).  

Alzheimer's disease is characterized by an accumulation of abnormal neuritic plaques and neurofibrillary tangles (3).

Plaques are spherical microscopic lesions that have a core of extracellular amyloid beta-peptide surrounded by enlarged axonal endings. Beta-amyloid peptide is derived from a transmembrane protein known as an amyloid precursor protein (APP). The beta-amyloid peptide is cleaved from APP by the action of proteases named alpha, beta and gamma-secretase. Usually, APP is cleaved by either alpha or beta-secretase and the tiny fragments formed by them are not toxic to neurons. However, sequential cleavage by beta and then gamma-secretase results in 42 amino acid peptides (beta-amyloid 42). Elevation in levels of beta-amyloid 42 leads to aggregation of amyloid that causes neuronal toxicity. Beta-amyloid 42 favours the formation of aggregated fibrillary amyloid protein over normal APP degradation. The APP gene is located on chromosome 21, one of the regions linked to familial AD. Amyloid deposition occurs around meningeal and cerebral vessels and in the grey matter in persons with AD. Grey matter deposits are multifocal and coalesce to form structures called plaques. However, brain scans have noted amyloid plaques in some persons without dementia and no plaques in some persons with dementia (8; 9). 

Neurofibrillary tangles are abnormal fibrillary intracytoplasmic structures in neurons formed by the accumulation/hyper phosphorylation of a microtubule related protein called tau (8; 9; 10). The primary function of the tau protein is to stabilise axonal microtubules. Microtubules run along neuronal axons and are essential for intracellular transport. Microtubule assembly is held together by tau protein. In AD, due to aggregation of extracellular beta-amyloid, there is hyperphosphorylation of tau, which then causes the formation of tau aggregates. Tau aggregates form twisted paired helical filaments known as neurofibrillary tangles. They occur first in the hippocampus and then can be seen throughout the cerebral cortex. Tau-aggregates are deposited within the neurons. There is a staging system developed by Braak and Braak (11) based on the topographical staging of neurofibrillary tangles into 6 stages. Braak staging is an integral part of staging and criteria for the diagnosis of AD. The Prescence of neurofibrillary tangles is more strongly correlated to Alzheimer's than the presence of plaques (10).

Another feature of AD is granulovacuolar degeneration of hippocampal pyramidal cells by amyloid angiopathy. Some reports indicate that cognitive decline correlates more with a decrease in the density of presynaptic boutons from pyramidal neurons in laminae III and IV, rather than an increase in the number of plaques. 

Neuronal loss in Nucleus Basalis of Myenert, leading to low Acetylcholine has also been noted. 

Vascular contribution to the neurodegenerative process in AD is not fully determined (12). The risk of dementia appears to be increased fourfold in patients with subcortical infarcts. The cerebrovascular disease also exaggerates the degree of dementia and its rate of progression.

Genetic Basis of Alzheimer Disease
Alzheimer's disease can be inherited as an autosomal dominant disorder with nearly complete penetrance. Dominantly inherited Alzheimer’s disease (DIAD), also known as autosomal dominant Alzheimer’s disease, is a form of dementia caused by rare, inherited gene mutations linked to mutations in 3 genes: the AAP gene on chromosome 21, Presenilin1 (PSEN1) on chromosome 14, and Presenilin 2 (PSEN2) on chromosome 1. APP mutations may lead to increased generation and aggregation of beta-amyloid peptide. PSEN1 and PSEN2 mutations lead to aggregation of beta-amyloid by interfering with the processing of gamma-secretase. Mutations in these 3 genes account for about 5 % to 10 % of all the cases and majority of the early-onset AD (13). 

Apolipoprotein E is a regulator of lipid metabolism that has an affinity for beta-amyloid protein and is another genetic marker that increases the risk of AD. Isoform e4 of APOE gene (located on chromosome 19) has been associated with more sporadic and familial forms of AD that present after the age of 65 (2). The presence of one APOEe4 allele does not always lead to AD, but among persons carrying one APOE- e4 allele, about 50% go on to develop AD, and those having two APOE- e4 alleles, have a 90% incidence of developing AD. Each APOE e4 allele also lowers the age of disease onset. The presence of the APOE e4 allele is an important risk factor for developing AD.

