Novel Monoclonal Antibody Detects Small Aβ Oligomers More Sensitively Than Lecanemab in Alzheimer's Disease CSF, Serum and Culture Media

Objective: Aqueously diffusible oligomers of the amyloid β-protein (oAβ) are neurotoxic and play a role in neuronal dysfunction in Alzheimer's disease (AD). Accurate quantification of oAβ in brains and biofluids could be valuable for understanding and monitoring AD. In this study, we aimed to examine the ability of 2 antibodies to quantify diffusible oAβ in AD tissue and biofluids. Methods: Two oligomer preferring antibodies, 71A1 and lecanemab, were compared to quantify oAβ assemblies in AD brain tissue, cerebrospinal fluid (CSF), serum, and culture media of human neurons expressing Aβ-altering mutations. Results: Both antibodies recognized synthetic aggregates of Aβ and detected significantly elevated oAβ levels in aqueous extracts of AD versus control brain tissues. Only 71A1 sensitively quantified diffusible oAβ species in CSF, neuronal media, and serum. Interpretation: Whereas lecanemab is an effective plaque-clearing immunotherapy that robustly detects higher-order Aβ aggregates in AD brain, its preferred Aβ targets are present at very low levels in biofluids. Our results demonstrate that 71A1 detects low-n, diffusible Aβ oligomers that predominate in CSF, serum, and neuronal media that associate with AD-related pathology. Together, these findings indicate that Aβ oligomer populations distribute differently in brain tissue versus biofluids and inform the selection of assays for monitoring oligomers during AD progression and treatment. ANN NEUROL 2026;99:1452-1465.