It was researched why there had been no significant advancement in the treatment of Alzheimer’s and why we have such little understanding of what causes the disease. The aim was to know how the brain of an Alzheimer’s patient is different from the brain of a healthy person, what increases the risk of the diseases and what studies and experiments/ trials are underway to find out how the disease can be treated.
This was achieved by using qualitative methodology as it allowed me to use a lot contextual data and provide a wide-reaching answer to the question- the question that was the centre of the project was very open; there are many different factors that could have been included. This ensured that many different research sources were considered.
After completing the project, it was found that the reasons why there is not a cure for Alzheimer’s is because of a lack of understanding of the development of neurodegenerative diseases and the brain. Also, there are many different views of how Alzheimer’s can be prevented and until there is a firm consensus on that, it is unclear on what type of treatment should be focused on. In addition, because of the long process of clinical trials, even though research is underway, it may take a long time until the results will be achieved and these results may not be successful in treating Alzheimer’s without harmful side effects. The cure for Alzheimer’s has not been found because it is not a physical disease that can be seen and targeted; the brain is to delicate to target with chemotherapy like cancers can be, for example. The conclusion was reached after using a range of research sources.
Recommendations for further research include the sources listed in the bibliography.
110 years without a cure. Why the treatment for Alzheimer’s is yet to be discovered.
Alzheimer’s is a neurodegenerative disease that was discovered in 1906 by Dr. Alois Alzheimer who described it as a ‘peculiar disease’ when one of his patients, Auguste D, was found to have profound memory loss, didn’t recognize her family and whose psychological state deteriorated. In her autopsy, Alzheimer found that Auguste’s brain had shrunk dramatically and that there were strange deposits around the nerve cells (www.alz.org). Alzheimer is not just acclaimed for finding Alzheimer’s but for also being a role model of how to treat neurodegenerative illness by having a close clinical relationship with the patient and using scientific tools that were new at the time. In 1910, the disease was named after Alzheimer. Alzheimer’s is quickly becoming an epidemic since in 2013 there were 508, 813 people with Alzheimer’s and there is a projection of 1,297,626 by 2051, an increase of 156% over the next 38 years. Alzheimer’s is the most common form of dementia (molecularneurodegeneration.biomedcentral.com, www.alzheimers.org.uk).
There have been some developments in the disease (www.alz.org): the invention of the electron microscope 1931 and its use during World War 2 allowed scientists to study brain cells in more detail and therefore understand their function better. During 1968, a scale for measuring cognitive and functional decline in the elderly was developed with which the amount of damaged brain tissue and brain lesions (abnormal tissue) could be estimated. Alzheimer’s was established as the most common form of dementia and a major challenge for public health in 1976 and since then there have been drug trials and national initiatives but still no cure. The pharmacological therapeutics that are available at the moment only relieve symptoms in the patients pathology (the substances in their blood and urine and cerebrospinal fluid) but does nothing to target the actual Alzheimer’s. Also, these treatments currently available only improve a 20% of the patient’s pathology and even then, only moderately and 60% of patients experience side effects. This high percentage of side effects and low percentage of success in trials is common and just adds to the evidence that attention has not been paid to the health of the elderly and dementia; there is a lot of development needed especially since there will be an increase of 156% in the next 35 years (www.alz.org, http://www.alzheimers.org.uk).
During a visit to a pathology department, Dr Christopher Pitt told me that when scientists are trying to find a cure, they first look at the disease at face value, at symptoms, then through studies and under a microscope to build an understanding. This leads to the hypotheses and drug propositions and ideas. I would like to set this research in this order, therefore my first question is, ‘What does Alzheimer’s look like and how does it progress?’
According to http://www.alzheimers.org, the first areas that are damaged in Alzheimer’s are the hippocampus which makes it more difficult for the individual to learn new information and form new memories since the hippocampus is needed to retrieve memories but not so much older memories. A lady that I was able to meet while on work experience in a hospital asked for my name multiple times over two days and I assume that she could not remember my face. I also observed a woman that would brush her scalp, missing the hair on her head because she remembered how to brush her hair but was not performing that task properly. The area that is generally affected next is the amygdale which allows the person recall memories based more on their emotional connection to the memories rather than the facts of the occasion, what actually happened. Over time, the cortex, which is the layer of brain cells that cover the hemispheres, is worn down therefore even older memories are lost and the brain shrinks.
