The Beta-Amyloid Hypothesis of Alzheimer's Disease

Currently there are limited treatments for Alzheimer's that only address the symptoms or slow down progression.  For example, people with Alzheimer's have been found to have a shortage of acetylcholine in their brain so drugs such as Reminyl work by maintaining existing supplies of acetyl choline, by acting as enzyme inhibitors of acetylcholinesterase. To form better treatments focus on the root causes of AD and brain pathology are necessary. I found it interesting to note that there are 100 billion nerve cells in an adult brain with branches connecting at over 100 trillion points, called the 'neurone forest'. Signals travelling through the neurone forest form the basis of memories, thoughts and feelings. Alzheimer's causes cell death and tissue loss, so a brain affected by Alzheimer's has fewer synapses and nerve cells. It seems that the most likely explanation is the amyloid hypothesis and more research into this could lead to treatments that tackle the underlying cause of Alzheimer's.

The amyloid precursor protein (APP) is found widely throughout the body. Little is known about it's function although it is speculated that it may bind to the surface of cells and help them attach to one another. A fault with the processing of the APP in the brain leads to production of a short chain of APP called beta-amyloid. The hypothesis is that the fault may lie within the overproduction of beta-amyloid or the mechanism that removes it from the brain or both. Production of this sticky protein fragment forms clumps called amyloid plaques which triggers the destruction and disruption of the nerve cells in the brain, causing Alzheimer's.

APP is made of up to 771 amino acids and beta-amyloid is produced when betascretase and gammasecretase enzymes break the chain, forming beta-amyloid of 38, 40 or 42 amino acids long. The chain which is 42 amino acids long is chemically stickier and more likely to form plaques. There are three genetic faults, which alter the role of gammasecretase, leading to increased production of beta amyloid 42.

The plaques build up in spaces between nerve cells affecting neurotransmission, and also damage neurones. This in turn causes an inflammatory response as the brain tries to repair itself. It is also thought to cause the formation of neurofibrillary tangles, which are twisted fibres of another protein called tau, that builds up inside cells. 

There is lots of evidence that beta-amyloid causes AD and destruction of nerve cells. For example beta-amyloid killed nerve cells cultured in a laboratory. Mice with human Alzheimer's genes inserted in their DNA developed proteins plaques and showed decreases in their memory and learning skills (measured by use of tests such as a water maze which requires memory). Of those mice, the ones given anti-amyloid vaccine developed the condition more slowly. Despite this evidence that amyloid is key to damage in Alzheimer's disease, the question still remains of exactly how the damage done. It seems that there are ingredients that are directly toxic to nerve cells, formed when the first few strands of protein stick together. Most damage is done during early stages, when the clumps are small and thus more mobile, enabling them to affect more nerve cells.

As neurones die throughout the brain, the affected regions begin to shrink in a process called brain atrophy. In the final stages of AD damage is widespread and brain tissue has shrunk significantly.

Treatments under development and testing aim to remove beta-amyloid or disrupt it's production from APP in the first instant.

Researchers are trying to develop drugs which prevent production of beta-amyloid from APP, by acting as inhibitors to the enzymes gamma and betasecretase. Several drugs which interfere with gamma-secretase have had some success and reached phase III trials.

Immunotherapy could be used, whereby an active vaccine is used to trigger a process that uses the immune system to clear away deposits or plaques of amyloid in the brain. After animal models were successful, human treatments were developed. In a trial in 2000, a vaccine caused 12 out of 360 to develop serious inflammation in the brain after the immune system overreacted to the treatment. This particular method of vaccine was less successful and had to be halted, however in post mortem examinations it was revealed that participants had fewer plaques than expected. If a safe vaccine can be developed this route of treatment could be very promising.

Dementia

Dementia has been at the top of the political agenda for many years now as politicians realise that they need to take action to tackle a disease that will soon affect one million people across the country. The Alzheimer's society has been working with authorities to create the worlds first dementia-friendly parliament.

