Alzheimer's Targets Missed: The Ineffectiveness of Focusing on Amyloid Beta and Tau

Today we will be examining an older research paper from 2019 that examines Alzheimer's Disease, its causes, and the possibility that our understanding of it may be incorrect. The paper challenges the traditional view that Alzheimer’s is mainly due to protein misfolding and buildup in the brain. With numerous clinical trials targeting these proteins yet failing to find a treatment, this research prompts us to reconsider the disease's true mechanisms. Our article aims to present these findings in a straightforward easy to understand manner, inviting readers to explore new perspectives on Alzheimer's and its potential avenues for treatment.

The paper is quite an intense read, but I tried to put it as simply as possible. I will highlight important things and key phrases that will help readers understand. All of the information in this page has been pulled from the article, Citation and DOI is below this introduction section. 

the following is a summary of the abstract, which acts as a good TLDR. there is some interesting and valuable information for those who wish to stick around and read through our summary.

For a long time, Alzheimer’s Disease was thought to be caused by the incorrect folding and clumping together of certain proteins. Specifically, two proteins named amyloid-beta (Ab) and tau were believed to start a harmful process in the brain that leads to AD’s main symptoms: worsening memory and ability to make decisions. 

Because of this, a lot of research focused on these proteins to find a cure, leading to many clinical trials. Despite this effort, no treatment has been found that can stop the disease from getting worse. Most treatments only offer temporary relief from symptoms. The failure of so many studies to find a cure is surprising and has made some scientists question if the problem with protein folding is really at the heart of AD. 

Recent findings, such as the discovery of these protein issues in elderly people without dementia, suggest that Ab and tau might not play as central a role as previously thought. This article looks into the roles of Ab and tau, from how they are made in the body to how they might cause disease, and discusses why finding a cure has been so challenging. It also explores whether targeting these proteins is a good strategy for finding a treatment that can stop AD.

Liyanage, S. I., & Weaver, D. F. (2019). Misfolded proteins as a therapeutic target in Alzheimer’s disease. Advances in Protein Chemistry and Structural Biology, 371–411. doi:10.1016/bs.apcsb.2019.08.003

The Common Forms of Dementia

Dementia, once thought to be a single disorder affecting memory, is now understood to encompass multiple subtypes. These subtypes all involve the progressive decline of memory and executive function but have different causes. 

They include vascular dementia, caused by problems with blood flow to the brain; and protein-associated dementias, identified by the presence of misfolded proteins, such as frontotemporal dementia (related to tau proteins), Lewy Body dementia (related to alpha-synuclein proteins), and Alzheimer's Disease (AD) (involving both amyloid-beta and tau proteins). 

AD itself is divided into early onset AD (EOAD) and late onset AD (LOAD), with EOAD being rare but aggressive and often linked to genetic factors affecting amyloid-beta. In contrast, LOAD's causes are less clear but may include lifestyle and environmental factors, with its progression being slower. 

The variability in how these subtypes progress and their underlying pathologies suggests that AD might better be considered a syndrome comprising multiple disease states rather than a single disease.



Amyloid-Beta Buildup and Alzheimer's

The accumulation of amyloid-beta (Ab) in Alzheimer's Disease (AD) results from both increased production and decreased removal. Enhancing Ab clearance mechanisms presents a potential therapeutic strategy, offering hope for not only halting but possibly reversing AD. Clearing amyloid-beta (Ab) from the brain involves complex systems. Special enzymes, such as neprilysin and insulin-degrading enzyme, help break down Ab. Brain cells known as glial cells also play a role in removing Ab by engulfing it. Moreover, Ab can be transported out of the brain through a process involving certain proteins and receptors, notably with the help of apolipoprotein E (ApoE). 

On the flip side, there's a receptor called RAGE that actually helps Ab enter the brain, indicating potential importance of Ab, and how there is a delicate balance between how much Ab enters and leaves the brain. 

Despite understanding how Ab is managed in the brain, efforts to develop treatments that effectively clear Ab haven't yet succeeded in clinical trials. Research also looks at indirect ways to tackle Ab buildup by addressing factors like metal ions, cholesterol, and inflammation, which can influence Ab levels. These factors play intricate roles in Alzheimer's disease, with metal ions and cholesterol potentially worsening Ab's harmful effects, and inflammation both resulting from and contributing to Ab buildup. This creates a feedback loop that fuels the disease's progression.