As Alzheimer’s progresses, other areas of the brain deteriorate: semantic memory and language breaks down and so it is hard to remember the specific name or a certain word. Temporal lobes which control the visual system make it hard for the patient to recognise faces, but because of the other lobes they may be able to recognise the the person when they hear their voice or feel an emotional connection the person. Damage to the right parietal lobe makes it difficult to judge three-dimensional distances (www.alzheimers.org). One of the men on the ward that I visited was walked up and down the corridors to test his judgement of three-dimensional spaces and his balance. Damage to the left parietal lobes is common in Alzheimer’s disease, leading to clumsiness/ apraxia as it allows us to distinguish our right from our left. Skills that are learned like playing an instrument are stored in the procedural memories and so are retained for the longest time but these do not help the patient with everyday tasks and living (www.alzheimers.org).
This may shed some light on why there hasn’t been a cure found with so many complications in the organ of the body that we know the least about and is the most complex; the brain. Also, with diseases like cancer, we can sequence tumour genomes and comparing then to the genomes of patients to track the formation and growth of tumors, however, with Alzheimer’s there is no tumour to biopsy, to track Alzheimer’s we need to find underlying mechanisms and do extensive lab tests that also form a barrier because we don’t have an excess of available brains to test on like there are tumours that can be tested on and even the new technology of growing cells in labs is not the same as the brains environment. Just on the surface, there are already many obstacles to overcome that don’t present themselves in other diseases.
Alzheimer’s doesn’t affect just one cell type; there are multiple cells that are thought to be involved. There are the neurons which are very important in responding to amyloid beta and memory, the astrocyte which becomes overactive when it tries to protect itself from the amyloid beta plaques. There are also microglial cell is an inflammatory cell which is also affected by the increase of amyloid beta peptides as well as blood vessel cells, epithelial cells and smooth muscle cells as described by Professor Dennis Selkoe (www.dnalc.org). The neurons are the cells that are ‘killed’ by Alzheimer’s which causes the brain to shrink just as Dr. Alzheimer observed in Auguste D.
It is quite strange that brain cells die when an individual develops Alzheimer’s because I know that neurons are strong and resilient cells that are formed to last all through life, they are the only cells that aren’t constantly being replaced, our neurons survive for our entire lives. Therefore what is it about Alzheimer’s that suddenly begins to kill of our strong brain cell?
Most researchers have now come to hold the build up of small proteins called amyloid beta peptides- like at www.ns.umich.edu, the website for the University of Michigan- which are identified as plaque in the autopsies of Alzheimer’s patients as the main cause of Alzheimer’s and cell death. Amyloid beta was actually discovered in 1984 but we are still unsure of why it is so deadly and how the protein is able to build up in Alzheimer’s patients, but many scientists their own ideas:
The immune system has a pattern recognition pattern (PPR’s) which allow it to cause an inflammatory response to foreigners like bacteria. These PPR’s are found in amyloid beta, implying that the harmful build up of amyloid beta is triggered by the inability of the immune system to clear the amyloid in the healthy brain before the disease develops as www.alzheimers.org.uk explains.
From here, the build up of amyloid beta and its affect on cell membranes of brain cells is what causes cell death. Amyloid beta peptides being present damage the cell membrane of nerve cells, allowing an unregulated movement of calcium ions into the nerve cells. The University Of Pennsylvania School Of Medicine has concluded, after finding calcium a ‘common denominator’ in two studies, that calcium is so important because it is how cells communicate and it needs to flow in a controlled manner for this to be effective. This lack of communication could lead to the loss of brain cells after prolonged exposure to this uncontrolled flow of calcium. In experiments in the conditions of a culture dish, researchers found that there was also correlation between the size range of the amyloid clumps and the ones that formed the most pores- mid-sized clumps form the most pores and so are the most responsible for neuronal death due to calcium flow. This knowledge does provide hope for a treatment though because if this pore/ hole formation in the cell membrane could be blocked could reduce or stop the calcium flow. This revelation has also proven that current treatments like Bapineuzumab which target the larger amyloid clumps aren’t effective as this study shows that mid-sized clumps do the most damaged.
