Results of Novel Assay Shed Light on Impact of Lecanemab on Neurodegeneration in Alzheimer Disease

Use of a novel highly sensitive immunoassay method specifically designed to quantify amyloid-β protofibrils (Aβ-PF) captured by lecanemab (Lequembi; Eisai) in human cerebrospinal fluid (CSF) has found that the concentration of so-called lecanemab-related Aβ-PF, or Lec-PF is significantly elevated in adults with Alzheimer's disease (AD) across all stages, from mild cognitive impairment to severe dementia, compared to individuals without the disease.¹

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The study published online January 6, in the Annals of Neurology, also revealed strong correlations between CSF Lec-PF levels and biomarkers of neurodegeneration, such as total-tau and neurogranin. This finding is of particular interest as it indicates that Lec-PF is associated with neurodegenerative processes that drive the progression of AD and not just the accumulation of amyloid in the brain. “This is the first report describing Aβ-PF species captured by lecanemab in human CSF,” investigators wrote, “and may explain the mechanism of the clinical effect of lecanemab.”¹

Lecanemab, a dual-acting monoclonal antibody that selectively binds Aβ-PF in addition to removing plaque, was approved by the US FDA in 2023 and is indicated for the treatment of AD, initiated in those with mild cognitive impairment or mild dementia stage of disease.² In the pivotal phase 3 CLARITY AD trial, lecanemab was associated with reduced late-stage amyloid plaques and either improved or stable scores on measures of cognition and function compared with placebo.³ All additional studies to date seeking to characterize Aβ-PF have been conducted using synthetic peptides at in vitro environments or in postmortem brains, according to study authors.¹ No previous studies have measured PF concentrations in human biological samples. Nor have profiles of PF, considered the most toxic form of Aβ and the therapeutic target of lecanemab, been understood across the full continuum of AD,¹ creating the foundation for the current investigation.

Study participants (n = 163) were recruited at Kanazawa University and Showa University Hospital in Japan. The cohort comprised participants assessed as follows:

• 48 cognitively unimpaired Aβ-negative (CU–)
• 8 cognitively impaired/diagnosed as suspected non-Alzheimer’s disease pathophysiology
• 9 cognitively unimpaired Aβ-positive (CU+)
• 34 Aβ-positive with mild cognitive impairment (MCI+)
• 64 Aβ-positive with AD dementia (AD+)

Mean age among the cohort was 70.74 years and approximately half (47.1%) were women, according to the study. Researchers, led by Moeko Noguchi-Shinohara of the department of at Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan, analyzed the association between Lec-PF observed at each level of cognitive impairment and Aβ40, Aβ42, phosphorylated tau (p-tau) 181, p-tau 217, total tau, and neurogranin.¹

FINDINGS

Noguchi-Shinohara and colleagues reported that Lec-PF concentration in CSF was correlated with all prespecified biomarkers, in all participants, regardless of stage of AD, with Spearman coefficients of 0.2 or higher. Notably, when evaluating the Aβ-positive group alone, Lec-PF showed a strong correlation (Spearman’s ρ 0.4 or higher) with total-tau and neurogranin, neurodegenerative markers downstream of Aβ in the Aβ cascade, suggesting that Lec-PF is a highly toxic pathological protein associated with neurodegeneration.¹

Among the study’s limitations the authors acknowledge the small sample size of the CU+ (n=9) and CI− (n=8) subgroups, making statistical power insufficient to thoroughly characterize CSF Lec-PF in preclinical AD and non-AD dementia cases. Larger proportions of these populations in future research will be critical to validate these findings. Additionally, incorporating imaging biomarkers such as tau-PET and MRI, which reflect tau pathology and neurodegeneration, will provide further insights into the characterization of Lec-PF.¹

Nonetheless, Noguchi-Shinohara point out that their findings “reveal novel pharmacological properties of lecanemab,” quantifying for the first time Aβ-PF that are bound by lecanemab in CSF, and revealing that CSF Lec-PF levels increase not only in early AD, the stage for which lecanemab is indicated, but also in moderate and late stages of AD dementia.”

They also noted the potential to assess efficacy of lecanemab using the assay to measure PF concentration in CSF before and after lecanemab treatment. In addition, because the concentration of Lec-PF in CSF correlates well with markers of neurodegeneration, levels may also be useful for predicting the AD prognosis.

References
1. Noguchi-Shinohara M, Shuta K, Hidetomo Murakami H, et al. Lecanemab-associated amyloid-β protofibril in cerebrospinal fluid correlates with biomarkers of neurodegeneration in Alzheimer's disease. Ann Neurol. 2025;00:1-14. doi:10.1002/ana.27175
2. Lequembi. Professional prescribing information. Eisai Inc and Biogen; 2024. Accessed January 7, 2025. https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf
3. Halsey G. New phase 3 data suggest benefits of early lecanemab initiation on Alzheimer disease progression, support long-term safety. Patient Care. October 31, 2024. https://www.patientcareonline.com/view/new-phase-3-data-suggest-benefits-of-early-lecanemab-initiation-on-alzheimer-disease-progression-support-long-term-safety