Alzheimer’s Disease: Scientists Are Still Hunting for the Missing Piece of the Puzzle

<blockquote> <h3>Fast Facts</h3> <ul> <li>Before the ‘amyloid hypothesis,’ there was the ‘cholinergic hypothesis,’ which states that a decline in the neurotransmitter, acetylcholine, is a cause of Alzheimer’s disease. This led to a handful of Alzheimer’s drugs — called cholinesterase inhibitors — to come out to inhibit enzymes that break down this neurotransmitter, such as donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®). All were ineffective at slowing Alzheimer’s progression. </li> <li>While most associate diabetes with issues related to blood sugar regulation, this unconventional term, ‘type 3 diabetes,’ introduces a new perspective. Type 3 diabetes, often referred to as brain diabetes, suggests that insulin resistance, a hallmark of type 2 diabetes, may also play a pivotal role in the development of Alzheimer's disease. It turns out that, in addition to amyloid plaques and tau tangles, the brains of patients with Alzheimer’s disease show changes in how it produces and uses energy.</li> <li>Studies have shown that people with type 2 diabetes are at a significantly higher risk of developing Alzheimer's, hinting at a potential shared mechanism between Alzheimer’s and diabetes. </li> </ul> </blockquote> <p>It starts off subtly. Misplaced keys. Using incorrect names. A missed appointment. Most don’t even know they have it until the forgetfulness interrupts their daily life — at which point, the changes to the brain are irreversible. </p> <figure><img src="https://cdn.storymd.com/optimized/2dZygYTjoG/original.jpg" alt width="698" height="466" /> <figcaption>Ten warning signs of Alzheimer's Disease <em>Source: TheVisualMD</em></figcaption> </figure> <p>Scientists still don’t know how to stop or reverse Alzheimer’s disease. The cause of the disease is still a hotly debated topic amongst scientists. For 3 decades sticky amyloid plaques in the brain were thought to be the culprit. But now, scientists are not so sure — it could be tau tangles, insulin resistance, or maybe something else — effectively making “treatments” that are available mere band-aids that only address the disease’s associated symptoms. </p> <p>There’s no effective treatment. There’s no cure. There’s not much of anything that can be done when it comes to Alzheimer’s disease. That wasn’t the plan — but, unfortunately, that’s how it’s turned out.</p> <p>Read on to learn: </p> <ul> <li>why — after many decades of research — the cause of the disease is still a mystery</li> <li>how one theory — the amyloid hypothesis — might have derailed Alzheimer’s research for almost 30 years </li> <li>what might be the actual cause of the disease if, in fact, the amyloid hypothesis is wrong </li> </ul> <h2>First came the ‘cholinergic hypothesis’</h2> <p>Before the ‘amyloid hypothesis,’ there was the ‘cholinergic hypothesis,’ which states that a decline in the neurotransmitter, acetylcholine, is a cause of Alzheimer’s disease. This led to a handful of Alzheimer’s drugs — called cholinesterase inhibitors — to come out to inhibit enzymes that break down this neurotransmitter, such as donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®). But this class of drugs never produced an outright cure or any meaningful clinical improvements of symptoms. And so, the cholinergic hypothesis was abandoned as the root cause of Alzheimer’s disease. However, cholinesterase inhibitors are still prescribed to manage the symptoms of Alzheimer’s for those who can tolerate their adverse side effects.</p> <h2>The rise of Alzheimer’s ‘amyloid hypothesis’ </h2> <p>Scientists moved on to another theory called the ‘amyloid hypothesis.’ This new hypothesis was first proposed in 1992 by Drs. John Hardy and David Allsop, and for about three decades, scientists believed that this theory was the missing piece of the puzzle of what causes Alzheimer’s disease. </p> <p>According to the amyloid hypothesis, Alzheimer’s is caused by a build-up of a protein — called amyloid-beta (â) — in the brain, which forms sticky clumps, referred to as amyloid plaques. These toxic amyloid plaques, sitting between brain cells, can damage and kill these brain cells, triggering a series of events that leads to the brain wasting away, and thus, Alzheimer’s disease. The more amyloid plaques present in the brain, the more advanced the disease. </p> <figure><img src="https://cdn.storymd.com/optimized/ZoBjgwCvoM/original.jpg" alt width="1005" height="223" /> <figcaption>Enzymes act on the APP (Amyloid precursor protein) and cut it into fragments of protein, one of which is called beta-amyloid and is crucial in the formation of senile plaques in Alzheimer <em>Source: National institute on aging</em></figcaption> </figure> <p>The amyloid hypothesis was simple and quite compelling since amyloid build-up in the kidneys and heart was shown to cause kidney failure and heart failure. It therefore made sense that amyloid clumps in the brain can cause brain failure. Around the same time, other scientists also discovered some of the molecular mechanisms behind the amyloid build-up. They