Developing Topics.

Background: We developed a highly sensitive immunoassay method using lecanemab that selectively captures amyloid-β (Aβ) protofibril (PF). To characterize Aβ-PF in human cerebrospinal fluid (CSF), we investigated the CSF Aβ-PF levels in patients with Alzheimer's disease (AD) at different disease stages. We also studied the association of CSF Aβ-PF with other AD-related biomarkers.

Method: The participants in this study consisted of 48 cognitively unimpaired Aβ-negative (CU-) including 25 young normal control (YNC) and 23 age matched control (AMC) (age≥50), 8 cognitively impaired diagnosed as suspected non-Alzheimer's pathophysiology (CI-), 9 cognitively unimpaired Aβ-positive (CU+), 34 Aβ-positive with mild cognitive impairment (MCI+) and 64 Aβ-positive with AD dementia (AD+). CSF Aβ-PF were analyzed by the immunoassay system using lecanemab as a tool antibody. The other CSF biomarkers were analyzed by the conventional enzyme-linked immunosorbent assay (ELISA) or the digital ELISA system (Simoa) (Figure 1).

Result: The CSF Aβ-PF levels significantly increased in MCI+ and AD+ compared to YNC or AMC in CU- group (Figure 2). CU+ also showed increase of CSF Aβ-PF levels while CI- did not although the differences were not significant. In Aβ-positive participants, the CSF Aβ-PF was strongly correlated with "N" biomarkers such as CSF total tau (t-tau) (Spearman rho = 0.634, p < 0.001) and neurogranin (rho = 0.434, p < 0.001) whereas the relatively lower correlations were observed for CSF Aβ42 (rho = -0.080, p = 0.415), Aβ42/40 (rho = -0.334, p < 0.001), tau phosphorylated at 181 residue (p-tau181) (rho = 0.294, p = 0.004), and p-tau217 (rho = 0.232, p = 0.018) which are known as plaque-associated biomarkers.

Conclusion: This is the first report describing lecanemab-captured Aβ-PF species in human CSF. The CSF Aβ-PF levels increased during AD continuum including MCI+ as well as AD+ stages. CSF Aβ-PF showed modest correlation with plaque-associated biomarkers in Aβ-positive participants and stronger correlation with neurodegeneration biomarkers, suggesting that lecanemab-associated Aβ-PF may be a toxic species involved in the amyloid cascade and underlie the clinical effect of lecanemab in AD.