Variants in the gene for the sortilin receptor, SORT1, which is essential for transporting APP from cell surface to the Golgi-endoplasmic reticulum complex, have been found in familial and sporadic forms of AD (6).

Treatment / Management
The Alzheimer’s drug development pipeline has agents representing a substantial array of treatment mechanisms and targets. Advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with Alzheimer’s (14). However, there is currently no cure for Alzheimer's which completely eradicate the disease.

As of January 25, 2022, there were 143 agents in 172 clinical trials. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease-modifying therapies represented 83% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent nearly 10% of agents in the clinical trials and drugs for the treatment of neuropsychiatric symptoms comprise of around 7%. There were agents in the pipeline, which were repurposed drugs approved for other indications. (3; 14; 15) 

Diet and regular aerobic exercise are some of the avenues that have known to decrease the risk of AD. However, there has been more recently an effort towards disease modifying therapies/agents, which can treat/cure or at most provide better quality of life and delaying of cognitive decline for people with the diseases (3; 14). 

Until recently, only two categories of drugs were approved for the treatment of AD: cholinergic agents and glutamatergic neurotransmission reduction. However, more recently, aducanumab was approved for treating the disease (15; 16).

Cholinergic Agents 
Cholinesterase inhibitors act by increasing the level of acetylcholine; a chemical used by nerve cells to communicate with each other and is important for learning, memory and cognitive functions. Of this category, 3 drugs: donepezil, rivastigmine, and galantamine are United States Food and Drug Administration (FDA) approved for the treatment of AD.

Donepezil can be used in all stages of AD. Galantamine and rivastigmine are approved for treatment in Mild cognitive impairment (MCI) and Dementia stage. Donepezil and galantamine are rapid, reversible inhibitors of acetylcholinesterase. Rivastigmine is a slow, reversible inhibitor of acetylcholinesterase and butyrylcholinesterase. Donepezil is usually preferred choice of acetylcholinesterase (AcH) inhibitors due to its once-daily dosing regimen. Galantamine is available as a twice-daily tablet or as a once-daily extended-release capsule and cannot be used in end-stage renal disease or severe liver dysfunction. Rivastigmine is available as oral and transdermal formulations. The most common side effects of cholinesterase inhibitors are gastrointestinal-like symptoms, nausea, vomiting, and diarrhoea. Sleep disturbances are more common with donepezil. Due to increased probable occurrences of vagal tone, bradycardia, cardiac conduction defects, and syncope, these medications are contraindicated in patients with severe cardiac conduction abnormalities.

Glutamatergic neurotransmission
The partial N-Methyl D-aspartate (NMDA) antagonist memantine blocks NMDA receptors and slows intracellular calcium accumulation. It is approved by the FDA for treating moderate to severe AD. Dizziness, body aches, headache, and constipation are common side effects. It can be taken in combination with cholinesterase inhibitors.

In addition to treating the disease directly it is also important to treat the associated comorbidities such as anxiety, depression, and psychosis, which are often present in the mid to late stages of AD. 

In June 2021, aducanumab received its first approval in the USA for the treatment of Alzheimer's disease. According to the FDA prescribing information, treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. However, there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. Aducanumab is currently under regulatory review in Japan and in Europe. Its long-term safety and tolerability are being evaluated in a multinational phase 3b clinical study in patients with early AD (MCI and mild AD).

Other Approaches 
Environmental and behavioural approaches are beneficial especially in managing behavioural problems. Simple approaches such as maintaining a familiar environment, monitoring personal comfort, providing security objects, redirecting attention, removing doorknobs and avoiding confrontation can be very helpful in managing behavioural issues.

To minimise caregiver burden, mild sleep disturbances can be reduced by providing exposure to sunlight and providing daytime exercise.