An international team of researchers from the University of Cambridge, Lund University and the University of Groningen have found that a drug called bexaratone which is an anti-cancer drug (www.cam.ac.uk) that targets the first step in the chain reaction that leads to this brain cell death. This first step involves nucleation which occurs when natural proteins in the body fold into the wrong shape and stick to other proteins which then lead to thin structures called amyloid fibrils forming; amyloid beta peptides again appearing to be the main cause of the problems in Alzheimer’s disease. The writers have described the nucleation step as responsible for small clusters called oligomers to be formed around nerve cells which cause the brain damages in Alzheimers and I think that these are the same structures that some scientists call amyloid plaques or tau protein. Bexaratone is a neurostatin-type molecule which tries to stop this primary nucleation step that causes the downwards spiral. So far, the drug is unsuccessful in cases where symptoms of Alzheimer’s were already apparent but in cases where the symptoms were yet to present themselves no evidence of Alzheimer’s appeared. In earlier studies of bexarotene, it had been suggested that the drug could actually reverse Alzheimer’s symptoms by clearing amyloid beta aggregates in the brain but researchers have now shown that the drug is more preventative as it inhibits the aggregation of amyloid beta.
Neurostatins are not a cure for Alzheimer’s, however, they could act as backup for the body’s natural defences against proteins folding into amyloid fibrils which can become impaired as we get older. One of the project leaders, Dobson compared neurostatins to statins that are used to prevent heart attacks; statins are not given to people who have just had a heart attack just like how neurostatins cannot be given to individuals who already can’t remember their family members- their role will be in prevention.
A different hypothesis in a study acknowledged by medicalnewstoday.com and carried out by Ted Dawson Ph.D. at John Hopkins University, used laboratory-grown cells and has built a new knowledge of programmed brain cell death. This is important because it is distinguished from the other types of cell death: apoptosis (programmed death in multi-cellular organisms), necrosis (caused by cell injury leading to the premature death of cells), autophagic (the regular type of cell death that includes the recycling of old material to form new cells) and is specific to neurodegenerative diseases like Alzheimer’s. They have named this new cell death as ‘parthanatos’. The team tested 160 proteins and found that a macrophage inhibitory factor- MIF- was the main cause of ‘parthanatos’ and they have also discovered chemical compounds that can block the MIF in the lab grown cells, protecting them from cell death. There is now an opportunity for this team to test their chemical compounds on animals with Alzheimer’s to see if it works as successfully as in their lab grown cells. This research may link to the theory above about amyloid beta peptides and unregulated calcium ions because if the autophagic type of cell death is not being carried out then old material and debris of cells like the amyloid beta protein aren’t disposed of and are allowed to just build up and form the plaques that are observed in the autopsies of Alzheimer’s patients.
Auriel Wilette, a researcher in Iowa State University found that people with higher levels of inflammatory proteins in their cerebrospinal fluid showed greater memory loss after two years compared to those with higher levels of neuronal pentraxin-2. Neuronal Pentraxin-2 is a naturally occurring protein that regulates immune function and the connections between neurons/brain cells therefore clearing away old or inefficient connections to make a path for new connections. Wilette has said that “If you have high levels of this synapse- building, inflammation- regulating protein, you may not have a much, if any, change to your memory.” This then opens up the treatment of neuronal pentraxin-2 if the production of the protein can be promoted, this will decrease inflammation and therefore the development of Alzheimer’s. This can be achieved by having complex jobs and hobbies or even social interactions because complicated cognitive tasks cause new connections to formed between neurons. Wilette is convinced that brain inflammation can be avoided without medicine and has criticised nonsteroidal anti- inflammatory drugs like pain relievers in reducing inflammation because they haven’t been proven to decrease the type of inflammation that reduces memory loss. This avoidance is mainly linked to diet as people who are overweight have a larger risk of developing Alzheimer’s as excess weight causes chronic inflammation. The university website, www.hsiastate.edu, includes all of the information concerning his studies.
A potential cause that was quite surprising for me was that in some studies, the amyloid beta deposition was only observed in Alzheimer’s after infection of herpes simplex virus type 1 in which case, the build up of amyloid beta peptides would be a defence mechanism to this infection. This is because HSV1 and other infections can reach the central nervous system and remain in a dormant state but become activated during aging as the immune system declines. The result is neuronal damage caused by recurring viral-induced inflammation leading to the synaptic dysfunction and neuronal loss that I have previously explained and ultimately Alzheimer’s (ww.content.iospress.com). The University of Manchester found this herpes simplex virus type 1 in those that had a genetic risk to the disease, stated at www.manchester.ac.uk.
