A collaborative research group led by Professor Kenjiro Ono of the Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, and Eisai, used a newly developed measurement system for lecanemab-associated amyloid-β protofibrils (Lec-PF) to demonstrate that the concentration of Lec-PF in human cerebrospinal fluid is elevated in patients with Alzheimer’s disease at all stages, from mild cognitive impairment to mild and severe dementia, compared with non-Alzheimer’s disease controls. Furthermore, this research identified that the concentration of Lec-PF in cerebrospinal fluid is significantly correlated with biomarkers reflecting neurodegeneration.
Lecanemab (*1) is a unique dual-acting antibody that selectivity binds to amyloid-β protofibril (PF *2) in addition to removing plaque, and is a treatment for patients with mild cognitive impairment and mild dementia due to Alzheimer’s disease (AD *3) (collectively referred to as early AD). The results of this study suggest that PF which is captured by lecanemab (Lec-PF), is present in the cerebrospinal fluid of patients with Alzheimer’s disease and that Lec-PF is a highly toxic pathological protein that causes neurodegeneration. This research has revealed part of the mechanism by which lecanemab demonstrates its effect of slowing the progression of Alzheimer’s disease.
Based on these findings, it may be possible in the future to measure Lec-PF concentration in cerebrospinal fluid before and after lecanemab treatment to assess the treatment’s efficacy. In addition, because the concentration of Lec-PF in cerebrospinal fluid correlates well with neurodegenerative markers such as total tau (*4) and neurogranin (*5), it is expected that these findings could also be useful in predicting the prognosis of Alzheimer’s disease patients.
This research was published in the online version of the international academic journal Annals of Neurology at 18:30 on January 6, 2025 (US Eastern Standard Time).
Research background and objectives
The amyloid cascade hypothesis is a leading theory regarding the cause of AD, which states that amyloid beta (Aβ) (*6) abnormally aggregates outside of neuron, followed by the formation of tau neurofibrillary tangles, which causes damage to neuron and leads to the onset of the disease. PF is more neurotoxic than amyloid fibrils and plaque, which are the final stages of abnormal aggregated Aβ, and it is believed that PF may cause neurodegeneration (reference: Amin L and Harris DA. 2021). Lecanemab is an anti-PF antibody that has been used in medical practice since 2023 as a treatment
for early AD. However, there have been no previous reports of measuring PF concentrations in human biological samples, and the profiles of PF, which is the therapeutic target of lecanemab, across the full AD continuum have not yet been understood.
In this study, the research group used a newly developed, highly sensitive Lec-PF measurement system to measure the concentration of Lec-PF in human cerebrospinal fluid (CSF) in subjects with preclinical AD (*7), mild cognitive impairment due to AD, and AD dementia, as well as patients with SNAP (suspected non-AD pathophysiology) (*8) and people with normal cognitive function, and analysed the association between Lec-PF and Aβ40, Aβ42, phosphorylated tau (p-tau) 181 (*9), p-tau 217, total tau, and neurogranin.
Summary of research results
The Lec-PF CSF concentration was significantly higher in patients with mild cognitive impairment or dementia due to AD (MCI+,AD+ groups in Figure 1) than in those with normal cognitive function (YNC and AMC groups in Figure 1).
Correlation analysis was conducted between the concentration of Lec-PF in cerebrospinal fluid and other cerebrospinal fluid markers (Aβ42, Aβ42/40 ratio, p-tau 181, p-tau 217, total-tau, neurogranin).
Future developments
Measuring the Lec-PF concentration in CSF before and after lecanemab treatment may be useful in assessing the efficacy of lecanemab treatment. In addition, because the concentration of Lec-PF in CSF correlates well with neurodegenerative markers, it may also be useful for predicting the prognosis of AD patients.
This research was supported by the Japan Agency for Medical Research and Development (AMED) Research and Development Grants for Dementia (Grant No. 22dk0207053), Grants-in-Aid for Transformative Research (Grant No. 23H03850), and Grants-in-Aid for Scientific Research (Grant Nos. JP19k07965, JP22k07514).