Attempts to intervene in these biological factors have yet to change the course of Alzheimer's disease after it has started, underscoring the difficulty of finding effective treatments. These challenges bring up questions about focusing solely on amyloid-beta in seeking treatments for Alzheimer's disease.

Amyloid-beta (Ab)  regulation mechanisms 

The following Ab regulation mechanisms, are different points for faliure in regulation of Ab in the body as represented in the figure above:

Do Amyloid-Beta Therapies Work?

The challenges in directly targeting amyloid-beta (Ab) for Alzheimer's Disease (AD) treatment have shifted focus towards managing physiological factors that influence Ab dynamics. This approach includes addressing metal ion balance in the body, cholesterol levels, and inflammatory stress, which are seen as critical to Ab behavior and offer potential therapeutic avenues.

Metal Ions: AD brains show significant changes in metal ion levels, with a decrease in serum ions like zinc and iron, and a potential increase in these ions within the brain, especially around amyloid plaques. These metal ions may contribute to Ab aggregation and toxicity. Strategies such as chelating these metals from the brain have been considered, but translating this into a clear therapeutic strategy remains challenging.

Cholesterol: Cholesterol is linked to aggravating Ab pathology. Genetic and epidemiological studies suggest high cholesterol levels increase AD risk. Cholesterol may influence the enzymes involved in amyloid precursor protein processing and directly contribute to Ab misfolding and aggregation. Statins and other cholesterol-lowering agents have been explored, with some studies suggesting a potential protective effect against AD onset, but no effective disease-modifying therapy has been identified post-disease onset.

Inflammation: The role of inflammation in AD is complex, with evidence suggesting that Ab and inflammation may synergistically drive each other, potentially creating a vicious cycle that accelerates AD progression. While reducing inflammation is a major target, no anti-inflammatory strategy has yet shown significant clinical benefits after AD onset.

The failure of therapies targeting amyloid-beta (Ab) in Alzheimer's Disease (AD) highlights a significant challenge in AD treatment. Despite the logical rationale for targeting Ab, given its involvement in various pathologies associated with AD, numerous clinical trials and research efforts have not resulted in effective therapies. The diminishing focus on Ab as a sole target and the increasing skepticism towards the amyloid hypothesis reflect this failure. Observations of significant plaque pathology in seniors without dementia and negative outcomes from anti-amyloid therapies have led to doubts about Ab's role in AD. These findings suggest that Ab might have a dual nature, being both potentially protective and harmful.

Reconciling the toxic and possibly protective roles of Ab presents a paradox that has not been fully addressed in research. The current understanding acknowledges the complexity of targeting misfolded proteins in AD therapy as being both a reasonable and flawed approach. Ab oligomers have been shown to be toxic, yet the failure of the amyloid hypothesis to provide a successful treatment is undeniable. Possible explanations for this failure include the heterogeneity of Ab and patient responses, limitations of traditional in vivo models and clinical trials, and the possibility that Ab is not entirely pathogenic.

IMPORTANT NOTE: While targeting Amyloid-Beta Buildup after the onset of Alzheimer's is considered to be ineffective at TREATING the disease. It is still an important factor to consider for those who may have increased risk of Alzheimer's, but have not yet been diagnosed. 

The data suggests this treatment cannot target ACTIVE Alzheimer's, but targeting the various Ab Buildup pathways is likely to be preventative.

TLDR: Conclusions regarding Amyloid-Beta and Alzheimers

Despite the widespread failure of treatments based on targeting amyloid-beta (Ab), completely abandoning the amyloid hypothesis may be premature. While it's becoming evident that therapies focusing solely on Ab, especially in later stages of Alzheimer's Disease (AD) when symptoms are present and misfolding has been ongoing, are unlikely to be effective, this doesn't negate the value of the hypothesis entirely. The detailed mechanistic understanding of Ab's role in AD—both in terms of its pathological and potential physiological functions—suggests that the problem may lie in the focus of previous research on aspects like plaques, which may not be the most effective targets. AD is a complex disease, influenced by a myriad of factors beyond just Ab, including other protein misfoldings and immune system responses. These factors likely interact, exacerbating the disease in a cycle that cannot be interrupted by targeting a single element. Future research might find more success with treatments that address multiple aspects of this proteopathy-immunopathy interaction, suggesting a need for a more nuanced approach to tackling AD.

