Our brains are the most important and defining parts of us as it handles everything that we do, whether it be walking, thinking, or even sleeping. Put simply, your brain is everything. So what happens when this “everything” is tampered with and not working properly?
Enter dementia, an illness characterized by the general loss of cognitive functions such as memory, judgment, or motor skills. It affects over 50 million individuals worldwide(generally over the age of 65) and is a major detriment to every society that it touches, costing trillions of dollars and burdening millions of people into becoming caregivers and taking care of those afflicted with this horrible illness.
Although accelerated by aging, dementia is NOT a normal part of aging, as the different causes of dementia such as Alzheimer’s disease, Lewy bodies, vascular disease, etc. do not follow the normal processes of aging. Moreover, people can suffer from multiple dementias(Lewy bodies and vascular for example), which just complicates things even more.
This loss of cognitive function sees the degradation of an individual, as family members and colleagues have to watch as their loved one slowly slips away, ultimately becoming an empty shell of what they once were. For the individuals themselves, their personality, will, and memories become washed away in the sands of time.
Also, this is just a little side note, but interestingly enough, what got me into Alzheimer's was actually a large musical project by Leyland Kirby called “Everywhere at the End of Time.” It is 6.5 hours long, but let me tell you, it really invokes some emotions and gives you dementia in musical form. I would highly recommend listening to it in one go, so you are really gonna have to block out your schedule, but I promise you, it is worth it.
Alright, back to your scheduled broadcast!
The Corrosive Parasite
With Alzheimer’s being the most common form of dementia, responsible for around 70% of all dementia cases, it’s no wonder that it has been the main focus of dementia research. But what even is it anyway? Currently, the two main markers we have right now are a) the accumulation of amyloid plaques, and b) tau tangles.
These plaques are just like the plaques in your teeth, except it’s much worse. They’re made out of clumps of amyloid-beta, a chemically “sticky” protein around(37–43 amino acids long), that clumps together and formed large plaques that coat the brain, promoting inflammation(an immune response) and neuron death.
Amyloid beta(Aβ) is actually a small section of a much larger protein, called the amyloid precursor protein, or APP for short. As shown above, you can see that the APP is turned into beta-amyloid after the beta(β) and gamma(γ) secretase cut the APP. Specifically, ratios of Aβ40 and Aβ42 are the main focus of scientists, as the former is more responsible for cerebrovascular plaques (blood vessels of the brain), and the latter being responsible for neuritic plaques (dendrites of neurons).
This is part of the amyloid-beta hypothesis, which is the belief that it is the accumulation of these plaques that causes Alzheimer’s disease. However, with sooo many drugs being developed to target these plaques, less than 1 percent seem to be effective. And its been now shown that some individuals that are older than 90 also have these plaques, but show no signs of neurodegeneration and a cognitive deficiency. So what gives? Well, maybe tau tangles might hold the answer.
The other part of Alzheimer’s is the tau tangles, which is when tau(τ) proteins aggregate together into tangles within the neurons. These tau proteins are essential in microtubule structure(basically the skeleton of the cell), and as the plaques clump together, the microtubules are unable to maintain the structure of the cell, and also come to promote neurodegeneration and cell death.
As tau kinases(move molecules from one protein to another) increase their activity, they phosphorylate(adding a phosphorous atom)the tau proteins, changing the function and shape of the tau proteins slightly. This leads them to leave the microtubule, and aggregate into large chains, eventually leading to huge tangles, and the microtubules to become destabilized.
So this seems like a plausible cause right? Well, not so fast. The tau protein hypothesis seems to be in the same boat as the amyloid beta hypothesis. Although they are the hallmarks of Alzheimer’s, they now appear to only be symptoms of more underlying problems.
The current goal of developing a disease-modifying treatment by 2025(National Alzheimer’s Project Act)seems right around the corner. Countless years have been dedicated to understanding the pathology of Alzheimer’s, but it still seems that we have a long ways to go. Funding can only bring us so far, and with millions being sunk into Alzheimer’s research, with little progress still being made, it is still clear that some adjustments in the approach must be made.
First and foremost, dementia research has been almost universally overshadowed by cancer research, with more than 5 times the amount of people choosing to work on cancer than on dementia research. What’s more, is that over 70 percent of individuals with PhDs in dementia leave the field within four years. This major drought of professionals in dementia research alone stifles discovery and innovation, with many of our greatest minds being used in other disciplines.
But even in this space that we are in, general scientific problems, such as the nature of publishing research papers, comes to majorly affect what we know about Alzheimer’s and dementia as a whole. With the majority of research papers being negatives, and with positive research papers having much less validation data, the pipeline for getting our information is severely lacking.
Another process that needs to be adjusted is not only research acquisition but the nature of the research itself. As I outlined previously, we really don’t know the specific pathways that go into creating Alzheimer’s. And adding onto that problem is that almost 70 percent of Alzheimer’s cases are also vascular dementia cases. This added layer of difficulty means that multiple disciplines must be in collaboration with one another.
Cross-discipline collaboration, whether it be with immunologists, lipid scientists, or even gynecologists may be essential in understanding not only the pathology of Alzheimer’s but allowing for a greater understanding of Alzheimer’s and how to properly treat and address its problems.
