Alzheimer’s disease (AD) is the sixth leading cause of death in the United States . It impacts the older population, most particularly, women, and it is a brain disorder that progressively destroys memory and thinking skills, and eventually, hinders one’s ability to carry out the easiest tasks such as turning on a stove or driving a car. Even though AD was discovered more than a century ago, finding a cure has been elusive. AD is an incurable disease because of the lack of a deeper understanding about amyloid plaques and tau tangles that form in the brain, the late diagnosis of the disease, and the inability to replicate the disease on animals to further research.
Alzheimer’s Root Cause – Amyloid Plaques and Tau Tangles
Alzheimer’s is a disease occurring in more than 5.5 million Americans, most of whom are around 65 years or older . AD is the most common source of dementia (loss of cognitive function such as thinking, reasoning, and remembering among older people) and was discovered by Dr. Alois Alzheimer in 1906. He had a female patient who had died of an unidentified mental illness, and after examining her brain tissue, he found many abnormal masses and tangled bunches of fibers which are now termed as amyloid plaques and tau tangles . These amyloid plaques and tau tangles are the main features of AD today. In addition to these characteristics, there is also a loss of connections between nerve cells, or neurons, in the brain .
Neurons are specialized cells that process and send information with the help of electrical and chemical signals throughout the brain. In healthy people, neurons control all sensations, movements, thoughts, memories, and feelings. These nerve cells communicate with each other through electrical signals that travel down axons. This causes the release of chemicals across tiny gaps called a synapse, to neighboring neurons. AD breaks up these communications in neurons, consequently, leading to a loss of function and cell death .
Microglia and astrocytes are two variants of glial cells. In the case of a bacterial infection, glial cells can get rid of bacteria in the area surrounding neurons to keep them healthy. In a person with AD, toxic changes such as the accumulation of amyloid plaques and tau tangles, destroy this healthy balance of microglia and astrocytes . These changes in the brain can occur years, even decades, before the first signs of AD appear. As these accumulations increase, neurons are destroyed, and as a result, the brain shrinks and loses various functions. For example, the brain could lose glucose that is needed to power activity, or the vascular system may fail to deliver sufficient blood and nutrients, such as omega 3, to the brain .
Eventually, neurons lose their ability to communicate and so the brain shrinks, beginning in the hippocampus, which is crucial to learning and memory. Then, an AD patient may experience memory loss, impaired decision making, and sometimes even language problems. As the advancement in brain imaging occurs, we are able to expand our understanding of the disease and possible cures .
The brain is the most complex part of our body with over 100 billion neurons which are interconnected to form a network that allows for information to flow throughout our body, from thought processing to movement. In Alzheimer’s, the patient loses some of the functional capabilities of the cells and the breakdown starts to have an impact on the neural functions. Scientists think that the main reason why this is happening is due to the two main abnormal proteins – amyloid plaques and tau tangles that irreparably damage the nerve cells .
During the progression of AD, toxic changes occur in the patient’s brain, including the aggregation of amyloid plaques and tau tangles. The proteins involved in these toxic changes are amyloid plaques, beta amyloids, and amyloid precursor proteins (APP). Amyloid plaques are protein parts that the body regularly produces. Beta amyloids are protein pieces cut from APP (in AD, APP is responsible for the production of beta amyloids).
The amyloid plaques are broken down and removed in healthy brains, however, in the brain of an AD patient, amyloid plaques clump together and become solid, insoluble accumulations between nerve cells. In the brain, the small strands can be easily dissolved in the fluid between cells. Sometimes, the enzyme that is used to cut the APP proteins is not always accurately cut, resulting in larger strands that are not able to dissolve in the fluid between nerve cells. The longer strands are “sticky” which allows them to start clumping into deposits called plaques. The presence of these plaques can trigger an immune response in the area resulting in neuron death. .