The expected benefits of the treatment are modest, and treatment should be stopped or modified if no significant benefits or if intolerable side effects are observed.

Preclinical or Presymptomatic
In this stage, individuals are asymptomatic with definite laboratory evidence. Identifying the biomarkers can help diagnosing Alzheimer disease in this stage. Low amyloid and increased tau proteins in cerebrospinal fluid (CSF) serve as a biomarker, but they are not specific for AD. Another analysis has indicated that a combination of different variables – ApoE4 positivity, scores on the paired associates immediate recall test and digits symbol substitution test, increased tau protein in CSF, right entorhinal cortex thickness and right hippocampal volume on magnetic resonance imaging (MRI), can predict the progression to MCI (17).

Mild Cognitive Impairment (MCI). 
In this stage, patients have impairment in either memory or in nonmemory domains, such as executive ability or language function. These individuals continue to work, socialise, and function independently. Patients with MCI progress to dementia at a rate of 10% per year (18). 

In this stage, patients have incapacitating memory impairment. Language changes, including anomia, paraphasia errors, decrease in spontaneous verbal output and a tendency for circumlocution to avoid forgotten words. Impairment of visuospatial abilities leads to loss of locational awareness and wandering in the familiar surroundings and constructional apraxia. Twenty to 40% of patients will have delusions. Visual hallucinations are more common, although, patients can also have auditory and olfactory hallucinations as well.

Disruptive behaviours occur in almost 50% of the patients. Patients also lose their normal circadian sleep-wake pattern, and their sleep becomes fragmented (19).

Enhancing Healthcare Team Outcomes
Alzheimer's disease is a progressive neurodegenerative disorder marked by behaviour and cognitive impairment that eventually interferes with daily functional living activities (19). The disorder has no cure, and its rate of progression is variable. Furthermore, the diagnosis of Alzheimer's disease in the early phase is difficult. The drugs currently available to treat the condition only work for the mild disease, but also have numerous side effects that are not well tolerated. AD is a systemic disorder that not only affects the patient, but also the entire family and supporting caregivers. Patients often wander, fall, have significant behaviour problems and loss of memory. Most patients end up in a tertiary care institution as they become unmanageable at home. Due to the nature of the disease, an interprofessional team approach to the disorder has been recommended. Many guidelines and recommendations have been made on how to approach, monitor, and treat Alzheimer patients. No one measure can prevent or arrest the disease at this time. Health care workers therefore have a critical role in ensuring that the patient with AD remains safe and leads a decent quality of life.

•    Physical therapy for exercise. There is now ample evidence that exercise can help reduce the progression of the disease (20) (Level III).
•    Nurses to educate the patient and family on medications, lifestyle changes, and performing daily living activities. To educate the partner on self-reporting of the worsening of symptoms.
•    Pharmacist to ensure that polypharmacy does not occur and that the patient is not developing adverse effects.
•    Clinicians to monitor patient progress and enhance the quality of life.
•    Caregivers to provide support.
•    Social workers to ensure that the patient has an adequate support system.
•    Dietitian to ensure that the patient is eating a healthy diet.
•    Mental health nurses to ensure that both the patient and caregiver are coping with the disorder.

Alzheimer's disease is initially associated only with impaired memory, but with time, the individual may develop severe cognitive and behavioural symptoms like depression, anxiety, anger, irritability, insomnia, and paranoia. As the disease progresses, most people will require assistance with daily living activities. Eventually, even walking becomes difficult, and many may not be able to eat or may develop swallowing difficulties that lead to aspiration pneumonia.

The time from diagnosis to death is variable; some individuals may die within five years, and others may remain alive for ten years, but overall, their quality of life becomes very poor. While an interprofessional approach to the management of Alzheimer patients is recommended, an analysis of several studies reveals that this approach has no impact on the care of their patients. However, because of the heterogeneity in the previous studies, more robust studies will be required to determine what type of approach works best for managing these patients.

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