This might imply that there is more than one cause of Alzheimer’s since I’ve discovered that obesity causes inflammation that increases the risk of Alzheimer’s and now that there is a genetic factor that may include the herpes simplex virus type 1 or affect people that are more susceptible to the herpes simplex virus type 1.
This conclusion is supported by a study by UCLA (newsroom.ucla.edu) which claims that Alzheimer’s has three distinct sub-types when it was formally thought of as a single disease. These subtypes are: Inflammatory shown by C-reactive protein markers in the blood which are present after infections of long term diseases like Alzheimer’s, Non -Inflammatory where there are metabolic abnormalities like insulin resistance or hormone deficiencies, and Cortical. The Cortical type affects younger people and doesn’t cause memory loss but does cause a loss of language skills and isn’t caused by an Alzheimer’s ‘gene’. Going forward, Dr Bredesen’s team will reasearch if these subtypes have different causes and so different potential treatments.
Another hypothesis of the cause of Alzheimer’s is metabolic abnormalities and this I believe would be linked to the ‘Cortical’ type and diet and exercise reversed the cognitive decline 9/10 patients due to these improving the bodies metabolism in a 2014 paper by Dr. Dale Bredesen . I do not completely trust this result because it is a small sample of patients and I don’t know what the conditions of the test are and from these results I would infer that all of the patients had just one type of Alzheimer’s. This hypothesis also fits with Wilette’s ideas of obesity increasing the risk of Alzheimer’s since if a person is over-eating and not exercising their metabolism is lower and therefore correcting these areas could reverse or slow down the progression of Alzheimer’s.
Other potential treatments have been put forward to combat the Alzheimer’s types that affect memory by re-activating the lost memory by re- stimulating the nerves with a high frequency train of optical pulses. Dr Leon Thal from UC San Diego University (ucsdnews.ucsd.edu) used rats to tests his theory because the build up of amyloid beta peptides in the brains of Alzheimer’s patients weaken synaptic connections in the same way that low frequency stimulation erased memories in rats. Their results have shown that they can reverse the processes that weaken the synapses and so this could also reverse the effects of Alzheimer’s in terms of memory. However, this will not stop the disease from developing, it will just restore memories which is still an interesting prospect.
Scientists in China have also been able to turn skin cells into new functional brain cells, one with cells extracted from Alzheimer’s patients and another from mice. They altered the gene expression of the skin cells and this could allow the growth of new neurons to replace the defective ones in Alzheimer’s patients. This is called iPS cell technology and it allows scientists to study the actual disease by indentifying ‘markers’ that distinguish a disease and not just a simulation or idea of it. iPS/ iPSC technology has been pioneered by Dr. Shinya Yamanaka and samples from a person can be regressed into their stem cell state where they can be differentiated into brain cells, an advancement covered by www.sfgate.com and molecularneurodegeneration.biomedcentral.com. iPSC’s are identical to embryonic stem cells with the ability to self renew as well as differentiate into different cells (molecularneurodegeneration.biomedcentral.com).
In the test that used skin cells from the patients themselves, the new neurons will have a low risk of rejection and so the new cells will be able to start working in the patient straight away without making the patient any sicker or compromising their immune system to decrease the risk of rejection an interpretation of www.sciencealert.com. The concern with making new cells is that the created cells may not work the same way as their natural counterparts. Another attempt at this was by Stanford University who inserted genes into skin cells that code for three types of transcription factors which are proteins that regulate gene activity by turning specific genes on and off. One of the Chinese scientists, Zhao has aims to formulate a, “chemical cocktail” which can be given to Alzheimer’s patients to grow new neurons directly in their body without any need for extracted cells. This is cell replacement therapy.
My only criticism of this hypothesis is that replacing cells may replace the function but the build up of amyloid beta or the inflammation will remain and how do we know that the new cells won’t be affected by Alzheimer’s also? I’d suggest that a mixture of all of the proposed treatments so far could be used to at least reduce inflammation so that the new cells can replace the damaged ones in a healthy brain environment otherwise the causes of Alzheimer’s will continue to damage the new cells.
