processed_data.tar.gz contains all files from the data directory associated with the 230418_TS_AgingCCC GitHub project and includes the following:CellRangerCounts/post_soupX/ : contains 12 directories for 12 samples, which each contain 3 files obtained from ambient RNA removal with soupX. Below is a representative example, but the post_soupX directory contains one directory for each of the 12 samples:S01_6m_AD/barcodes.tsvgenes.tsvmatrix.mtxpre_soupX/ : contains 12 directories for 12 samples, which each contain 2 files obtained from Cell Ranger after aligning fastq files to the reference genome. Below is a representative example, but this directory contains 1 directory for each individual sample:S01_6m_AD/outs/filtered_feature_ bc_matrix.h5raw_feature_bc_matrix.h5 PANDA_inputs/PANDA_exp_files_array.txt: Text files with files paths to expression inputs for PANDA gene regulatory networks.mm10_TFmotifs.txt: Mouse TF motif input for PANDA gene regulatory networks. Previously published in Whitlock et al. 2023 mm10_ppi.txt: Mouse protein-protein interaction information from SringDB input for PANDA gene regulatory networks. Previously published in Whitlock et al. 2023 ccc/nichenet_v2_prior/gr_network_mouse_21122021.rds : accessed in December 2023, gene regulation network – gene regulatory information from MultiNicheNetligand_target_matrix_nsga2r_final_mouse.rds:  accessed in December 2023, ligand target matrix for mouse from MultiNicheNet.ligand_tf_matrix_nsga2r_final_mouse.rds: accessed in December 2023, mouse ligand tf matrix for signaling path determination from MultiNicheNetlr_network_mouse_21122021.rds : accessed in December 2023, ligand-receptor matrix from MultiNicheNetsignaling_network_mouse_21122021.rds : accessed in December 2023, signaling network – protein-protein interaction information from MultiNicheNet for mouseweighted_networks_nsga2r_final_mouse.rds : accessed in October 2023, networks weighted by literature evidence from MultiNicheNet for mousemultinichenet_output.rds : MultiNicheNet output for 3xTg-AD snRNA-seq data12m_signaling_igraph_objects.rds : list of igraph objects for 93 LRTs and their signaling mediators at 12 months6m_signaling_igraph_objects.rds :list of igraph objects for 2 LRTs and their signaling mediators at 6 monthselisa/: CSV files of measured OD values for every ELISA.240319_ELISA_Ab40.csv: OD measurements for Ab40240319_ELISA_Ab42.csv: OD measurements for Ab42240319_ELISA_total_tau.csv: OD measurements for Total Taupanda/: PANDA gene regulatory networks for each time point and condition in excitatory and inhibitory neurons. Used for differential gene targeting.excitatory_neurons_AD12.Rdataexcitatory_neurons_AD6.Rdataexcitatory_neurons_WT12.Rdataexcitatory_neurons_WT6.Rdatainhibitory_neurons_AD12.Rdatainhibitory_neurons_AD6.Rdatainhibitory_neurons_WT12.Rdatainhibitory_neurons_WT6.Rdatapseudobulk/: includes pseudo bulk matrices for every cell type which were used for downstream analyses. Each matrix also includes metadata information on condition and time point.all_counts_ls.rds: List of all the pseudo bulk matrices (below).astrocytes.rds: pseudobulk matrix for astrocytes. Include time point and condition information for downstream analyses.endothelial_cells.rds: pseudobulk matrix for endothelial cells. Include time point and condition information for downstream analyses.ependymal_cells.rds: pseudobulk matrix for ependymal cells. Include time point and condition information for downstream analyses.excitatory_neurons.rds: pseudobulk matrix for excitatory neurons. Include time point and condition information for downstream analyses.fibroblasts.rds: pseudobulk matrix for fibroblasts. Include time point and condition information for downstream analyses.inhibitory_neurons.rds: pseudobulk matrix for inhibitory neurons. Include time point and condition information for downstream analyses.meningeal_cells.rds: pseudobulk matrix for meningeal cells. Include time point and condition information for downstream analyses.microglia.rds: pseudobulk matrix for microglia. Include time point and condition information for downstream analyses.oligodendrocytes.rds: pseudobulk matrix for oligodendrocytes. Include time point and condition information for downstream analyses.opcs.rds: pseudobulk matrix for oligodendrocyte progenitor cells. Include time point and condition information for downstream analyses.percicytes.rds: pseudobulk matrix for pericytes. Include time point and condition information for downstream analyses.rgcs.rds: pseudobulk matrix for retinal ganglion cells. Include time point and condition information for downstream analyses.pseudobulk_split/: Includes pseudo bulk count matrices split by time point and condition. Used for input to PANDA for gene regulatory network construction.excitatory_neurons_AD12.Rdataexcitatory_neurons_AD6.Rdataexcitatory_neurons_WT12.Rdataexcitatory_neurons_WT6.Rdatainhibitory_neurons_AD12.Rdatainhibitory_neurons_AD6.Rdatainhibitory_neurons_WT12.Rdatainhibitory_neurons_WT6.Rdataseurat_preprocessing/filtered_seurat.rds : merged and filtered seurat objectintegrated_seurat.rds : seurat object integrated using harmonyclustered_seurat.rds : clustered seurat objectprocessed_seurat.rds : processed seurat object with final cell type assignments at specified resolution Raw data publicly available on GEO under series accession: GSE261596

