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

Amyloid-beta (A beta) deposits are a relatively late consequence of A beta aggregation in Alzheimer's disease. When pathogenic A beta seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize A beta seeds before A beta deposition becomes detectable in A beta precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived A beta assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of A beta deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic A beta seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease-currently defined as A beta 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. Uhlmann et al. show that the preclinical phase of Alzheimer's disease may in fact be a relatively late manifestation of a much earlier pathogenic and targetable process of seed formation and propagation.