Being the most common cause of dementia, as well as being very poorly understood, Alzheimer’s disease is one of the scarier diseases out there. The brain is already not well understood by scientists, nor are the mechanisms of protein interaction, so a disease which combines both is particularly difficult. Today, I’ll go over what is known about Alzheimer’s disease, what the remaining mysteries are, and how other topics such as neurology inform the study of this disease.
How the Brain Works
Before we start with Alzheimer’s, I should probably give a very brief primer on the basics of neurology. Nerve cells, or neurons, are cells that specialize in sending information quickly and precisely. To do this, each nerve cell has multiple hair-like protrusions called dendrites and a long tail called an axon. Each of these structures grow to almost touch other nearby neurons, creating a web of connected neurons. Each neuron creates an electric charge by pumping charged ions of sodium and potassium across their cell membranes. To send messages, neurons pass proteins called neurotransmitters between each other. When neurotransmitter proteins bind to signal proteins on a neuron’s dendrites, it triggers a chain reaction that releases the cell’s electric charge. Discharging tells proteins on other parts of the neuron to release neurotransmitters, which triggers the same process in neighboring neurons. While it can take several seconds for a messenger protein to travel from one end of a neuron to the other, this electrical signal can travel the same distance in a millionth of a second. This video from Crash Course provides more details.
How neurons encode memory and process information is…wildly complex. This is an ongoing area of study both in neurology and in computer science as scientists try to replicate this system with computers. What they have discovered requires matrix multiplication and advanced calculus to adequately describe, so I’ll keep this very basic. If you’re really curious, this video from Layerwise Lectures details a method used in programming neural networks to save memory in a network of neurons, but it is extremely complicated and is only one way our brains might work. But put simply, what we call memory is when the connections between two or more neurons grow strong enough that one firing routinely causes the other to fire. Neurons can move their dendrites and axons, and when a particular connection between two neurons is being used very frequently, that connection grows stronger. For example, let’s say you train your pet to associate a particular smell with receiving a treat, causing them to start salivating. The smell triggers particular neurons associated with smell to fire, which triggers a complex web of neuronal firing within the brain. Immediately after, when they eat the treat, neurons associated with taste and oral sensation fire along a pathway of neurons that eventually triggers salivation. Because these two neural pathways are being triggered in short succession (odor and treat-to-salivation), any neurons that link these two pathways will grow more strongly connected. Eventually, the odor neurons firing will trigger the salivation neurons to fire by themselves. Now, this is the most basic form of memory, it gets more complicated once it involves events, images, and abstract concepts. We’re not entirely sure how complex memories are stored, though it possibly involves small networks of neurons connected in such a way that they return to a particular arrangement with a simple stimulus. But the most important thing to remember for Alzheimer’s disease is this; neurons need to communicate with each other to maintain memory.
Alzheimer’s Symptoms
The problem with determining what causes Alzheimer’s disease is that there are multiple mechanisms by which this disease damages the brain, and we don’t yet understand how all of these mechanisms are related to each other. There are two primary mechanisms of damage; amyloid plaques and neurofibrillary tangles.
Amyloid plaques
Probably the more famous of the two, amyloid plaques are clumps of the peptide amyloid beta. These plaques grow inside brain tissue, blocking neurons from signaling to each other and possibly damaging the neurons themselves. These plaques start with Amyloid precursor protein (APP), a protein that sticks through the cell membrane to send and receive signals. APP is found primarily in neurons and is linked to several important functions of the brain tissue. APP gets cut into specific parts to create free-floating peptides (protein chunks) in the brain, likely to serve as signal molecules to send specific messages. There are a couple of places where APP can be cut, creating slightly different signal molecules. One of these signal molecules is called amyloid-beta; the intended purpose of which is again not understood but some studies suggest links to some minor logistical functions. Whatever its normal cause, amyloid beta is overproduced in the brains of Alzheimer’s patients, and when amyloid beta reaches a certain concentration, the peptides start to clump together to form plaques that physically block neurons from forming connections.
Neurofibrillary tangles
Neurofibrillary tangles, or tau tangles, are another type of protein clump that causes Alzheimer’s, though this one forms inside individual neuron cells and kills them directly. All cells contain structures called microtubules; long, thin filaments assembled from multiple proteins that form the cell’s cytoskeleton. They hold the cell in a particular shape and serve as a highway for motor proteins to transport materials around the cell. But in the neurons of Alzheimer’s patients, these microtubules are disrupted. One of the proteins important to holding together the structure of microtubules, tau proteins, is modified in a way that causes them to clump together into protein tangles. Not only do these tau tangles disrupt the neurons directly, but the loss of normal tau function causes the microtubules to disintegrate, both of which lead to the neuron’s death. For more details on both of these mechanisms, here’s a video by the NIH’s National Institute of Aging.
