Why do we still not understand what causes Alzheimer’s?

 

By Tré LaRosa
NeuLine Health

“In the hand, the human brain is a jelly-like mass, easily deformed by touch. However, its unassuming appearance belies the complexity within. The brain’s inner workings are mysterious. But our understanding of them is improving, as is our ability to apply that knowledge elsewhere.”

From “The brain” by Richard Hodson, published in Nature Outlook

 

There are two answers to the question of why we don’t yet fully understand Alzheimer’s. The simple answer is that the brain is remarkably complex, it’s the primary organ for cognition thus making investigation into the organ risky, and also research into the brain and mind are, relatively speaking, nascent fields. The more nuanced answer provides context into those stipulations. Alzheimer’s — a neurodegenerative form of dementia — is a condition with a constellation of symptoms that result from damage to the brain so there is nothing to be said about Alzheimer’s without first discussing what some call “the most complicated object in the universe,” the brain.

Before we delve into how complex the brain is with its hundred billion interconnected neurons, first a poetic reflection on the brain and the mind. Broadly, the brain is responsible for controlling thoughts, memory, emotion, touch, motor skills, vision, breathing, temperature, hunger, and every process that regulates our body. The brain also gives rise to my — and your — ability to sense, process, and conceptualize the world around me. Cognitive decline is devastating not only because a person’s memory fading is tragic, but because this also often results in those with the condition struggling to perceive and process the world around them. There’s a beautiful quote by the famous astrophysicist Carl Sagan that isn’t specifically about the brain but about humans in general that applies here: “The cosmos is within us. We are made of star-stuff. We are a way for the universe to know itself.” Additionally, our brain provides us with the very ability to investigate the organ itself. It almost seems like science fiction that an object could develop in nature that eventually gains the ability to understand how the object itself functions. Humans are the only sentient organisms capable of asking questions, performing experiments, gleaning understanding from the empirical evidence, and then ultimately extrapolating the lessons learned from one realm to another. Animals may be able to basically comprehend cause-and-effect, but nowhere near to the extent of humans. This is the result of the “jelly-like” organ in our skulls.

In the two blogs I’ve written about some of the unseen links (gingivitis and air pollution) to Alzheimer’s, I’ve emphasized the difficulty in teasing out the genetic and environmental risk and causative factors that contribute to the development of dementias including Alzheimer’s. This is a key point in the conversation about why we don’t fully understand AD. As Alzheimer’s is a condition with histopathological hallmarks that can only be seen upon autopsy, it is diagnosed by deduction using available imaging, blood tests, and a neuropsychological evaluation. What causes the histopathological hallmarks of AD — the neurofibrillary tangles and amyloid plaques — is also responsible for causing Alzheimer’s since we know that these histopathological hallmarks affect cognition. These may seem like the same questions, but they aren’t, not really.

Imagine you injure your ankle by slipping off a curb as you’re walking your dog. Immediately, you experience pain, and within minutes, your ankle begins swelling. Hours later, your ankle is bruised. Out of an abundance of caution, you get it checked out at an emergency room or urgent care. A doctor orders x-rays and evaluates your ankle. It’s discovered that you have mildly fractured your ankle. A doctor sends you on your way with a care plan. We know what directly caused your broken ankle, but the cause of the break was just the first part; the resulting swelling, pain, and bruising are from the anatomical break itself, which was caused by the slip. The factors that took the slip from a non-injury to a break are both genetic and environmental. Environmentally, it’s possible that your bones are weaker due to low calcium levels in your blood, and had your calcium levels been normal, your ankle might not have broken. Additionally, there are genes that have been found to be connected to our bone density, so perhaps you possess one of these genes, thus making it more likely that your bone density is weaker, and therefore more likely to fracture an ankle upon slipping. Ultimately, those factors don’t matter all that much in the case of a broken ankle since you have a confirmed diagnosis and an established treatment protocol to resolve the diagnosis. In the case of Alzheimer’s, however, there are two major limitations: Alzheimer’s can only be definitively diagnosed via autopsy and treatment is still severely lacking. The combination of these factors results in there needing to be further research into what causes the development of the histopathological hallmarks of AD in the brain, and also why these histopathological hallmarks actually result in the clinical manifestations, as in the constellation of symptoms that people associate with Alzheimer’s and that are used to give a likely but not definitive Alzheimer’s diagnosis. As answers to both of these questions — what directly causes the neurofibrillary tangles and amyloid plaques and why do neurofibrillary tangles and amyloid plaques result in cognitive decline and memory loss — begin to come into focus, researchers and healthcare personnel can develop better strategies for prevention, diagnosis, and treatment of AD and related dementias, all while researchers and doctors are actively working on prevention, diagnosis, and treatment concurrently.

Another quote that is relevant to this subject is from none other than Albert Einstein. Einstein purportedly said, “The more I learn, the more I realize how much I don’t know.” At its core, science is founded on curiosity. Curiosity, though, is not inherent; it is learned and honed. When you don’t know anything about a subject, it’s hard to develop questions to drive our knowledge further. Science relies on incremental understanding; if we seek to describe the universe, we must understand the fundamental laws of gravity and thermodynamics, but as we understand gravity and thermodynamics, more questions arise. Sometimes, in scientific and medical research, it can feel that for every question we answer, we find ourselves asking ten more. That doesn’t mean we aren’t making progress; in fact the opposite is occurring. The more we understand, the better we get at framing our questions, developing hypotheses, performing experiments, and interpreting the results. When it comes to understanding a condition like Alzheimer’s which affects an organ as complex as the brain, these issues compound to create a challenge that will take immense scientific collaboration, effort, and wherewithal to solve.

While the brain might be one of the most complex objects in the universe, there is relentless research and effort going into understanding both the organ itself and the conditions that affect it, especially Alzheimer’s. We have made huge leaps and bounds in recent decades and will continue to do so, hopefully to the benefit of all of us, especially those affected by neurodegenerative diseases. We have a better understanding of the brain and Alzheimer’s today than we did 50, 25, or even ten years ago. This should inspire optimism, but until a cure is found, science and medicine need to advance expediently to reduce the suffering caused by this tragic condition.

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