Volunteering at a care home first brought about my interest into this topic, after which I read a book called, 'Contented Dementia'. This book taught me a lot about how you should care for people with dementia. Putting yourself in their shoes is crucial. Although there are common symptoms, it is not a universal disease; we are all individuals and it affects people in different ways.

Dementia is the umbrella term for a chronic or persistent disorder of the mental processes caused by brain disease. It is marked by memory disorders, personality changes and impaired reasoning. There are many forms of dementia and here is a brief overview of the most common forms being, dementia with Lewy bodies, Frontotemporal dementia, vascular dementia and Alzheimers.

Alzheimer's
This is the most common form of dementia and with the ageing population it is becoming an increasing problem and is a condition that healthcare professionals will need to really understand in order to provide good care.
Causes
Researchers are unsure of where the progressive nature of Alzheimer's starts from, however sufferers have been found to have abnormal amounts of amyloid plaques (protein), fibres (tau tangles) and acetyl choline in the brain. This reduces effectiveness of nerve cells and destroys them gradually- that is why it is progressive in nature. Over time it spreads to areas of the brain such as, grey matter (responsible for thought processing) and hippocampus (responsible for memory). In my next post I will delve deeper into amyloid hypothesis.
Symptoms
Whilst there are common symptoms, it's vital to remember that everyone is unique and it will affect each person in different ways. Common symptoms include mood swings, feeling sad, angry, scared frustrated at their increasing memory loss, more withdrawn due to loss of confidence. They have difficulty with everyday activities and will need more and more support as it progresses.


Dementia with Lewy Bodies (DLB)
Causes
Unsurprisingly, this form of dementia is caused by Lewy bodies. Lewy bodies are tiny deposits of proteins in nerve cells. named after the doctor who discovered them. Researchers do not yet understand how they appear in the brain or contribute to dementia. However their presence is linked to low levels of acetyl choline and dopamine (chemical messengers) which leads to a loss of connection in nerve cells. It is progressive and leads to death of nerve cells and brain tissue. Lewy bodies are also the underlying cause of Parkinson's disease, collectively called Lewy body disorders.
Symptoms

This type of dementia shares symptoms with Alzheimer's and Parkinson's disease. Symptoms partly depend on where the Lewy bodies are in the brain. Lewy bodies at the base of the brain are linked to problems with movement (motor symptoms) - the main feature of Parkinson's disease. Lewy bodies on the outer layers of the brain link to problems with mental abilities (cognitive symptoms), characteristic of DBL. These symptoms can both occur together. 1/3 of people with Parkinson's develop dementia, whilst 2/3 of people with DBL develop motor symptoms. 

Symtoms unique to DBL can include convincing visual hallucinations and less common auditory hallucinations, which can be very distressing. Delusions such as ideas that strangers live in the house or that a spouse has been replaced with an identical impostor can be distressing for carers and relatives.

Later stages include problems with speech or swallowing, leading to chest infections and risk of choking. This requires extensive nursing care. On average a person may live eight years after first symptoms.

Who is affected
It is thought that Lewy bodies accounts for 10% of all dementia cases but is under-diagnosed and mistaken for other diseases, so only accounts for 4% of recorded dementia. It is particularly important to have an accurate diagnosis of DBL because sufferers can react well to some medications but badly to others. There is equal chances of both men and women developing dementia and it is more common in people over 65. There are very few risk factors identified to increase chances of developing DBL.


