Quantitative 3D microscopy reveals a genetic network predicting the local activity of anti-Aβ compounds

Genetic and biochemical evidence suggests a role for amyloid-β (Aβ) in Alzheimer9s disease, yet many anti-Aβ treatments are clinically ineffective. Regional heterogeneity of efficacy may contribute to these disappointing results. Here we compared the regiospecificity of various anti-Aβ treatments by combining focused electrophoretic whole-brain clearing, amyloid labelling and light-sheet imaging with whole-brain analyses of plaque topology in Aβ-overexpressing mice. Aβ plaque numbers progressed from around 192009000 to 295009000 over a 9-month period. We then assessed the regiospecific plaque clearance in mice subjected to β-secretase inhibition, amyloid intercalation by polythiophenes, and anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance signatures, with polythiophenes emerging as potent anti-Aβ compounds with promising pharmacokinetic properties and the anti-Aβ antibody showing only minor effects. By aligning (25 um)^3 voxels that showed drug effectiveness to spatial transcriptomics atlases, we identified genes matching regiospecific Aβ clearance. As expected, Bace1 expression was highly correlated with the regiospecific efficacy of BACE inhibition. In addition, we found that voxels cleared by polythiophenes correlated with transcripts encoding synaptic proteins, whereas voxels cleared by BACE inhibition correlated with oligodendrocyte-specific genes. The differential regional susceptibility of distinct plaque populations to specific treatments may explain the clinical failure of anti-Aβ therapies, and suggests that combinatorial regimens may improve functional outcomes.