Introduction In today’s society

In today’s society, Alzheimer’s disease is the most common form of dementia that causes loss of memory, speech, movement, and the ability to think clearly. This disease eventually results in loss of life; with dementia being the leading cause of death in the United Kingdom from 2016. However, in the year 2050, Alzheimer’s disease is predicted to become an even larger burden on society. As average age life expectancy is continually rising, for example the average age could be 130 years of age by 2050, we will experience more people getting AD as it is mostly common in people aged 65 years and over. This will mean the majority of the world will have people who will suffer from AD; estimated to be approximately 131.5 million people. Without a cure for AD, this will result in a massive decline in the world’s population due to Alzheimer’s disease related deaths, and if the majority is over 65, this could mean even more than the estimated 131.5 million people will die. The cost of dementia across the world is around $1 trillion, with only 50 million people diagnosed with the disease. However, if the amount of people suffering from AD rises to 131.5 million people or even over, we could fall into a financial crisis as it would consume most of our money. In this essay, the argument will be what challenges the world will face in 2050 and what pathology would be best suited for a drug that will tackle it. Mechanisms of the disease have been heavily researched and there are many proteins that could be potential targets.
Historical Background of AD and its symptoms explained
Alzheimer’s disease was discovered Alois Alzheimer in the early 20th century. His first patient to receive a formal diagnosis was a woman called Auguste. D. She was admitted to Alois Alzheimer when her husband realised that she was experiencing memory loss and frequent delusions, and her mental state was continuing to decline gradually. Whilst she was still alive, she was given simple questions which would prove to be very difficult to answer. For example, she was asked for her husband’s name, yet she did not fully understand the question according to Alzheimer. She was also asked to write her name and was only able to write “Mrs” before forgetting the rest. This suggests that the condition she was in must have been a later stage of Alzheimer’s disease as she could not even remember her name, whilst in the early stages you cannot remember recent events but you can remember long-term memories. Following Auguste’s death in 1906, Alzheimer had her patient records and brain transferred. Under the microscope, he discovered abnormal pathologies which had infiltrated her brain. These included the shrinking of the cortex and the identification of neurofibrillary tangles and neuritic plaques. It is now known that these two pathologies are tau and amyloid-? pathology, which are the two main pathologies associated with AD. Tau’s normal role in the brain is to bind and stabilize microtubules, whilst amyloid-?’s normal role is in synaptic scaling and signalling. The symptoms which are related with AD are memory loss, mild cognitive impairment, vision and spatial issues which are symptoms from the early stages. Some of these symptoms were found in Auguste. D, but they were more advanced. In later stages, symptoms progressively worsen; as you’re not able to perform daily tasks efficiently, you get lost frequently, your anxiety and aggression increases, and even handling money becomes a problem. This shows that as AD worsens, normal routine becomes difficult. As the disease advances, emotional control is lost and the ability to cope with simple tasks becomes a struggle. Finally, during the most severe stages, patients end up bedbound as the body begins to shut down. The symptoms involved are the inability to communicate, weight loss, loss of bowel and bladder control, and many more. The most frequent cause of death with AD is aspiration pneumonia, which occurs when the person cannot swallow properly, and food and water begins to enter your lungs as a replacement to air. With these symptoms, it can prove a hard task to care for patients with AD. The brain of someone suffering from AD consists of an overall shrinkage of brain tissue. Sulci (plural for sulcus), which are grooves in the brain, become bloated. Gyri (plural for gyrus), which are folds of the outer layer of the brain, shrink drastically. Furthermore, the ventricles which contain cerebrospinal fluid enlarge. Severe shrinkage occurs in the hippocampus which causes the decline in memory storage.
With this in mind, the state AD will be in during 2050 will be on a bigger scale, making it an extremely serious situation.
Pathologies tested for drug use
The two main pathologies are tau and amyloid-?. Tau’s deficiency in AD involves the collapse of microtubules, the axonal transport becoming compromised, and signal transmission being inhibited. Amyloid-? deficiency in AD involves it clumping together to form clusters of amyloid-beta which weaken communication and plasticity in the synapses, discontinuing the brain’s function of forming or retrieving memories. These two pathologies are most targeted for drug use. However, they are not always deemed as trustworthy.
Amyloid-? is targeted because many experiments have targeted this protein, only to see that it affects the development of AD. For example, a scientific paper named “Rapid appearance and local toxicity of amyloid-? plaques in a mouse model of Alzheimer’s disease (Meyer-Leuhmann et al, 2008)” shows that the accumulation of amyloid-? plaques is a critical mediator of neuritic pathology. However, many other experiments have countered this statement. For example, a research called “30% of cognitively normal individuals have high levels of A? Plaques in PET Scans” shows that A? plaques do not have any effect on AD as the number of people with A? plaques in the PET Scan was 30%.
Tau is targeted because it contributes to neurodegeneration by forming tangles. This is shown as there is a study dedicated to the tau protein, called “Stable Isotope Labelling Kinetics of Human Tau in Alzheimer’s Disease”. This study show that the tau protein has a substantial effect on Alzheimer’s Disease’s progression. Also, the scientific paper called “Neuropathol staging of Alzheimer-related changes” shows how tangles can cause severe damage regarding neurofibrillary changes. However, tau is not really targeted as much because of amyloid-?’s contribution to the disease. Therefore, tau does not have the most attention for being targeted for drug use.
