On 16 November, Dr. Ruth Uhlmann and Prof. Mathias Jucker published an article in Nature Neuroscience, showing reduced Alzheimer-like pathology following removal of pre-amyloid seeds during the very earliest stages of disease development in mice. Accumulation and aggregation of misfolded beta-amyloid proteins in the brain is a pathological hallmark of Alzheimer’s disease (AD). Monoclonal antibody strategies currently being developed (e.g Aducanumab) are based on the principle that removal of these toxic protein aggregates will address the underlying AD pathology, resulting in improvements in cognition. However, the results of secondary prevention trials for antibodies such as aducanumab, solanezumab and ganteremumab have been mixed. Potential explanations include not targeting a sufficiently early stage of AD, or non-optimal targeting of the disease-inducing forms of amyloid.
To address these questions, the researchers turned to animal models of AD, which replicate certain aspects of the human disease process. In particular, they wanted to look at the very earliest stages of AD, before amyloid deposition in the brain is detectable, to see whether targeting the pre-amyloid seeds could be beneficial. Using ultrasensitive tests, they showed that insoluble amyloid proteins could be detected in the brains of AD mice 1-2 months before more substantial amyloid aggregates were evident using standard tests. Surprisingly, treatment of young AD mice with a murine version of Aducanumab was able to remove the pre-amyloid seeds, resulting in an 80% reduction in amyloid seeding activity and plaque deposition in later life. Analysis of the plaques present in Aducanumab-treated animals suggested that the plaques were less mature than those in control-treated animals. Together, these results indicate that there may be much earlier stages of AD, prior to amyloid deposition, that could be targeted for treatment.
