Anti–Aβ antibody therapy for Alzheimer disease

Abstract

Alzheimer disease (AD) is the most common dementia disease and is characterized by major pathological features in the brain, such as senile plaques composed of amyloid beta protein (Aβ), neurofibrillary tangles of tau protein, and neuronal cell death. In the pathophysiology of AD, the “amyloid hypothesis” has been proposed, which posits that abnormal aggregates of Aβ causes damage to neurons with phosphorylated tau. Recently, the pathological significance of not only insoluble Aβ fibrils that accumulate as amyloid in the brain, but also eraly and intermediate aggregates such as oligomers and protofibrils has been emphasized (oligomer hypothesis). In particular, the pathogenesis of Aβ protofibrils, the target molecule of lecanemab, has attracted attention following the positive results of a phase 3 clinical trial in early AD patients and its approval in the United States, Japan, and other countries. We mainly used high–speed atomic force microscopy to show that lecanemab not only binds to and surrounds protofibrils with high affinity, but also binds to spherical oligomers and inhibits the further aggregation process of Aβ, thereby reducing neurotoxicity. Donanemab is also an antibody that has been shown to be effective in phase 3 clinical trials. Donanemab is an antibody that targets N3pG Aβ (Aβ pyroglutamylated at the 3rd N–terminal residue) fibrils in Aβ plaques. In a phase 3 clinical trial targeting early AD patients, the mean change in the integrated Alzheimer Disease Rating Scale (iADRS) score, the primary endpoint, at 76 weeks was 35.1% lower in the donanemab group with mild to moderate tau deposition compared to the placebo group.

Although there are many issues such as ARIA (amyloid–related imaging abnormalities) to be resolved, and it should be noted that some countries are cautious about approving drugs, the development of disease–modifying therapies for AD, mainly anti–Aβ antibodies, is progressing steadily.