These are not the only two biochemical changes the brain experiences with Alzheimer’s disease, but they are the two most noteworthy as they directly harm the formation and recall of memory by damaging neurons or the connections between them. While scientists understand how amyloid plaques and tau tangles form, we don’t yet fully understand what causes APP to be predominantly cut into amyloid-beta or what causes the modification of tau proteins to become unregulated (many proteins are modified in some way after they’re assembled, and how these modifications are regulated is, again, not well understood in all circumstances). The problem for researchers is that these two damage mechanisms aren’t obviously related, so we don’t understand how both occur at the same time in all Alzheimer’s patients. A big part of Alzheimer’s research is figuring out how one symptom is causing the other or how a yet unknown mechanism is causing both.
Hypotheses
Research into how Alzheimer’s disease works has been ongoing for decades, so of course many explanations have been proposed over that time. These hypotheses often come with potential avenues of treatment; if you find the root cause, you find something to aim at. These treatments will often alleviate symptoms in some patients, but we have yet to find a magic bullet. Some theories include;
Amyloid and/or Tau hypotheses
Probably the most obvious two hypotheses, either the formation of amyloid plaques cause the formation of tau tangles, or vice versa. Proponents for the Tau hypothesis point out that Alzheimer’s is just one of several neurodegenerative diseases caused by tau tangles developing in nerve cells. Proponents for the amyloid hypothesis point out that several genetic mutations in APP are correlated with an increased risk of Alzheimer’s disease or with developing the disease earlier in life. Treatments have been tested that target plaques and that target tangles, and while a few have alleviated symptoms, none have permanently halted the disease’s progression.
Chronic inflammation
Many diseases associated with old age are caused by chronic inflammation. (I’ll talk about why at a later date) Inflammation puts mechanical stress on tissues, which causes cells to produce toxic substances that damage DNA and disrupt protein regulation. The brains of Alzheimer’s patients have been found to have elevated inflammation and high levels of pro-inflammatory cytokines. Constant inflammation over time could explain the deregulation of tau proteins that lead to tangle formation. As for amyloid plaques, one of the cells whose job it is to clean out toxins and debris from the brain is the microglia, an immune cell that exclusively serves the brain and spinal cord. Because amyloid plaques have been found at lower levels in healthy brains, it's possible that the plaques we see in Alzheimer’s patients are the result of microglia not cleaning up properly because they’re involved in an inflammatory response. Why only certain people suffer these symptoms and why the microglia would respond to chronic inflammation by not clearing out these plaques has yet to be determined, but it is still a promising hypothesis.
Blood-brain barrier
I mentioned above that the brain has its own line of immune cells, because the rest of the immune system isn’t allowed in the brain. The brain is so fragile and so integral to the body’s functioning that it is physically separated from the rest of the body. The blood-brain barrier is a layer of cells that surround the blood vessels running through the brain tissue, blocking both deadly pathogens and overzealous immune cells from entering the brain. The cells of the BBB take in nutrients and oxygen from the blood which it passes to the brain while taking in waste from the brain to pass to the blood, with only molecules recognized by the BBB let through. Alzheimer’s patients have been shown to have a weaker blood-brain barrier, allowing toxins from the rest of the body into the brain, which would trigger inflammation which would trigger everything else. It’s also been suggested that amyloid plaques could make their way into the small blood vessels that supply the brain, causing vascular problems that further weaken the BBB, creating a feedback loop. Research is still ongoing, but it’s another interesting hypothesis.
This is by no means a comprehensive list of all the hypotheses put forth to explain Alzheimer’s disease. Several neurotransmitters and other molecules have been found to be upregulated or downregulated in Alzheimer’s patients, pointing to potential causes or treatment targets. There are also a few genes associated with Alzheimer’s, though not with all cases. I mentioned earlier variants of APP that are associated with earlier onset Alzheimer’s disease, but only 5% of Alzheimer’s patients have that variant. There’s also a gene called TREM2 that’s associated with microglial cell’s ability to clean out amyloid plaques, but research hasn’t been done yet to determine the prevalence of disease-causing variants among Alzheimer’s patients. If there is a single, unified cause of Alzheimer’s disease in all patients, we haven’t found it yet.
There’s a concept with genetic diseases called the liability-threshold model. Put simply, the majority of diseases with genetic components aren’t the result of a single bad gene, one bad gene is more likely to be taken out of the genepool. Instead, most disease-causing genes (as well as environmental or lifestyle factors) act as “points” for or against a particular disease. Once enough points are accumulated, you get the disease. It’s a model that helps us to visualize how such a complex system can produce diseases which don’t have a single apparent cause. So it’s quite possible that there is no single cause of Alzheimer’s disease for all people. It could be that the brain becomes more vulnerable as it ages, so a single wrench in the works creates a cascade that affects multiple points of failure. Either of these points of failure could start the cascade, but they’re interconnected enough that they are all affected by the end. The good news is that research is still ongoing, for Alzheimer’s disease in particular and the aging brain in general. It would seem we live in an age where the diseases with simple causes have all been dealt with, leaving us with only the complex ones to solve. Yay us.
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