Tau Protein and Alzheimer's Disease

Before scientists linked it to Alzheimer's Disease, the tau protein was just one of many proteins that helped keep the cell's structure stable. Discovered in 1975, tau was known for helping cell structures called tubulin filaments stick together. It wasn't thought of as something that could cause disease. About ten years later, researchers found out that tau was the main ingredient in certain brain tangles found in AD patients, making it an important area of study for understanding and treating AD.

From the beginning, the role of tau in AD stirred up debate. Early on, the focus was more on amyloid-beta , especially in regards to its role in the early stages of AD. This made tau seem less important. But later studies showed that tau is not just a bystander; it's involved on its own in AD and other brain diseases, leading some scientists to think that tau might actually kickstart AD.

As our understanding has grown, so has the interest in targeting tau for AD treatments, either alone or together with other disease factors. This change in thinking acknowledges tau's significant role in AD, pushing past previous beliefs and suggesting we need to look at AD treatment from multiple angles.

More on Tau: How it Contributes to Alzheimer's

The mechanism by which tau becomes pathological in Alzheimer's Disease significantly differs from that of amyloid-beta. Amyloid-beta is problematic as soon as it's made, but tau starts off as a normal, functioning protein and only becomes harmful after going through several changes. Scientists have discovered that certain modifications, like adding phosphate groups (a process called phosphorylation), can turn tau from helpful to harmful. This change makes tau stop supporting the cell's structure and start clumping together, forming toxic clusters and tangles that can damage the brain.

For a while, researchers thought the big clumps of tau were the main problem, but now they're more concerned about smaller clusters called oligomers, which are very toxic and can interfere with important cell functions, like transporting materials, energy production, and communication between cells.

Interestingly, tau can spread from one cell to another, which wasn't initially expected since it's an issue that starts inside cells. This spreading could help explain how AD gets worse over time, making tau a key area of interest for understanding and treating AD. Even though we're not sure if tau or Ab starts the disease, or if it begins differently in different people, focusing on how tau moves and causes damage is a hot topic in AD research. This work is crucial for finding new ways to tackle the disease, highlighting the complex nature of AD and the need for targeted approaches to its treatment.

Imagine tau as a protein that helps maintain the structure inside cells, kind of like the beams in a building. When tau gets chemically altered through processes (Translational Modifications) like phosphorylation (adding phosphate groups) and others, it changes shape. This change means tau can no longer do its job of supporting the cell's structure, leading to instability within the cell. As a result, tau starts clumping together into harmful clusters and tangles that can damage the cell.

Moreover, these altered tau proteins can even move to neighboring cells, almost like breaking through walls to invade adjacent rooms, where they can continue causing harm. This spreading contributes to the problems seen in diseases like Alzheimer's, where tau tangles are a hallmark of the disease's damage to the brain.

Theraputic Targets for Tau

Tackling tau protein issues in Alzheimer's disease is tricky because we can't just get rid of tau. Unlike amyloid-beta (Ab), tau is needed by the brain to help keep its structure intact. So, treatments have to carefully target only the harmful actions of tau without affecting its normal, necessary functions. Previous attempts focused on stopping tau from getting too many phosphate groups added to it (a process known as phosphorylation) or preventing tau proteins from clumping together. However, these approaches haven't worked out well. Now, scientists are looking into new methods, like boosting the brain's overall stability or using immune system-based therapies to specifically address the damaging aspects of tau. Despite the growing interest in these new tau-targeting treatments, none have yet proven effective enough to become widely used medications.

Conclusion

Studying misfolded proteins like amyloid-beta (Ab) and tau as potential targets for treating Alzheimer's Disease (AD) has sparked a lot of debate among scientists and companies. While research has shown these proteins play a harmful role in various cell functions and contribute to the disease, finding effective treatments based on this knowledge has been challenging. Despite many studies, no successful treatment has come out of it, leading some to doubt whether focusing on these misfolded proteins is the right approach.

However, it's too soon to give up on the idea entirely. Many past studies may have not targeted the most harmful forms of these proteins or used flawed models of the disease, among other issues. This doesn't mean the whole concept is wrong, but it highlights how complex AD is, involving many different factors that work together to worsen the disease. Just like treating high blood pressure often requires multiple medications, AD might need a combination of treatments that target different parts of the disease at once. Finding and developing such comprehensive treatments, and figuring out the best way to use them in patients, is a crucial step forward in the fight against Alzheimer's.