A Study On Beta-amyloid Brings Us Closer To The Cause Of Alzheimer’s

Alzheimer’s is one of the most devastating neurodegenerative diseases, affecting millions of people around the world. For decades, research has focused on the accumulation of amyloid plaques in the brain as the main cause of this condition. However, the results of numerous clinical trials designed to eliminate these plaques have proven to be largely ineffective, raising doubts about this traditional theory.

A recent study published in Brain offers a revolutionary perspective; Instead of focusing on plaque removal, he suggests that the real cause could be related to the loss of a key protein, Aβ42, essential for neuronal health. This finding could transform our understanding of Alzheimer’s and open the door to new treatment strategies that focus on restoring the balance of this protein rather than fighting plaques.

Alzheimer’s and previous theories about amyloid plaques

Alzheimer’s is the most common form of dementia and is characterized by a progressive loss of memory, cognition and behavior, affecting millions of people around the world. At a biological level, it has been identified that the disease is associated with two main brain alterations: the accumulation of amyloid plaques outside neurons and tangles of tau protein within them.

Since the early 1990s, the amyloid cascade hypothesis has been the dominant theory in research into the causes of Alzheimer’s. This theory proposes that the disease begins when fragments of a protein called amyloid-BETA (Aβ42) clump together, forming oligomers that become the characteristic plaques of the disease. These plaques, it is hypothesized, interfere with communication between neurons, triggering a series of events including inflammation and neuronal damage, ultimately leading to the loss of cognitive functions.

Over the years, this hypothesis has been supported by numerous studies, including genetic studies that have shown that some mutations in genes responsible for amyloid production are linked to rare inherited forms of Alzheimer’s. However, despite technical support, attempts to treat the disease by removing amyloid plaques have not been successful. More than 30 clinical trials attempting to reduce plaques have either failed or shown no significant benefits in cognitive improvement, and in some cases, symptoms have even worsened.

This failure has led to questioning the idea that the accumulation of amyloid plaques is the main cause of the disease. In fact, some studies have noted that many older people with amyloid plaques in their brains never develop dementia, sparking debate about whether the plaques are a direct cause or just a secondary symptom of Alzheimer’s.

A new approach: the importance of Aβ42 in Alzheimer’s

Recent research led by Alberto J. Espay and his team at the University of Cincinnati has introduced a significant change in our understanding of Alzheimer’s. Instead of focusing solely on the accumulation of amyloid plaques as the main cause of the disease, this study suggests that what could really be behind cognitive decline is the decrease in a specific type of amyloid protein: Aβ42.

Aβ42 is a protein fragment that is produced naturally in the brain during regulatory cellular processes and under healthy conditions. Although Aβ40 is the most abundant form of amyloid-beta, Aβ42, although less common, has a much greater tendency to aggregate and form the amyloid plaques that are associated with Alzheimer’s. Traditionally, the accumulation of Aβ42 in the form of plaques has been considered to be one of the main causes of neuronal damage. However, the approach of Espay and his team calls this theory into question.

Instead of thinking that amyloid plaques are the main cause of Alzheimer’s, the team proposed that the true cause could be the loss of the soluble form of Aβ42, which plays an essential role in neuronal health and synaptic function. According to this hypothesis, when levels of Aβ42 in its soluble form decrease, neurons may be affected, eventually leading to cognitive decline and dementia. That is, the key to Alzheimer’s could not be the presence of plaques, but the lack of the Aβ42 protein in its normal form.

A particularly interesting finding from this study is that certain recently approved treatments, such as the monoclonal antibodies aducanumab, lecanemab, and donanemab, have been shown to increase Aβ42 levels in the cerebrospinal fluid, which has coincided with cognitive improvements in some patients. This suggests that, rather than removing amyloid plaques, or that it might be less crucial than previously thought, what really benefits patients is the increase in Aβ42 levels, which could have a protective effect on neurons.

This twist in theory opens new avenues for Alzheimer’s research and treatmentsuggesting that future therapeutic approaches could focus on restoring normal Aβ42 levels rather than removing amyloid plaques.

New findings and analysis: Aβ42 as a key factor in the disease

In their research, Espay’s team not only developed a new theory, but also conducted a comprehensive analysis using data from 24 randomized clinical trials of monoclonal antibodies designed to treat Alzheimer’s. These trials included nearly 26,000 patients with early or moderate Alzheimer’s, and focused on two key biomarkers: levels of amyloid plaques (measured by imaging) and levels of Aβ42 in the cerebrospinal fluid. Additionally, patients’ cognitive outcomes were assessed using standard tests such as the Alzheimer’s Disease Rating Scale and the Clinical Dementia Classification.

The results of this analysis revealed that The increase in Aβ42 levels was closely related to a cognitive improvement, as significant or more significant than the reduction of amyloid plaques. Specifically, treatments that increased Aβ42 levels showed a consistent correlation with better results on cognitive tests. In contrast, treatments that reduced Aβ42 levels, such as some enzyme inhibitors, worsened cognitive performance.

This finding is crucial because suggests that amyloid plaques are not the direct cause of Alzheimer’s, but could be a protective response of the brain to neuronal damage. According to the new proposed hypothesis, the real threat could be the loss of soluble Aβ42, which plays a fundamental role in neuronal health and synaptic function. When levels of this protein decrease too much, cognitive decline accelerates.

Therefore, the study reinforces the idea that restoring normal Aβ42 levels could be a more effective therapeutic strategy than simply trying to remove amyloid plaques. This new perspective may pave the way to more effective treatments for Alzheimer’s in the future.

The findings of this study mark a paradigm shift in the treatment of Alzheimer’s. While the traditional approach has been to reduce or eliminate amyloid plaques, new data suggest that what really matters may be restoring levels of soluble Aβ42 in the brain.

This protein not only accumulates in plaques, but plays an essential role in neuronal health and in the transmission of signals between neurons. When its levels fall, brain function deteriorates, which could trigger the progression of the disease.

This discovery has important implications for future therapeutic strategies. Unlike current treatments, which focus on removing amyloid plaques, new research could focus on seeking to increase levels of soluble Aβ42 without causing harmful side effects, such as brain inflammation or reduction in brain size. effects observed in some monoclonal treatments.

However, although the results are promising, the study has some limitations. The researchers worked with aggregate data from clinical trials, meaning they did not have access to individualized patient information. This reduces the ability to capture individual differences in response to treatments.

The next step will be to test therapies that specifically increase Aβ42 levels without the risks associated with plaque removal. This could open new doors for Alzheimer’s treatment, offering hope to millions of people affected by this devastating disease.