Neurofibrillary tangles are insoluble twisted fibers that are located in the brain’s cells. The tau tangles are made up of proteins called tau, that makes up part of a structure called a microtubule. Microtubules help transport nutrients or other necessary substances from one part of a nerve cell to another. In a patient with AD, the twisted fibers create tau tangles when the tau proteins are misfolded in a very particular way. The tau forms a C-shape in the main part of the tangle where the loose ends stick out randomly. After one tangle has been created, it triggers a collection of more tau to make the tangle bigger. Scientists have not discovered why or what is responsible for shaping the tau proteins into these specific forms, but there is most likely an unidentified molecule involved. Amyloid plaques kill neurons by destroying connections between nerve cells. Tau tangles aggregate inside the neurons and intrude with cell machinery to create and recycle proteins which then kills the cell .
Difficulty in Finding a Cure for Alzheimer’s
Billions of dollars have been spent on finding a cure for AD, but researchers are nowhere near understanding the disease in its entirety . Unfortunately, the question of reducing or being able to dissolve amyloid plaques has not been answered despite being heavily focused on for the past few years in drug development. After failures in numerous clinical trials, doctors and researchers have begun to wonder if clearing amyloid plaques is sufficient to cure AD.
Although a significant amount of research has gone into finding a cure for AD, the research process has been highly inefficient. For example, even though more than 400 trials have been done on people with potential treatments for AD, no drugs have been put on the market .
Ever since Alois Alzheimer discovered the disease, there has not been any grand theory that really explains how Alzheimer’s starts to impact the human brain. In fact, a Texas businessman who lost family members announced a $4 million prize for researchers who can help explain the disease. James Truchard, the former CEO of National Instruments, said, “The pieces of this puzzle are out there. ApoE4, beta-amyloid, tau, microbes, inflammation, metabolism, FOXP3, and APP are only some of the genes, peptides, and biological processes that have been identified as contributing to Alzheimer’s, but they have not been synthesized into a ‘grand unified theory’ of Alzheimer’s that might lead to a treatment or cure. I’m hoping there’s some genius out there who will put them together” .
Researchers have started to take a more holistic view to address the quest of finding a cure for AD. The sections below discuss why it has been so difficult to find a durable AD cure.
Difficulty in Understanding Alzheimer’s
Researchers have been working to figure out an approach to clear the accumulation of toxic proteins that form in the brain of patients with AD. The brain’s circulation is tightly controlled, unlike circulation in other parts of the body, which means that it is able to keep out harmful substances, such as damaging chemicals or infections. This also means that the brain does not allow medications to enter its domain, so, scientists are not able to get rid of excess toxins like amyloid plaques and tau tangles since medications cannot cross the blood brain barrier, thus unable to reach the brain . The pharmaceutical company, Biogen in Cambridge, Massachusetts has been doing trials with a drug called aducanumab that has been halted after ongoing trials that were not yielding promising results. Derek Lowe, an organic chemist says, “the situation [of amyloid plaques and tau protein tangles] is clearly more complicated than people have hoped, because otherwise, all the attempts to address amyloid…would have yielded some tiny bit of clinical benefit” . Another researcher, Richard Hodes, director of the National Institute on Aging said, “it’s critical as we await more information about [the aducanumab] study…that we continue to actively and broadly pursue multiple candidate targets” .
From the analysis of these two researchers, it is very clear that the research community focusing on AD do not have enough knowledge about how drugs can be used to reverse the toxic build-up in the brain. In order to create a cure for a disease, it is important to understand every aspect of it and create a drug that can “counter” the effects that the disease has on the human body. However, because researchers have not been able to discover a way to even get medicine into the brain, they do not understand all the factors that go into play when amyloid plaques and tau tangles collect inside and on nerve cells. After clinical trial failures, researchers are still unsure if looking for a way to stop the toxic build-up is the right move to finding a cure for AD.
Late Diagnosis Prevents Cure
Scientists have learned that the accumulation of amyloid plaques and neurofibrillary tangles attacks the brain long before a patient manifests memory loss or cognitive decline due to the improvement in brain scanning technology . This is a serious problem because scientists can only test drugs on AD patient’s once they showcase these symptoms, but by the time that happens, they do not have much time to live. This is one of the main reasons for constant failure in clinical trials on AD, simply because the drugs are given too late.