Even though there is research going on to successfully treat Alzheimer’s, all of these are in their early stages and after there has been success in the lab, there then need to be animal trials then human clinical trials as explained by fda.gov and this is why alzheimers.org.uk even states that there are no drug treatments. These clinical trials and even the initial testing process present problems of their own. Although the model in theory appears good and effective for finding new drugs: controlling who qualifies for the trials, the length of the study, having a control group- there are ways of avoiding to publish negative results which then ensures that a drug is developed further. Such as, if a drug only works for a certain amount of time, like six months and then it stops working to improve a condition that lasts for a long time, like Alzheimer’s (nine years on average before death), then the effectiveness of the drug is questionable. If a drugs trial was completed in four months or if the four-month results were published, the drug appears like a miracle worker. This is the case for a current Alzheimer’s drug called donepezil which other treatments are compared to even though donepezil is not that effective.
One such drug is RVT-101, which is part of the ‘Mindset’ programme (petitioned on alzheimersglobalstudy.com) – a stage three clinical trial that is investigating if the experimental drug in combination with donepezil will help those with mild to moderate Alzheimer’s to perform everyday activities. To be successful, the drug must be more effective than just using donepezil on its own. Donepezil is one of the five pharmacological agents that the US Food and Drug Administration have approved (molecularneurodegeration.biomedical.com). It is the most used drug for dementia because it is approved to treat all stages of Alzheimer’s according to www.alz.org.
Donepezil itself works by inhibiting the levels of acetylcholinesterasein the brain which may reduce the symptoms of dementia in some patients by reducing the breakdown of acetylcholine and leading to increased communication between nerve cells. Donepezil is only successful in 40-70% of cases, a very large margin due to the fact that there have been both controlled and uncontrolled trials. In the controlled trials the, 74% of patients with mild to moderate Alzheimer’s disease had adverse effects and 81% in patients with severe Alzheimer’s had these same adverse effects. As well as this, the positive effect of the drug is only felt for nine months on average when Alzheimer’s is a degenerative disease and lasts nine years after diagnosis before the patient dies; some cases even record patients enduring Alzheimer’s for 20 years after diagnosis (healthline.com). Therefore, the available drugs are in no way feasible especially when the cost to the (£21 a year per patient even though the drug stops working after nine months) NHS is taken into account.
Also, older, people, who are more likely to already be on medication, whether for another illness or for prevention, taking donepezil could react with the pre-existing medicine and cause negative effects; even with interaction with a common drug like ibuprofen can increase the risk of stomach/bowel bleeding (drugs.com, FDA.com). This is another thing that I observed during work experience on the drugs round; some patients had five pills to be taken at the same time as well as an injection. All of these had been prescribed to treat pre-existing illnesses and so a drug that reacts adversely with these other drugs is not practical in any healthcare environment.
According to drugs.com, donepezil causes the side effects of diarrhoea, loss of appetite, muscle cramps, nausea, trouble in sleeping, unusual tiredness or weakness and vomiting commonly and so in comparison to this, it would be easy for a new drug to seem amazing in comparison even if the actual results of the drug aren’t as promising. This is sadly, the tale of pharmaceuticals; new drugs that aren’t very successful and have many awful side effects- side effects on top of the illness that the patient already has- are put on the market because they’re better than nothing which is arguable because taking no drugs doesn’t cause side effects. The bench mark for new drugs is extremely low; the criteria is to be better than no treatment at all and this then opens up loopholes for companies to hide their negative test results and make their drugs seem more effective than they actually are; the pharmaceuticals industry and if a product sells it doesn’t matter that the product doesn’t actually work.
The website, molecularneurodegeneraion.biomedcentral.com, supports that this system subjects patients to a cycle of drugs that are ineffective as it shows that several new drug candidates targeting amyloid beta have been tested in clinical trials and all of them have failed to improve cognitive or functional ability of patients with Alzheimer’s disease, adversely causing serious side-effects. For a drugs or treatments that actually modify the disease, a better understanding, a firm understanding- not a mixture of various hypothesis and tests that are currently available. However, instead of waiting for drugs that are actually effective to be available, patients are given the drugs that are more detrimental than helpful in the meantime. There is an epidemic of Alzheimer’s arising as populations get older but feeding these populations with useless drugs is not the answer.