Vascular Dementia 
Causes
Brain cells are killed due to reduced oxygen supply to the brain as blood vessels to the brain narrow or become blocked. This can occur gradually after damage to blood vessels deep in the brain, after a series of small strokes or suddenly after a large stroke. Symptoms overlap with  with the most common form of dementia, that is, Alzheimer's. It is not uncommon for people to have mixed dementia, such as both Alzheimer's and vascular dementia.
Factors that increase risk are the same as those which increase the risk of cardiovascular disease (makes sense). Risk factors are anything which causes damage to the vascular system, including high blood pressure, high cholesterol diabetes and heart problems.
Symptoms
Typically symptoms appear suddenly after a stroke or in a step progression, where it will stay at a constant level then suddenly deteriorate. Symptoms are similar to Alzheimer's but symptoms particular to vascular dementia include problems with concentration, communication, speed of thinking, and memory. Seizures could occur, periods of acute confusion, symptoms of stroke such as weakness of paralysis. Hallucinations, misperceptions, behavioural changes, difficulty walking and unsteadiness can also occur. These, however may not be directly as a consequence of the disease, but other factors play a part. For example behavioural changes could be as a result of care needs not being wholly met.


Frontotemporal Dementia 
Causes 
This is a less common form of dementia but is the significant cause of dementia in under 65s. The cause is not yet known, but it is assumed to be caused by a mixture of genetic and lifestyle factors. It occurs to due death of nerve cells in the frontal and temporal lobes. Frontal lobes situated behind the forehead- on the right side they control behaviour and emotions and language on the left. Temporal lobes on either side of the brain have many roles such as understanding of words on the left side. The death of nerve cells is linked to lumps of abnormal proteins inside cells. These build up and become toxic causing brain cells to die and the lobes to shrink over time. A mutation in the tau gene can cause frontotemporal dementia, leading to a build up of the protein which usually is involved in transporting chemical messengers between nerve cells. It can also be caused by the progranulin gene or a recently discovered gene called c9orf72 that can also cause motor neurone disease.
Symptoms
This is hard to diagnose because it is not associated with memory loss in the early stages. In addition this dementia can occur in middle aged people which is unusual. Brain damage leads to changes in behaviour, personality and difficulty with language.

With dementia becoming so prevalent in society today, more needs to be done amongst us all to create communities which are aware and supports the needs of those living with dementia. This is what the Dementia Friends campaign is all about. Anybody can become a dementia friend and if you are interested, here is a short video about it: https://dementiafriends.org.uk/

Book Review: Bad Science by Ben Goldacre

Ben Goldacre's engaging and comical style writing persuades you to join his view of science. His thorough research and facts support a strong argument against all groups who present 'Bad Science' in research.

He particularly shuns homeopaths as he believes they are no better than placebo stating that they 'cherry pick' trials. Whilst this may well be true, it contradicts claims in the book I have read called, 'What the Drug Companies Wont Tell You and You're Doctor Doesn't Know',  by Michael T Murray, claiming that the trial methods are all included and accuse drug companies of paying scientists to 'cherry pick' the results and not homeopaths. For me, it is easier to believe Ben Goldacre's claims, as he takes a more unbiased approach, by highlighting 'Bad Science', in both mainstream and alternative drug industries.

From this I have learnt to be critical in all investigations that you do first hand, which is so important in modern day evidence-based medicine. There are so many factors to control in investigations and in this book I learned the importance of randomisation and double blind trials. A particular topic that grabbed my attention was placebos. I also found it interesting to note that the method of placebo used can affect how effective the placebo is. For example an injection of salt water is more effective as a placebo than a sugar pill because the injection is a far more dramatic event. The manner of the doctor can also alter the placebo effect. Patients report better improvements in their health, when prescribed the same treatment from a more warm, empathetic and reassuring doctor, than doctor who is cold and less reassuring. This makes me reflect on the kind of doctor that I would want to be. It also highlights why double blind trials are vitally important in investigations.

I feel as a prospective doctor it is important to know about the science behind the medicine, rather than prescribing drugs blindly to patients. The drug companies are the base of the healthcare system and without them there would be next to no treatments. In order to advance the field medicine, scientists need to be precise and critical with their investigations. In addition it is important not to waste money on unnecessary research. For example, utilising tools such as Meta-analysis, whereby you collate results from trials, each too small to be conclusive. After all, information can save lives.