Extended Data Fig. 5: The fold change size and directionality of all DE genes after bumetanide treatment in the five large excitatory neuronal cell types in aged apoE4-KI mouse hippocampus mimicked the fold change size and directionality after bumetanide treatment in PC3 cells in the CMap database.

a, Scatterplot of average number of cells per cell cluster (of clusters with > 50 cells) in apoE4-KI hippocampi versus the percentile of CMap score against the DE genes in those clusters after bumetanide treatment (see Methods for details). The top 300 DE genes by p-value of the first five cell clusters (all excitatory neuronal cells) have a CMap score above the top 90 percentile of all drugs in the CMap database. b, Graphs of compounds ordered by CMap score against DE genes in Dentate Gyrus Granule Cells (see Methods for details). Bumetanide has one of the highest positive scores, suggesting that the signature in these cells in vivo is similar to the signature in the CMap database. c, Correlation analysis plot of rank of FC of genes in apoE4-KI Dentate Gyrus Granule Cells after bumetanide treatment versus rank of FC of genes in the CMap database after bumetanide treatment. There is a positive correlation (by the “lm” linear model method, geom_smooth function with default parameters (Ggplot2 v_3.2.1)) with an R² = 0.08829 and an unadjusted P-value = 3.6 ×10⁻¹², indicating that the FC of genes in these two signatures of DE genes after bumetanide treatment mimic each other. The shaded region represents the 95% confidence interval for predictions from the linear model. d, Graphs of compounds ordered by CMap score against DE genes in apoE4-KI CA1 neurons (see Methods for details). Bumetanide has one of the highest positive scores, suggesting that the signature in these cells in vivo is similar to the signature in the CMap database. e, Correlation analysis plot of rank of FC of genes in apoE4-KI CA1 neurons after bumetanide treatment versus rank of FC of genes in the CMap database after bumetanide treatment. There is a positive correlation (by the “lm” linear model method, geom_smooth function with default parameters (Ggplot2 v_3.2.1)) with an R² = 0.08091 and an unadjusted P-value = 1.9 ×10⁻¹⁰, indicating that the FC of genes in these two signatures of DE genes after bumetanide treatment mimic each other. The shaded region represents the 95% confidence interval for predictions from the linear model. f, Graphs of compounds ordered by CMap score against DE genes in apoE4-KI CA 2/3 Neurons (see Methods for details). Bumetanide has one of the highest positive scores, suggesting that the signature in these cells in vivo is similar to the signature in the CMap database. g, Correlation analysis plot of rank of FC of genes in apoE4-KI CA2/3 neurons after bumetanide treatment versus rank of FC of genes in the CMap database after bumetanide treatment. There is a positive correlation (by the “lm” linear model method, geom_smooth function with default parameters (Ggplot2 v_3.2.1)) with an R² = 0.06221 and an unadjusted P-value = 9.9 ×10⁻⁷, suggesting that the FC of genes in these two signatures of DE genes after bumetanide treatment mimic each other. The shaded region represents the 95% confidence interval for predictions from the linear model.