AlzKB-BR extends the Alzheimer's Knowledge Base (AlzKB) by integrating brain region-specific transcriptomic information from the Allen Human Brain Atlas (ABA). The goal is to improve the biological interpretation of knowledge graph-based drug repurposing predictions for Alzheimer's disease (AD) by incorporating neuroanatomical context.

• Obtain transcriptomic data from the Allen Human Brain Atlas (ABA)
• Perform one-versus-all differential expression analysis using limma
• Generate gene–brain region relationships
• Extend AlzKB to create AlzKB-BR

• Compare AlzKB and AlzKB-BR
• Train the RotatE knowledge graph embedding model
• Evaluate performance using MRR, Hits@1, Hits@3, and Hits@10

• Predict missing Drug–Treats–Disease relationships
• Aggregate predictions using Robust Rank Aggregation (RRA)
• Apply statistical and biological filtering

• Interpret candidate drugs using AD-associated brain regions
• Analyze associated gene sets using GeneAgent
• Review supporting clinical trial and literature evidence

.
├── data/
│   ├── Allen_Human_Brain_Atlas/
│   ├── AlzKB/
│   │   └── CYPHERL/
│   └── AlzKB-BR/
│       └── CYPHERL/
│
├── output/
│   ├── DEG_results/
│   ├── Validation_results/
│   └── Drug_selection_results/
│
├── scripts/
│   ├── data_acquisition_curation.R
│   ├── probe_to_ensembl_mapping.R
│   ├── differential_expression_analysis.R
│   ├── calculate_z_scores.R
│   ├── validate_rotate_model.py
│   ├── robust_rank_aggregation.R
│   ├── construct_brain_region_relationships.ipynb
│   └── biological_refinement.ipynb
│
├── figures/
├── supplementary/
└── README.md

• Allen Human Brain Atlas (ABA) transcriptomic data
• Probe-to-gene mapping
• Differential expression analysis using limma
• BrainRegion ontology construction
• Integration into AlzKB-BR

• PyKEEN
• RotatE knowledge graph embedding
• Optuna hyperparameter optimization
• 10 independent random seeds

• Robust Rank Aggregation (RRA)

• Median + Median Absolute Deviation (MAD) filtering

• Biological refinement

  • FDA-approved drugs
  • AD-associated genes
  • Brain-region relevance
  • Pharmacogene exclusion

• GeneAgent (GPT-4 based)
• AD-associated brain regions
• Drug indications
• ClinicalTrials.gov
• Literature review

• Added 330 BrainRegion nodes
• Added 25,174 brain region-related relationships
• Preserved RotatE knowledge graph completion performance
• Identified 36 prioritized AD drug candidates
• Identified 22 candidate drugs unique to AlzKB-BR
• Improved biological interpretation through neuroanatomical context

• Python
• R
• Neo4j
• PyKEEN
• limma
• Optuna
• GeneAgent