found that people with a family history of Alzheimer’s also had mutations in the very genes that encode for making amyloid. </p> <p>When taken together, it was very conceivable that the amyloid hypothesis was correct, and so it was the guiding theory for decades. </p> <h2>The fall of the amyloid hypothesis — when it’s too good to be true</h2> <p>For decades, this single overriding hypothesis guided the majority of research on Alzheimer’s disease because scientists now had a roadmap to a potential cure. As might be expected, scientists all over the world focused their research on treatments that targeted these amyloid plaques. But even with decades of research and millions — if not billions — of dollars going towards funding research aimed at preventing amyloid plaques, almost none of the ‘anti-amyloid’ drugs that came out showed any meaningful benefits to patients with the disease. </p> <p>After another decade of failed treatments, a small group of scientists started to question this widely held amyloid hypothesis. Was the role of amyloid plaques as central to the cause as once believed? In 2006, a pivotal study — published in the journal <em>Nature</em> — essentially confirmed that amyloid plaques in brain tissue are the primary cause of Alzheimer’s. </p> <p>In the study, researchers proved the existence of a specific type of amyloid protein, called amyloid-beta 56 (aâ*56), and that it was the key amyloid protein involved in clumping and forming plaques in the brain. More specifically, the researchers claimed that aâ*56 was responsible for memory and thinking problems in rats that were injected with it. </p> <p>With the findings from this <em>Nature </em>paper, researchers in the Alzheimer’s space gained renewed vigor in their belief in the amyloid hypothesis. This paper, published in a highly reputable science journal, was one that other researchers trusted and relied on, and since its publication, it has been cited over 2,000 times by other scientists to support their own work. Despite previous uncertainties about the amyloid hypothesis, government agencies and the pharmaceutical industry continued to invest in this hypothesis. </p> <p>Then a scandal broke — new evidence came to light in 2021 that the researchers of this pivotal study had falsified images and manipulated data. In a flash, the amyloid hypothesis — again — was called into question.</p> <p>To many scientists, it made sense to reject the amyloid hypothesis. Because, while amyloid plaques are always present in the brains of patients with Alzheimer’s, scientists also found these plaques in about 30% of people who display no signs of the disease. In addition, many anti-amyloid drugs that specifically target these amyloid plaques have been shown to be ineffective at treating or even slowing down the progression of the disease. </p> <p>So, is the amyloid hypothesis wrong? </p> <h2>Amyloid is more the smoke, not the fire </h2> <p>To say that the amyloid hypothesis is completely wrong and that it should be discarded would be overstating it. </p> <p>Alzheimer’s disease is a complex puzzle that takes place in the folds of the brain — an inherently difficult area to study. So, rather than outright rejection of the amyloid hypothesis, some scientists advocate for a refined perspective. </p> <p>There is convincing evidence that amyloid plaques play some role in Alzheimer’s disease — so completely discounting the role of these amyloid plaques would be wrong. Perhaps the amyloid hypothesis is simply a piece of the puzzle—a puzzle that requires multiple pieces to form a coherent picture. Amyloid build-up may be a secondary player in Alzheimer’s — just not the root cause of the disease.</p> <p>So, if amyloid plaques are not the instigator of Alzheimer’s, are there other theories on what causes Alzheimer’s disease?</p> <h2>Beyond amyloid — the tau connection </h2> <p>The amyloid hypothesis has dominated Alzheimer's research; however, tau proteins have been gradually creeping into the spotlight, prompting a paradigm shift in scientists’ understanding of Alzheimer's.</p> <p>Tau is a protein that naturally exists in the brain, where its primary function is to stabilize microtubules — which are essential structures for maintaining the integrity of neurons. In a healthy brain, tau proteins are well-behaved, playing a crucial role in normal brain cell function. </p> <p>The trouble begins when tau proteins undergo abnormal changes, leading to misfolding and clumping. These misbehaving tau proteins can accumulate in the form of neurofibrillary tangles — commonly referred to as tau tangles — inside neurons, which leads to disruption of their function. It turns out that, in the brains of Alzheimer’s patients, the present of these tau tangles blocks the internal transport system of neurons. With a build-up of tau tangles in the brain, there is a corresponding deterioration of brain cell-to-cell communication, which seems to manifest in clinical symptoms such as cognitive impairment and memory loss. </p> <p>Could the ‘tau hypothesis’ implicating tau tangles as the main culprit in Alzheimer’s disease be the cause? Possibly. In