LECANEMAB-associated amyloid-β protofibrils in cerebrospinal fluid (CSF) correlate with neurodegeneration biomarkers in Alzheimer’s disease (AD), recent research has shown, supporting lecanemab’s therapeutic potential in targeting toxic amyloid species.
The Clarity AD phase III trial previously established lecanemab as a promising treatment for early AD by reducing amyloid markers and slowing cognitive decline. To deepen the understanding of its effects, this study quantified amyloid-β protofibrils (Aβ-PF) bound by lecanemab (Lec-PF) in CSF across the AD continuum. Using a novel, highly sensitive immunoassay, researchers measured CSF Lec-PF alongside other biomarkers such as Aβ42, Aβ40, total tau, p-tau181, p-tau217, and neurogranin in 163 Japanese participants spanning five groups, from cognitively unimpaired Aβ-negative individuals (CU–) to those with Aβ-positive AD dementia (AD+).
CSF Lec-PF levels were significantly elevated in participants with mild cognitive impairment (MCI+) and AD+ compared to CU– individuals. Importantly, Lec-PF levels modestly correlated with plaque-associated biomarkers in Aβ-positive participants but showed stronger associations with neurodegeneration biomarkers like total tau and neurogranin. These findings suggest that CSF Lec-PF not only reflects amyloid plaque pathology but also proximally tracks neurodegenerative processes in AD.
This study highlights the unique pharmacological properties of lecanemab, an approved AD medication, in targeting toxic Aβ species. It demonstrates that Lec-PF levels increase across all AD stages, including early, moderate, and late stages. The strong link between Lec-PF and neurodegeneration aligns with lecanemab’s therapeutic mechanism of reducing Lec-PF toxicity and amyloid plaque burden. These results also establish the CSF Lec-PF assay as a potential tool to assess lecanemab’s treatment efficacy and predict patient outcomes.
Future considerations include integrating Lec-PF assays into clinical practice for personalised treatment strategies and further studies to explore lecanemab’s long-term benefits across the AD continuum. These findings reinforce the role of lecanemab in reshaping AD management by targeting the toxic amyloid species central to disease progression.
Katrina Thornber, EMJ
Reference
Noguchi‐Shinohara M et al. Lecanemab‐associated amyloid‐β protofibril in cerebrospinal fluid correlates with biomarkers of neurodegeneration in alzheimer’s disease. Annals of Neurology. 2025;DOI:10.1002/ana.27175.
