Version history

{
  "description": "APOE4 is the strongest genetic risk factor for late-onset AD. How APOE4 specifically disrupts lipid homeostasis in astrocytes, cholesterol transport, and its downstream effects on neuronal function are poorly defined.",
  "domain": "neuroscience",
  "status": "partially_addressed",
  "priority_score": 0.9,
  "importance_score": 0.95,
  "tractability_score": 0.7,
  "novelty_score": 0.75,
  "composite_score": 0.82,
  "source": "agent_identified",
  "evidence_summary": "{\"hypothesis_matches\": [{\"id\": \"h-541d61c3\", \"title\": \"Astrocyte-Selective APOE4 Silencing via Lipid Nanoparticles\", \"target_gene\": \"APOE4\", \"target_pathway\": null, \"match_score\": 0.57, \"composite_score\": 0.5319094969453281, \"status\": \"proposed\"}, {\"id\": \"h-c9c79e3e\", \"title\": \"APOE4-Selective Lipid Nanoemulsion Therapy\", \"target_gene\": \"APOE\", \"target_pathway\": \"APOE-mediated cholesterol/lipid transport\", \"match_score\": 0.57, \"composite_score\": 0.4360731331239531, \"status\": \"proposed\"}, {\"id\": \"h-seaad-fa5ea82d\", \"title\": \"APOE Isoform Expression Across Glial Subtypes\", \"target_gene\": \"APOE\", \"target_pathway\": \"Lipid Metabolism / Cholesterol Transport\", \"match_score\": 0.5, \"composite_score\": 0.4443403342524345, \"status\": \"proposed\"}, {\"id\": \"h-99b4e2d2\", \"title\": \"Interfacial Lipid Mimetics to Disrupt Domain Interaction\", \"target_gene\": \"APOE\", \"target_pathway\": \"Apolipoprotein E lipid transport\", \"match_score\": 0.47, \"composite_score\": 0.4047961202616306, \"status\": \"proposed\"}, {\"id\": \"h-11795af0\", \"title\": \"Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs)\", \"target_gene\": \"APOE\", \"target_pathway\": \"Apolipoprotein E lipid transport\", \"match_score\": 0.4, \"composite_score\": 0.5940704149617542, \"status\": \"proposed\"}, {\"id\": \"h-d0a564e8\", \"title\": \"Competitive APOE4 Domain Stabilization Peptides\", \"target_gene\": \"APOE\", \"target_pathway\": \"Apolipoprotein E lipid transport\", \"match_score\": 0.4, \"composite_score\": 0.5764005155895072, \"status\": \"proposed\"}, {\"id\": \"h-44195347\", \"title\": \"APOE4 Allosteric Rescue via Small Molecule Chaperones\", \"target_gene\": \"APOE\", \"target_pathway\": \"Apolipoprotein E lipid transport\", \"match_score\": 0.4, \"composite_score\": 0.520488824804739, \"status\": \"proposed\"}, {\"id\": \"h-a20e0cbb\", \"title\": \"Targeted APOE4-to-APOE3 Base Editing Therapy\", \"target_gene\": \"APOE\", \"target_pathway\": \"Apolipoprotein E lipid transport\", \"match_score\": 0.4, \"composite_score\": 0.4794740198496571, \"status\": \"proposed\"}, {\"id\": \"h-9d29bfe5\", \"title\": \"Membrane Cholesterol Gradient Modulators\", \"target_gene\": \"ABCA1/LDLR/SREBF2\", \"target_pathway\": \"Cholesterol efflux / lipid transport\", \"match_score\": 0.37, \"composite_score\": 0.5669671832437174, \"status\": \"proposed\"}, {\"id\": \"h-9d22b570\", \"title\": \"Programmable Neuronal Circuit Repair via Epigenetic CRISPR\", \"target_gene\": \"NURR1, PITX3, neuronal identity transcription factors\", \"target_pathway\": \"CRISPRa epigenetic activation of dopaminergic transcription factor network\", \"match_score\": 0.37, \"composite_score\": 0.4470493886505538, \"status\": \"proposed\"}], \"total_matching_hypotheses\": 19, \"gap_tokens_sample\": [\"AD\", \"APOE4\", \"APOE4-driven\", \"astrocytes\", \"cholesterol\", \"defined\", \"disrupts\", \"downstream\", \"dysregulation\", \"effects\", \"factor\", \"genetic\", \"homeostasis\", \"late-onset\", \"lipid\"], \"updated_at\": \"2026-04-06T08:21:05.941775+00:00\"}",
  "resolution_criteria": "Resolution requires: (1) lipidomics assay quantifying cholesterol, phospholipids, and sulfatides in APOE4 vs APOE3 astrocytes showing ≥30% alteration in lipid transport proteins; (2) co-culture with iPSC-derived neurons demonstrating downstream synaptic dysfunction; (3) at least one mechanistic study showing that restoring lipid homeostasis reverses neuronal toxicity. Each must be published in a peer-reviewed journal and replicated in an independent lab cohort (n≥3 biological replicates).",
  "market_price": 0.5
}