{"artifact":{"id":"ad-master-plan-202604280307","artifact_type":"research_plan","entity_ids":"[\"Alzheimer's disease\", \"AD\", \"TREM2\", \"APOE\", \"BDNF\", \"GFAP\", \"LRP1\"]","title":"AD Master Plan — Q-CAUSAL Portfolio for Alzheimer's Disease","quality_score":0.85,"created_by":"ad_master_plan_synthesizer","provenance_chain":"[]","content_hash":"69d0c368fb83b032f0e161acd4f83f47945cf51c96113a3c0a65441fe4e53715","metadata":{"title":"AD Master Plan — Q-CAUSAL Portfolio for Alzheimer's Disease","_origin":{"url":null,"type":"internal","tracked_at":"2026-04-28T03:07:57.975103"},"disease":"Alzheimer's disease","task_id":"49710980-455b-4f69-8bfc-dd77337b52b5","created_by":"ad_master_plan_synthesizer","artifact_type":"research_plan","targets_count":5,"branch_details":[{"gene":"TREM2","cost_usd":986500.0,"timeline":"18-24 months","prereg_id":null,"hypothesis":"TREM2 enhancement reduces microglial dysfunction and downstream tau pathology, slowing AD progression","kill_criteria":["TREM2 loss-of-function variants show no AD risk modulation in replication cohort (OR=1.0, p>0.05)","Microglial TREM2 knockout in 5xFAD mice fails to alter amyloid plaque burden","TREM2 agonist fails to reduce tau pathology in P301S tauopathy model"],"druggability_score":0.75,"upstreamness_score":0.91},{"gene":"APOE","cost_usd":983500.0,"timeline":"18-24 months","prereg_id":null,"hypothesis":"APOE4-driven lipid dysregulation and synaptic phagocytosis drive AD; converting APOE4 to APOE3 reduces amyloid and restores synaptic function","kill_criteria":["APOE4→APOE3 conversion shows no amyloid reduction in Phase 3 trial","APOE isoform switching fails to improve cognitive endpoints at 18 months","Lipid代谢 correction fails to modify disease progression in APOE4 carriers"],"druggability_score":0.55,"upstreamness_score":0.89},{"gene":"BDNF","cost_usd":967000.0,"timeline":"18-24 months","prereg_id":null,"hypothesis":"BDNF-mediated hippocampal synaptic rescue restores CA3-CA1 connectivity and prevents downstream tau-mediated neurodegeneration in AD","kill_criteria":["BDNF upregulation fails to improve hippocampal-cortical connectivity in MCI patients","CA3-CA1 synaptic rescue does not translate to behavioral improvement in AD patients","TrkB agonist shows no disease-modifying effect in 12-month trial"],"druggability_score":0.68,"upstreamness_score":0.78},{"gene":"GFAP","cost_usd":958000.0,"timeline":"18-24 months","prereg_id":null,"hypothesis":"GFAP-positive reactive astrocytes mediate regional vulnerability through dysfunction of metabolic support, driving AD progression in affected regions","kill_criteria":["GFAP-reactive astrocyte subtyping shows no association with regional vulnerability","Astrocyte GFAP knockdown fails to alter disease trajectory in AD mouse model","Astrocyte-targeted intervention does not modify neuronal survival outcomes"],"druggability_score":0.6,"upstreamness_score":0.72},{"gene":"LRP1","cost_usd":952000.0,"timeline":"18-24 months","prereg_id":null,"hypothesis":"LRP1-mediated tau uptake disruption in neurons initiates the earliest tau propagation cascade; blocking LRP1 prevents downstream spreading","kill_criteria":["LRP1-dependent tau uptake blockade shows no effect on tau propagation in human iPSC neurons","LRP1 agonist fails to reduce tau seeding in 12-month observational study","Blood-brain barrier LRP1-mediated clearance mechanism is not replicable in human studies"],"druggability_score":0.55,"upstreamness_score":0.68}],"synthesized_at":"2026-04-28T03:07:53.508123+00:00","_schema_version":1,"parallel_branches":["TREM2","APOE","BDNF"],"research_plan_ids":["rp-ad-trem2-202604280307","rp-ad-apoe-202604280307","rp-ad-bdnf-202604280307","rp-ad-gfap-202604280307","rp-ad-lrp1-202604280307"],"aggregate_cost_usd":4847000.0,"aggregate_timeline":"30 months","portfolio_rationale":"TREM2 and APOE are the most upstream nodes with strong causal evidence (MR + KO + eQTL) and should be pursued in parallel since they operate via distinct mechanisms (microglial metabolic fitness vs. astrocytic lipid homeostasis). BDNF provides the synaptic resilience backbone — pursued sequentially after TREM2/APOE interim data. GFAP and LRP1 are lower confidence but address distinct vulnerability nodes (reactive astrogliosis, tau uptake) and are deprioritized to sequential evaluation.","preregistered_plans":5,"sequential_branches":["GFAP","LRP1"],"upstream_target_ids":["ut-ad-trem2-202604280307","ut-ad-apoe-202604280307","ut-ad-bdnf-202604280307","ut-ad-gfap-202604280307","ut-ad-lrp1-202604280307"],"portfolio_kill_criteria":["Phase 2 trial for top-scoring target (TREM2) fails primary endpoint → deprioritize microglial axis","APOE4 conversion therapy shows serious adverse events in >5% of patients → halt APOE branch","Both TREM2 and APOE branches fail independently → kill all sequential branches, reassess upstream hypothesis","Biomarker analysis reveals tau pathology is upstream of ALL five targets → redirect portfolio to tau initiation","No single target achieves p<0.01 in 24-month interim analysis → redistribute budget to best performer"]},"created_at":"2026-04-27T20:07:57.975191-07:00","updated_at":"2026-04-27T20:07:57.975191-07:00","version_number":4,"parent_version_id":null,"version_tag":null,"changelog":null,"is_latest":1,"lifecycle_state":"active","superseded_by":null,"deprecated_at":null,"deprecated_reason":null,"dependencies":null,"market_price":0.5,"origin_type":"internal","origin_url":null,"lifecycle_changed_at":null,"citation_count":0,"embed_count":0,"derivation_count":0,"support_count":0,"contradiction_count":0,"total_usage":0.0,"usage_score":0.5,"usage_computed_at":null,"quality_status":null,"contributors":[],"answers_question_ids":null,"deprecated_reason_detail":null,"deprecated_reason_code":null,"commit_sha":null,"commit_submodule":null,"last_mutated_at":"2026-05-16T14:51:34.657673-07:00","disputed_at":null,"gap_id":null,"mission_id":null,"intrinsic_priority":null,"effective_priority":null,"artifact_id":"30f36477-2b77-40e3-80a7-b1d10b9e2d65","artifact_dir":null,"primary_filename":null,"accessory_filenames":null,"folder_layout_version":1,"migrated_to_folder_at":null,"hypothesis_id":null,"authorship":{"kind":"human","contributors":[{"role":"author","actor_ref":"ad_master_plan_synthesizer"}]},"epistemic_tier":"T3_provisional","created_by_agent_id":null},"outgoing_links":[],"incoming_links":[],"current_artifact_id":"ad-master-plan-202604280307","is_canonical":true,"supersede_chain":["ad-master-plan-202604280307"]}