In fact, Dr. John C. Morris, an Alzheimer’s specialist at Washington University in St. Louis, says, “there’s a lot of brain cell damage [by the time the patient is given drugs] and we’re trying to treat a very damaged brain” . This means that there is no point in inducing a patient with certain drugs when too much of the brain is already damaged. If the drugs are given earlier in the progression of the disease, tailored toward certain biomarkers in the brain, then treatment or possibly prevention, would have a higher rate of success. Researchers are doing this by, “trying to go earlier and earlier in the course of the disease…by locating how people move through these stages and what indications there are of each stage,” says Neil Buckholtz, chief of the Dementias and Aging Branch at the National Institute on Aging .
Many research projects are involved in doing just that. American and Colombian scientists are working together to plan to test treatments on Colombians that are destined to get AD, but have not showcased their symptoms yet, in order to see if dementia can be prevented or remarkably delayed. Although the diagnosis of the disease happens very late in its progression , significant work has gone into testing certain drugs on people that are most likely going to develop AD, through genetic mutations that can guarantee development of dementia, figuring out how people progress through the stages of the disease and what those stages are, and more .
Alzheimer’s is Hard to Replicate in Animals
Another important factor that plays into why researchers have not found a cure for the irreversible disease is that it is not easily replicable in animals. Drug testing on animals has been a reliable technique for the pharmaceutical industry to bring drugs quickly to the market. Researchers have been attempting to manipulate Alzheimer’s on animals by inducing symptoms that mimic dementia in humans so that they can test drugs on them before testing on people, but it has proven to be very difficult . However, Matthew Campbell, a geneticist at Trinity College Dublin has noticed that, “while mouse models have provided astounding new insights into disease mechanisms, they don’t reflect the entire biology of the disease” .
Mouse models that can better reflect a more common and sporadic form of AD is something that researchers are now looking into. Researchers are very aware that certain areas of the disease, which are mimicked in mice, drift significantly from AD in humans. For example, one of the mouse models used to study AD involves overexpressing certain proteins that have mutations which result in a bigger aggregation of amyloid beta. These proteins include APP and PSEN1, which is a type of enzyme called gamma secretase that is required in APP processing. Even though this approach is used to understand amyloid plaques better, it is not very efficient since according to Takaomi Saido, a neuroscientist at the RIKEN Center for Brain Science in Japan, “humans do not overexpress APP or PSEN1” . Thus, we need more knowledge and better data to replicate the disease in various animal species.
As previously discussed, it has been challenging to find a promising strand of research that might lead to an AD cure. Some of the research and lab work that is currently going on in different institutes includes working with amyloid plaques and preventing tau tangles and reducing inflammation. Researchers are producing new drugs to stop beta amyloids from clumping and encourage the immune system to keep harmful proteins away from the brain as well as figuring out how to fix the brain cell inflammation that occurs in AD .
Creating new drugs and medications to cure AD is a very slow and difficult task. To help speed up the discovery process, an association of multiple pharmaceutical companies, nonprofit foundations, and government guides, have partnered to create the Coalition Against Major Diseases (CAMD), where data from different AD clinical trials can be shared .
In addition to the partnership between different associations, there is a lack of funding and volunteers for clinical trials. According to James Pickett, the head of research at Alzheimer’s Society in the UK says, “dementia is the biggest health and social care challenge of our generation, but research into the condition has been hugely underfunded. This lack of funding has hampered progress and also restricted the number of scientists and clinicians working in the dementia field” . Considering that we live in an app-heavy world, perhaps more cognitive, and neurological tests can take place to develop a more robust dataset and a volunteer network of millions of users that might lead to some early detection techniques that researchers have not been able to hone in on. By refining our collaborative approaches to researching an AD cure, the probability of success will improve and provide a source of hope for millions of patients and their families who go through this incurable disease.
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