processed_data.tar.gz contains all files from the data directory associated with the 230418_TS_AgingCCC GitHub project and includes the following:CellRangerCounts/post_soupX/ : contains 12 directories for 12 samples, which each contain 3 files obtained from ambient RNA removal with soupX. Below is a representative example, but the post_soupX directory contains one directory for each of the 12 samples:S01_6m_AD/barcodes.tsvgenes.tsvmatrix.mtxpre_soupX/ : contains 12 directories for 12 samples, which each contain 2 files obtained from Cell Ranger after aligning fastq files to the reference genome. Below is a representative example, but this directory contains 1 directory for each individual sample:S01_6m_AD/outs/filtered_feature_ bc_matrix.h5raw_feature_bc_matrix.h5 PANDA_inputs/PANDA_exp_files_array.txt: Text files with files paths to expression inputs for PANDA gene regulatory networks.mm10_TFmotifs.txt: Mouse TF motif input for PANDA gene regulatory networks. Previously published in Whitlock et al. 2023 mm10_ppi.txt: Mouse protein-protein interaction information from SringDB input for PANDA gene regulatory networks. Previously published in Whitlock et al. 2023 ccc/nichenet_v2_prior/gr_network_mouse_21122021.rds : accessed in December 2023, gene regulation network – gene regulatory information from MultiNicheNetligand_target_matrix_nsga2r_final_mouse.rds:  accessed in December 2023, ligand target matrix for mouse from MultiNicheNet.ligand_tf_matrix_nsga2r_final_mouse.rds: accessed in December 2023, mouse ligand tf matrix for signaling path determination from MultiNicheNetlr_network_mouse_21122021.rds : accessed in December 2023, ligand-receptor matrix from MultiNicheNetsignaling_network_mouse_21122021.rds : accessed in December 2023, signaling network – protein-protein interaction information from MultiNicheNet for mouseweighted_networks_nsga2r_final_mouse.rds : accessed in October 2023, networks weighted by literature evidence from MultiNicheNet for mousemultinichenet_output.rds : MultiNicheNet output for 3xTg-AD snRNA-seq data12m_signaling_igraph_objects.rds : list of igraph objects for 93 LRTs and their signaling mediators at 12 months6m_signaling_igraph_objects.rds :list of igraph objects for 2 LRTs and their signaling mediators at 6 monthselisa/: CSV files of measured OD values for every ELISA.240319_ELISA_Ab40.csv: OD measurements for Ab40240319_ELISA_Ab42.csv: OD measurements for Ab42240319_ELISA_total_tau.csv: OD measurements for Total Taupanda/: PANDA gene regulatory networks for each time point and condition in excitatory and inhibitory neurons. Used for differential gene targeting.excitatory_neurons_AD12.Rdataexcitatory_neurons_AD6.Rdataexcitatory_neurons_WT12.Rdataexcitatory_neurons_WT6.Rdatainhibitory_neurons_AD12.Rdatainhibitory_neurons_AD6.Rdatainhibitory_neurons_WT12.Rdatainhibitory_neurons_WT6.Rdatapseudobulk/: includes pseudo bulk matrices for every cell type which were used for downstream analyses. Each matrix also includes metadata information on condition and time point.all_counts_ls.rds: List of all the pseudo bulk matrices (below).astrocytes.rds: pseudobulk matrix for astrocytes. Include time point and condition information for downstream analyses.endothelial_cells.rds: pseudobulk matrix for endothelial cells. Include time point and