A fibril-selective single-domain antibody targets pathogenic amyloid-β assemblies and protects human neurons

Alzheimer disease is characterized by extracellular amyloid-β deposition that contributes to neuronal dysfunction and degeneration. Although anti-amyloid-β antibodies reduce plaque burden, their use requires monitoring for amyloid-related imaging abnormalities. Here, phage display against immobilized Aβ40 fibrils representing a patient-relevant polymorph identified J8, a fibril-selective, Fc-free single-domain antibody. J8 bound fibrils with high apparent affinity, showed no detectable binding to monomeric Aβ40, decorated fibril surfaces, and recognized plaque-associated amyloid in Alzheimer disease brain tissue. During concurrent fibril exposure, J8 reduced apoptotic signaling in human induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids. Single-nucleus profiling of pooled organoids identified fibril-associated stress programs and opposite-direction expression patterns in the FibJ8 condition; fibril-associated changes showed the strongest directional concordance with advanced disease pathology. These findings identify J8 as a fibril-selective candidate and support organoid-based evaluation of anti-amyloid reagents as a fit-for-purpose preclinical tool.