Alzheimer’s Disease Breakthrough Unveiling the Mechanism Behind Lecanemab’s Role in Slowing Progression 2025

New Insights into Lecanemab’s Role in Slowing Alzheimer’s Disease Progression

A groundbreaking study led by Professor Kenjiro Ono of the Institute of Medical, Pharmaceutical, and Health Sciences at Kanazawa University, in collaboration with Eisai Co., Ltd., has uncovered a crucial aspect of how the antibody treatment, lecanemab, slows the progression of Alzheimer’s disease (AD). The team employed a newly developed, highly sensitive system to measure the concentration of amyloid-β protofibrils (Lec-PF) in human cerebrospinal fluid (CSF).

This innovative measurement revealed that the concentration of Lec-PF is elevated in AD patients at all stages of the disease, ranging from mild cognitive impairment (MCI) to both mild and severe dementia, compared to healthy controls. Furthermore, the study discovered that Lec-PF levels in the CSF were strongly correlated with other biomarkers indicative of neurodegeneration.

Lecanemab is a dual-action antibody that specifically targets amyloid-β protofibrils, a toxic intermediate form of amyloid-β, in addition to promoting the removal of amyloid plaques from the brain. The treatment is currently being used for patients with early AD, specifically those with MCI or mild dementia due to Alzheimer’s disease.

The findings from this research suggest that the Lec-PF detected in the cerebrospinal fluid of Alzheimer’s patients is highly toxic and plays a significant role in the neurodegeneration associated with the disease. This study is a significant step in understanding how lecanemab works to slow the progression of Alzheimer’s disease, and it opens new possibilities for monitoring the drug’s effectiveness and predicting patient outcomes.

These findings, published on January 6, 2025, in the online version of Annals of Neurology, could help inform future clinical approaches, including the use of Lec-PF concentration measurements in the CSF to track the effectiveness of lecanemab treatment. In addition, because Lec-PF levels correlate with neurodegenerative markers like total tau and neurogranin, the study suggests that Lec-PF could also serve as a prognostic indicator for Alzheimer’s disease progression.

Research Background and Objectives

The study builds on the amyloid cascade hypothesis, which posits that Alzheimer’s disease begins when amyloid-beta (Aβ) proteins aggregate outside neurons. This accumulation is followed by the formation of tau neurofibrillary tangles, which damage neurons and ultimately lead to the cognitive decline associated with AD. While amyloid plaques and fibrils are often seen as the hallmark of AD, it is the amyloid-β protofibrils (PF), intermediate forms of amyloid-beta, that are believed to be more toxic and potentially responsible for the neurodegeneration seen in Alzheimer’s patients. Previous research has shown that PF may play a key role in the disease’s progression (Amin L and Harris DA, 2021).

Lecanemab, an antibody specifically developed to target and neutralize amyloid-β protofibrils, has been used in clinical settings since 2023 to treat early Alzheimer’s disease. However, until this study, there had been no direct measurements of PF in human biological samples, and little was known about how PF behaves across the continuum of Alzheimer’s disease.

The aim of this research was to fill this gap by developing a highly sensitive Lec-PF measurement system capable of detecting these toxic amyloid-β protofibrils in the cerebrospinal fluid (CSF) of Alzheimer’s patients at different stages of the disease. The team also sought to explore how Lec-PF concentrations correlate with other well-established biomarkers of Alzheimer’s, such as amyloid-beta peptides (Aβ40, Aβ42), tau proteins (total tau, phosphorylated tau), and neurogranin, which reflect neuronal injury and neurodegeneration.

Summary of Research Results

The research demonstrated that Lec-PF concentrations were significantly elevated in the cerebrospinal fluid of patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD), compared to healthy controls. This finding suggests that Lec-PF is not only a marker of Alzheimer’s disease but also an indicator of disease severity. Patients with MCI or AD dementia had markedly higher Lec-PF concentrations than individuals with normal cognitive function, reinforcing the link between Lec-PF and Alzheimer’s progression.

Further analysis revealed that Lec-PF concentrations in CSF correlated strongly with other biomarkers associated with neurodegeneration, such as total tau, phosphorylated tau (p-tau), and neurogranin. These biomarkers are known to reflect neuronal injury and neurodegeneration, processes that are central to Alzheimer’s pathology. The correlation between Lec-PF and these biomarkers was particularly notable in patients with positive amyloid-beta (Aβ) deposits, suggesting that Lec-PF plays a crucial role in the neurodegenerative cascade that follows amyloid plaque accumulation.

The study found that, across all subjects, the concentration of Lec-PF in CSF had a Spearman correlation coefficient of 0.2 or higher with several other cerebrospinal fluid markers, including Aβ42, Aβ42/40 ratio, p-tau 181, p-tau 217, total tau, and neurogranin. However, the strongest correlations were observed in the Aβ-positive group, where Lec-PF levels correlated with total tau and neurogranin at Spearman coefficients of 0.4 or higher. These findings suggest that Lec-PF is closely linked to the pathological processes that lead to neurodegeneration in Alzheimer’s disease, making it a key player in the disease’s progression.

Implications for Future Developments

One of the most promising aspects of this research is its potential to enhance the clinical management of Alzheimer’s disease. The ability to measure Lec-PF concentration in cerebrospinal fluid before and after lecanemab treatment could offer a novel way to monitor the drug’s efficacy. By tracking changes in Lec-PF levels, clinicians may be able to assess how well lecanemab is working in individual patients and adjust treatment strategies accordingly. This approach could help optimize treatment outcomes for patients with early Alzheimer’s disease.

Additionally, the strong correlation between Lec-PF levels and other neurodegenerative biomarkers suggests that Lec-PF could serve as a prognostic tool. By measuring Lec-PF concentrations alongside other biomarkers such as tau and neurogranin, doctors could gain a better understanding of how quickly a patient’s Alzheimer’s disease is progressing. This information could be invaluable for guiding treatment decisions and providing patients and their families with more accurate predictions about the course of the disease.

The study’s findings also hold promise for advancing our understanding of the role of amyloid-β protofibrils in Alzheimer’s disease. Since Lec-PF is an intermediate form of amyloid-beta, it provides a more detailed view of the amyloid cascade than the plaques and fibrils that are typically studied. By focusing on this earlier stage of amyloid-beta aggregation, researchers may be able to identify new therapeutic targets and strategies for slowing or halting the progression of Alzheimer’s disease.

Support and Funding

This research was supported by several key funding sources, including the Japan Agency for Medical Research and Development (AMED), which provided grants for dementia research (Grant No. 22dk0207053), transformative research (Grant No. 23H03850), and scientific research (Grant Nos. JP19k07965, JP22k07514). The collaboration between academia and industry, represented by Kanazawa University and Eisai Co., Ltd., highlights the importance of partnerships in advancing medical research and developing novel treatments for Alzheimer’s disease.

Source Link

Newsletter Updates

Enter your email address below and subscribe to our newsletter