However, to me, I almost get the same vibes with this 2025 plan as I do with all of those acts to limit greenhouse gas emissions(Paris Agreement, Kyoto Protocol, etc.). It is a daring goal, but there are large underlying and systematic changes that have to be made that can’t be made in 4 years(as of today). This current limit of four years means that only those drugs that are currently in the pipeline(already in clinical trials)will have any hope of actually making it and becoming approved by the FDA. But this in itself has been a major difficulty.
A New Way to See Alzheimer’s
Only five FDA-approved drugs exist that target Alzheimer’s, with the most recent one being approved in … 2003. Yea, almost two decades ago. Despite all the changes and advancements that we have made, we have yet to get a successful drug that actually makes a substantial impact when it comes to the treatment of Alzheimer’s.
The current drugs are all on the market are all based around the cholinergic hypothesis, which is that there is just a deficit of the neurotransmitter, acetylcholine, in Alzheimer’s. However, these drugs only see moderate success in slowing but not doing anything to stop, stall, or even reverse some effects of Alzheimer’s. It seems like a new approach is definitely in need.
A Gum Disease?
First and foremost, the actual pathology is beginning to see more complex developments, with the main area of interest being that of immunology or infections. One interesting finding is how infection of gum disease(Porphyromonas gingivalis) in the brain may play a role in the production of plaques and tangles within the brain. However, more work still needs to be done.
As mentioned by Casey Lynch and her colleagues, the complexity of Alzheimer’s makes it difficult to state that this bacteria is the definitive cause of the disease, and it could only merely be disrupting a pathway that is still left unknown to us. But despite this, this discovery may help pave the path for much more discovery into the actual pathology of Alzheimer’s.
Alright, I know I’ve already gone over four different hypotheses as to what causes Alzheimer’s, but I find it crucial to mention this one as well. Amyloid plaques and tau tangles may actually be the result of infections since many people with AD seem to be more afflicted by different bacterial infections and herpesviruses(main focus). Moreover, these insoluble plaques may actually be a defensive mechanism to combat pathogens? Sounds good right? Well, again, it’s not that simple.
The first question to ask is are people developing AD from these pathogens or does the development of AD(and the weakening of the body) make it easier for these pathogens to take hold of individuals? Being that we are looking for any patterns, it is possible that we are making the wrong connections here, that the microbial resistance offered by the plaques is not an evolutionary response, but just a sheer coincidence. We still cannot definitively prove or disprove this argument.
Our Own Bodies’ Fault
Inflammation has always been a common hallmark of AD, along with the formation of plaques and tangles. And being that inflammation may actually be the cause of these tangles, the focus has now been on looking at the neuroimmune system, which is separate from our own body’s immune systems, since inflammation is an immune response from the body(making it easier to fight infections.
Inmune bio has been leading the charge in this area, targeting the TNF(tumor necrosis factor). Despite being primarily focused on cancer research, this protein was not only significant in cancer, but was found to actually increase neurodegeneration and neuroinflammation, thus prompting a look into Alzheimer’s as well. This is a prime example of the necessity and utility of cross disciplinary action, as without this initial research into cancer, we would have never even batted an eye to TNF’s relevance to AD
But it is clear that a lot more work still needs to be done in this regard. We still have yet to get a full understanding of the immune system of the brain, the interactions that it has with the normal immune system, and how exactly the neuroimmune system plays a role in AD pathology. But we can be sure that the neuroinflammation present in AD makes understanding the immune system a top priority.
However, one major direction that we are headed is into identifying more biomarkers of AD, that may help in not only early detection and treatment but possibly aid in our understanding of the pathology of AD. Organizations such as the Alzheimer’s Drug Discovery Foundation have even been running accelerators, helping to fund research into understanding more peripheral(mainly blood) and digital biomarkers can help to make the general screening process much cheaper than getting CSF or using PET scans.
But this process is not easy. The fact that we don’t have a perfect understanding of the pathology of AD means that we can’t exactly disregard every biomarker, making it a long and tedious selection process in order to find true novel biomarkers. It’s almost a “no man left behind policy” because we cannot be sure that even “outlandish” biomarkers may be true or crucial in our understanding of AD.
The Murky Waters of AD
A common thread that has been staggering AD development has just been the complex and unknown nature of AD. We still have yet to understand its pathology completely, and as we are only just now working with other disciplines, such as immunologists, the true causes are limitless. This sets the president for massive exploration, but also makes it difficult in pinpointing specific areas to look at. We are exploring an unmarked forest, hoping to find a box of treasures among the vast expanse of the unknown.
Being that dementia research has not been near as funded or focused on as cancer research, this big question mark as to where to look makes it extremely daunting, as we may find that looking in one part of the pathology forest may be nothing but a waste of money, time, and effort(except for the fact that we have 1 less place to look). But even then, we might just be missing something, and have to go over the area multiple times, leveraging this cross-disciplinary action.
It seems that even after a century of AD’s discovery, we still are a long way away from conquering this beast of a disease. It slowly eats away at each afflicted individual, as they come to lose what it is that makes them human. However, there are many hurdles that need to be crossed and obstacles that need to be addressed before we can truly make substantial progress in this research. And by continuing to explore the mysteries and oddities of nature, we can come to conquer some of humanity’s greatest foes.
“Science knows no country, because knowledge belongs to humanity, and is the torch which illuminates the world” — Louis Pasteur