condition information for downstream analyses.ependymal_cells.rds: pseudobulk matrix for ependymal cells. Include time point and condition information for downstream analyses.excitatory_neurons.rds: pseudobulk matrix for excitatory neurons. Include time point and condition information for downstream analyses.fibroblasts.rds: pseudobulk matrix for fibroblasts. Include time point and condition information for downstream analyses.inhibitory_neurons.rds: pseudobulk matrix for inhibitory neurons. Include time point and condition information for downstream analyses.meningeal_cells.rds: pseudobulk matrix for meningeal cells. Include time point and condition information for downstream analyses.microglia.rds: pseudobulk matrix for microglia. Include time point and condition information for downstream analyses.oligodendrocytes.rds: pseudobulk matrix for oligodendrocytes. Include time point and condition information for downstream analyses.opcs.rds: pseudobulk matrix for oligodendrocyte progenitor cells. Include time point and condition information for downstream analyses.percicytes.rds: pseudobulk matrix for pericytes. Include time point and condition information for downstream analyses.rgcs.rds: pseudobulk matrix for retinal ganglion cells. Include time point and condition information for downstream analyses.pseudobulk_split/: Includes pseudo bulk count matrices split by time point and condition. Used for input to PANDA for gene regulatory network construction.excitatory_neurons_AD12.Rdataexcitatory_neurons_AD6.Rdataexcitatory_neurons_WT12.Rdataexcitatory_neurons_WT6.Rdatainhibitory_neurons_AD12.Rdatainhibitory_neurons_AD6.Rdatainhibitory_neurons_WT12.Rdatainhibitory_neurons_WT6.Rdataseurat_preprocessing/filtered_seurat.rds : merged and filtered seurat objectintegrated_seurat.rds : seurat object integrated using harmonyclustered_seurat.rds : clustered seurat objectprocessed_seurat.rds : processed seurat object with final cell type assignments at specified resolution Raw data publicly available on GEO under series accession: GSE261596

Supplemental File 6: SBAE-associated drugs’ DrugBank ID (drug_id), known drug targets (targets), drug metabolism enzymes (enzyme), transporters (transporter), and carrier (carrier). This file also contains the list of SBAE-associated drug targets (SBAE_Drug_Targets) and drug metabolism enzymes (SBAE_Drug_ENZ)

Supplemental File 3: Fisher’s exact test results

Supplemental File 3: Fisher’s exact test results

Supplemental File 4: ALPACA pathway results for the core genes of the sex-specific communities across tissues

Supplemental File 4: ALPACA pathway results for the core genes of the sex-specific communities across tissues

Supplemental File 5: GO semantic similarity analysis results from gprofiler2 functional enrichment of the unique sex-specific activator and repressor edges

Supplemental File 5: GO semantic similarity analysis results from gprofiler2 functional enrichment of the unique sex-specific activator and repressor edges

Supplemental File 6: SBAE-associated drugs’ DrugBank ID (drug_id), known drug targets (targets), drug metabolism enzymes (enzyme), transporters (transporter), and carrier (carrier). This file also contains the list of SBAE-associated drug targets (SBAE_Drug_Targets) and drug metabolism enzymes (SBAE_Drug_ENZ)