Another aspect of Alzheimer’s is care, an area that is currently threatened. According to Age UK, the number of people with unmet needs rose from 800,000 in 2010 to more than 1 million in 2011. A nurse shared with me that patients are regularly woken up during the night for medication. Her main issue with this was that the patients have spent their entire lives waking up early to go to work and that in their retirement, no matter how dependant that are on care, should be allowed to rest and wake up in their own time being respected. This is important to consider because although a cure is the ultimate way that the livelihood’s of the patients can be improved, primary care while we wait for this cure is being developed is the most that can be done in this present time.
In conclusion, a lack of attention has been spent on diseases that affect the elderly, maybe because we have never had an elderly population as we do today where the predicted living age is eighty-two years compared to the seventy-one years in the 1960’s (visual.ons.gov.uk); we have not been properly prepared. I would imagine that some economists would blame this failure to adapt the NHS on the economic landscape and financial crisis. However, I would disagree with this because after WW2 there was rationing and austerity and Britain was even applying for the EEC and relying on American financial support to remain afloat financially( Access to History: Britain 1951-2007) and this was the era in which the NHS flourished and was established as a national service. It could be possible that the NHS and services that would benefit Alzheimer’s are no longer the priority of the government; in the 1960s, investing in the NHS procured many votes as part of the socialism movement (A History of Modern Britain) and possibly the focus is on maintaining the current NHS, not on moving it forward.
History may provide the answer, as in the 1960’s there was a strong youth culture such as the Mods and Rockers, and generations after this also found themselves feeling alienated from the older generation before them. This is supported by the song ‘My Generation’ by The Who with the lyrics “I hope I die before I get old” and “Why don’t you all f-fade away” (www.azlyrics.com), which shows the attitudes of the young towards the old. Our political and financial unrest has left the population trying to forget the needs of the older generation, not out of malice but out of fear encouraged by a media that if the older generation are cared for, other services to ‘our’ generation and the generation of our children will be taken away. I think that the media and even the government encourage Social Darwinism so that we only care about our own survival and not on fighting for equal healthcare for all generations.
Linked to this is that those with Alzheimer’s are older and therefore their mortality is closer than those with other diseases like cancers which affect all generations of peoples. I think that this demonstrates a disconnect between the NHS and drugs companies and governments because the Hippocratic Oath (guides.library.jhu.edu) states that ‘I am to care adequately for the sick.’ Doctors are supposed to care adequately for everyone but how can they do so when the resources supplied are distributed unequally. If there is not a demand, both social and financial then there won’t be a difference made. Beyond the drugs and the complex science, do we care about our elderly as much as we care about the newborns receiving vaccines and the mothers and fathers with cancer)? Is there more commercial money in the elderly than in alcohol related diseases? Until this changes and we stop seeing or allowing people to be ranked in order of how much money they can make pharmaceutical companies and how much money they are ‘draining’ out of the NHS for wanting to live a better life, no longer how short that have to live, the cure Alzheimer’s will not be realised. Alternatively, a profitable treatment will be found that works on reversing the symptoms that I have explored and then the chances and lives of Alzheimer’s and dementia patients will be improved.
I think that the main reason why there hasn’t been a cure for Alzheimer’s in the last 110 years is that we need more knowledge about how to treat neurodegenerative diseases in general and this will only come with time. In addition, medicine is no longer about finding cures; it is more about the treatment and improving the lives of patients. An example would be my grandfather as he had a heart attack- he is not cured of his heart attack, the strain it had on his body will always remain but he has had physiotherapy to build up his strength and antibiotics to help his immune system to fight off other diseases. The diseases that we are now fighting don’t have a cure, we have prevention and treatment; the concept of a cure is unrealistic to how modern medicine works. This is supported by the Hippocratic Oath, taken by all physicians which has the fundamental of ‘’Do No Harm’ (en.wikipedia.org, guides.library.jhu.edu). The modern version of the Oath even has the line ‘I will prevent disease whenever I can, for prevention is preferable to cure’ and this demonstrates the attitudes and expectation of practitioners today.
©Being Multicellular 2018. All Rights Reserved.
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