Version history

{
  "description": "Tau pathology spreads through synaptically connected brain regions in Alzheimer disease following a stereotyped anatomical pattern. Mechanisms of trans-synaptic tau propagation via extracellular vesicles, tunneling nanotubes, and synaptic release need clarification.",
  "domain": "neuroscience",
  "status": "partially_addressed",
  "priority_score": 0.88,
  "importance_score": 0.92,
  "tractability_score": 0.75,
  "novelty_score": 0.8,
  "composite_score": 0.83,
  "source": "agent_identified",
  "evidence_summary": "{\"hypothesis_matches\": [{\"id\": \"h-var-3b982ec3d2\", \"title\": \"Closed-loop tACS targeting entorhinal cortex layer II SST interneurons to block tau propagation and restore perforant-path gamma gating in Alzheimer's disease\", \"target_gene\": \"SST\", \"target_pathway\": \"Entorhinal cortex layer II SST interneuron-mediated perforant-path gamma gating and suppression of trans-synaptic tau propagation to hippocampus\", \"match_score\": 0.5, \"composite_score\": null, \"status\": \"proposed\"}, {\"id\": \"h-var-55da4f915d\", \"title\": \"Closed-loop transcranial focused ultrasound targeting entorhinal cortex layer II SST interneurons to restore perforant-path gamma gating and block tau propagation in Alzheimer's disease\", \"target_gene\": \"SST\", \"target_pathway\": \"Entorhinal cortex layer II SST interneuron mechanosensitive activation via tFUS-driven PIEZO1/TREK-1 signaling, restoration of perforant-path gamma gating, and suppression of trans-synaptic tau propagation to hippocampus\", \"match_score\": 0.5, \"composite_score\": null, \"status\": \"proposed\"}, {\"id\": \"h-29ef94d5\", \"title\": \"Epigenetic Memory Reprogramming for Alzheimer's Disease\", \"target_gene\": \"BDNF, CREB1, synaptic plasticity genes\", \"target_pathway\": \"CREB/BDNF epigenetic regulation of synaptic plasticity\", \"match_score\": 0.44, \"composite_score\": 0.49103059326293774, \"status\": \"proposed\"}, {\"id\": \"h-var-d98a992599\", \"title\": \"Closed-loop tACS targeting entorhinal cortex layer II SST interneurons to activate AMPK-autophagy flux and degrade intracellular tau before exosomal packaging in Alzheimer's disease\", \"target_gene\": \"SST\", \"target_pathway\": \"Entorhinal cortex layer II SST interneuron-driven GABAergic hyperpolarization activating AMPK-ULK1-beclin-1 autophagy flux to degrade tau oligomers before exosomal trans-synaptic propagation to hippocampus\", \"match_score\": 0.44, \"composite_score\": null, \"status\": \"proposed\"}, {\"id\": \"h-a87702b6\", \"title\": \"Cholesterol-CRISPR Convergence Therapy for Neurodegeneration\", \"target_gene\": \"HMGCR, LDLR, APOE regulatory regions\", \"target_pathway\": \"Brain cholesterol homeostasis (HMGCR synthesis \\u2192 CYP46A1 elimination)\", \"match_score\": 0.3, \"composite_score\": 0.5150203412333288, \"status\": \"proposed\"}, {\"id\": \"h-var-14d7585dd1\", \"title\": \"Closed-loop tACS targeting entorhinal cortex layer II PV interneurons to suppress perisomatic burst firing and block tau propagation via the perforant path in Alzheimer's disease\", \"target_gene\": \"PVALB\", \"target_pathway\": \"Entorhinal cortex layer II PV interneuron-mediated perisomatic inhibition of stellate cells, suppression of high-frequency somatic bursting, and reduction of anterograde vesicular tau propagation via the perforant path\", \"match_score\": 0.3, \"composite_score\": null, \"status\": \"proposed\"}, {\"id\": \"h-fdaae8d9\", \"title\": \"Trans-Synaptic Adhesion Molecule Modulation\", \"target_gene\": \"NLGN1\", \"target_pathway\": \"Synaptic function / plasticity\", \"match_score\": 0.24, \"composite_score\": 0.33763444613187854, \"status\": \"proposed\"}, {\"id\": \"h-3a4f2027\", \"title\": \"Trinucleotide Repeat Sequestration via CRISPR-Guided RNA Targeting\", \"target_gene\": \"HTT, DMPK, repeat-containing transcripts\", \"target_pathway\": \"CRISPR-Cas13 RNA targeting / trinucleotide repeat expansion\", \"match_score\": 0.2, \"composite_score\": 0.515020341233329, \"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\": 0.2, \"composite_score\": 0.4470493886505538, \"status\": \"proposed\"}, {\"id\": \"h-e23f05fb\", \"title\": \"Multi-Modal CRISPR Platform for Simultaneous Editing and Monitoring\", \"target_gene\": \"Disease-causing mutations with integrated reporters\", \"target_pathway\": \"Multiplexed CRISPR editing with integrated fluorescent reporters\", \"match_score\": 0.2, \"composite_score\": 0.4470493886505538, \"status\": \"proposed\"}], \"total_matching_hypotheses\": 11, \"gap_tokens_sample\": [\"AD\", \"alzheimer\", \"anatomical\", \"brain\", \"clarification\", \"connected\", \"disease\", \"extracellular\", \"following\", \"nanotubes\", \"pathology\", \"pattern\", \"propagation\", \"regions\", \"release\"], \"updated_at\": \"2026-04-06T08:21:05.937372+00:00\"}",
  "resolution_criteria": "Resolution requires: (1) Mechanistic elucidation of >=1 tau propagation pathway with biochemical evidence; (2) In vivo validation in >=2 AD mouse models showing >=40% reduction in spreading with pathway-specific intervention; (3) Human imaging biomarker validated against postmortem tau burden (AUC >= 0.80); (4) KG edges capturing mechanism-to-phenotype relationships. Deliverable: mechanistic paper + validated biomarker.",
  "market_price": 0.5
}