Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life

Amyloid-v (Av) deposits are a relatively late consequence of Av aggregation in Alzheimer's disease. When pathogenic Av seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Av seeds before Av deposition becomes detectable in Av precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Av assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Av deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Av seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease-currently defined as Av deposition without clinical symptoms-may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.