fact, recent research suggests that tau abnormalities may even happen before amyloid plaque accumulation. </p> <figure><img src="https://cdn.storymd.com/optimized/lqLNYVuKoX/original.jpg" alt width="698" height="339" /> <figcaption>Neurofibrillary tangle <em>Source: TheVisualMD</em></figcaption> </figure> <p>Further supporting the significance of these tau tangles, certain genetic mutations have been linked to an increased risk of developing Alzheimer's, and many of these mutations are related to tau proteins. This genetic connection underscores the importance of tau in Alzheimer’s disease. </p> <p>Scientists who are in support of the tau hypothesis, however, do not believe tau is the lone instigator. In fact, they believe that tau proteins and amyloid-â proteins may interact synergistically, with each protein influencing the behavior and accumulation of the other.</p> <p>So, while tau tangles may have recently emerged as central figures in the Alzheimer's story, many advocates of the tau hypothesis recognize that Alzheimer's is a multifaceted disease influenced by various genetic, environmental, and lifestyle factors. And while these tau tangles are a hallmark of Alzheimer's, they are just one piece of a much larger puzzle. </p> <h2>The diabetes connection: could Alzheimer’s disease actually be type 3 diabetes?</h2> <p>While Alzheimer's is viewed as a neurodegenerative disorder and diabetes as a metabolic disease, there may be a connection between the two seemingly unrelated conditions, and this audacious hypothesis has been gaining traction in recent years. </p> <p>What’s the connection? Well, high-level cognitive abilities and complex behaviors require a tremendous amount of energy. Because of this, the brain has an insatiable sweet tooth — meaning that it requires and consumes about 25% of the body’s glucose supply to function properly, despite only constituting about 2% of the body’s total weight. Knowing that, it’s not too farfetched to think that impaired insulin signaling in the brain could contribute to the cognitive dysfunction and decline that’s seen in people with Alzheimer’s. </p> <p>And so, at the core of this hypothesis lies insulin resistance — a hallmark of type 2 diabetes — and now, potentially, Alzheimer's disease. This is why Alzheimer’s disease is sometimes referred to as ‘type 3 diabetes’, or ‘brain diabetes.’ </p> <p>Traditionally, insulin is viewed as the hormone responsible for regulating glucose levels in the body, but it also plays a pivotal role in brain function. Recent studies have shown that insulin exerts a significant influence on the brain, affecting various cognitive functions such as memory and learning.</p> <p>But there’s more to the story. Another intriguing connection between Alzheimer's and type 3 diabetes revolves around the amyloid-â protein. Recent studies suggest that insulin resistance can hinder the brain’s ability to use glucose effectively, leading to an accumulation of amyloid plaques — which is still a defining feature of Alzheimer's disease. </p> <p>It was discovered when examining the brains of people with Alzheimer’s, that in addition to amyloid plaques and tau tangles, their brains showed changes in how it produces and uses energy. As a result, this metabolic disruption by way of insulin resistance is thought to lead to a shortage of energy in brain cells, impairing their function, and ultimately contributing to the cognitive decline seen in Alzheimer's.</p> <p>Other studies have also shown that people with type 2 diabetes are at a significantly higher risk of developing Alzheimer's, hinting at a potential shared mechanism between Alzheimer’s and diabetes. But more research is needed to fully understand this link. </p> <p>And so, taken all together, the suggestion that Alzheimer’s may, in fact, be type 3 diabetes isn’t so outlandish. With that said, however, it’s also important to note that both diabetes and Alzheimer's are complex, multifaceted conditions influenced by genetic, environmental, and lifestyle factors.</p> <h2>The takeaway</h2> <p>In the end, whether or not Alzheimer's is definitively labeled as ‘type 3 diabetes’ or whether or not the ‘tau hypothesis’ is actually the cause of Alzheimer’s disease, are not really what matters. What is important is that as scientists continue to unravel the web of connections between insulin resistance, diabetes, tau tangles, amyloid plaques, and Alzheimer's, they inch closer to a more comprehensive understanding of all these conditions, and more importantly, new ways to treat them — offering hope to those whose lives are impacted by Alzheimer’s disease. </p><h2>More on Alzheimer's Disease</h2><ul><li><a href="https://soulivity.storymd.com/journal/qjo8do91nm-alzheimer-s-disease" target="_blank">Alzheimer's Disease: Risk Factors, Treatment, Prevention</a></li><li><a href="https://soulivity.storymd.com/journal/pwgxzqnu4j-diabetes-and-brain-health" target="_blank">The Effects of Diabetes on the Brain</a></li><li><a href="https://soulivity.storymd.com/journal/zjbxrk5f2w-insulin-resistance" target="_blank">Insulin Resistance: Causes, Symptoms, Prevention</a></li></ul>