APP, PSEN1 and PSEN2 are targeted for drug use in AD as well. This is because these genes can form mutations within the brain, causing the disease to spread. APP is a neuronal signalling protein, which increases the amount of APP or sticky A? peptides in AD. PSEN1 and PSEN2 cut APP to produce A? peptides and increase the production of A? peptides. However, since 10% of AD cases are familial and contain the mutations of these genes, it would cause the production of something that happens 10% of the time. Alzheimer’s disease has a lot of triggers, so finding a consistent target is not likely.
Risk Factors and Lifestyle to help for treating AD
Amyloid-? is not a trustworthy source for curing AD, as case studies like Bapineuzumab and Solanezumab show that Amyloid-? show little or no effect on curing AD. So various studies have taken place to pinpoint the activity of the brain but also humans.
A Genome-Wide Association Study was held to identify genes which could find new therapeutic targets away from the amyloid hypothesis. This is due to the fact that 90% of AD cases are sporadic meaning it will not be produced through genetics. The genes targeted to be the main variants were APOE, TREM2 and SORL1. APOE’s normal function is to clear A? from the brain and cerebral vasculature. However, it increases the risk of AD through the regulation of lipid homeostasis, synaptic transmission, and inflammatory damage to the blood-brain barrier. TREM2 sends signals through the transmembrane adapter protein to activate phagocytosis of pathogens and cellular debris. But, TREM2 increases AD occurrence through amyloid-related neuroinflammation and phagocytosis of amyloid and neuronal debris. SORL1 is an intracellular sorting receptor as APP is being trafficked. On the other hand, its effect on lipoprotein signalling pathways increases the risk of AD. These genes can be targeted for curing AD as they are within the 90% of AD cases so creating a drug for it can cure the majority of cases.
Lifestyle is also linked to whether Alzheimer’s disease will form in the brain. This is due to multiple factors. One of them is your social status. Without interacting with others, you ill not really develop any memories of things which are not connected to your usual routine. Also, developing mental states like depression can result in an increased risk for developing AD later in life. Seeing as Alzheimer’s Disease occurs in people aged 65+, and when you are that old you would not really go out frequently, it will be more likely for you to develop AD through this manner. Furthermore, this links into your activity rate and healthy lifestyle. This suggests that if you live in an environment which supports physical activity and healthy eating, you will reduce the risk of AD. This prevents obesity, which can render you from being active. Another way of contracting the disease is by smoking. This is because it increases the risk of cardiovascular disease, diabetes, strokes, the blood vessels narrowing in the brain and the heart and causing oxidative stress damage in the brain. The majority of these effects are connected to the brain, which implies that they can cause neurodegeneration through the various consequences of smoking. Alcohol also contributes to Alzheimer’s disease developing. This is because alcohol reduces the volume of the brain’s white matter which helps transmit signals between different brain regions, leading to issues in the way the brain communicates. By giving up smoking and drinking alcohol you could prevent a higher risk of being afflicted with AD.
The target that neurologists should focus on is amyloid-?, because AD is caused by the excessive accumulation of amyloid-? in the brain. Many sources contradict this, but there are many investigations which support the Amyloid Cascade Hypothesis. Examples of this include the “Pooler et al (2015). Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol Commun. 3:14.”, and “Rapid appearance and toxicity of amyloid-? plaques in a mouse model of Alzheimer’s disease (Meyer-Leuhmann et al, 2008). Both of these sources dictate that amyloid-?’s increase can cause AD to take form. This shows that the Amyloid Cascade Hypothesis is trustworthy.
On the other hand, there are arguments against the Amyloid Cascade Hypothesis which are considered too. One of them is “Tangle and neuron numbers, but no amyloid load, predict cognitive status in Alzheimer’s Disease (Giannakopoulos et al, 2003)”, which informs us on the fact that amyloid is not present, but there are still tangles active. Another is “APP/PSEN1 Transgenic Mice have substantial amyloid deposits but no neurodegeneration (Webster et al, 2014)”. This informs us that mice which have a sufficient amount of amyloid are not experiencing any neurodegenerative symptoms, which does not support the Amyloid Cascade Hypothesis. The most important counter argument placed and has been seen is that all tests involving amyloid-? have failed, which means that if neurologists continue to experiment with amyloid-?, they may find that the tests fail too. These counter arguments have not changed the neurologists minds about amyloid-? being the main cause for Alzheimer’s disease. This is because some scientists have suggested that the concentrations of the drug were too low or that the patients were treated too late. Others have suggested that amyloid-? is the trigger, therefore it will no work after activation.
In 2050, Alzheimer’s disease will be worse than what it is at its current state. However, drug trials and further research will be able to figure out the best target for AD. Amyloid-? is the pathology which should be targeted because it has the most history involving AD and can produce successful treatment for people suffering from AD. Even though there are researchers who doubt the Amyloid Cascade Hypothesis is relevant, it has proven to be the most trustworthy protein in the sense that it effects AD greatly.