{"artifact":{"id":"upstream-target-ad-mapt-d1e71ab0","artifact_type":"upstream_target","entity_ids":"[\"MAPT\", \"Alzheimer's disease\"]","title":"MAPT (microtubule-associated protein tau) as upstream causal node in AD tauopathy","quality_score":0.7,"created_by":"agent:q-causal-3:d1e71ab0-0796-4bda-8744-9218708f7529","provenance_chain":"[]","content_hash":"1e2803fdba2d88ba8c83bf9bc5908793c32444aebeb7727c3e771d4694c981df","metadata":{"_origin":{"url":null,"type":"internal","tracked_at":"2026-04-28T03:12:48.036270"},"disease":"alzheimers","audit_trail":{"gnomad":{"pLI":null,"oe_lof":null,"variant_count":0,"lof_intolerant":false},"clinvar":{"total":20,"benign_count":0,"pathogenic_count":0,"sample_pathogenic":[]},"task_id":"d1e71ab0-0796-4bda-8744-9218708f7529","verdict":"advance","disgenet":{"top_ad_scores":[],"ad_associations":0,"total_associations":0,"contradicting_associations":0},"run_date":"2026-04-28T03:12:48.022297+00:00","skeptic_summary":"\n\n# MAPT Target Assessment — Neurodegeneration Skeptical Review\n\n## TRANSLATIONAL_RISK: high\n\n---\n\n**PRIOR_FAILED_ANALOG:** Multiple. ABBV-8E12 (tilavonemab) Phase II NCT02880956 — anti-tau antibody failed to meet primary endpoint. BIIB080 (tau ASO) Phase I/II completed, data awaited but previous ASO programs have shown modest effects. Semagacestat (BACE-1 inhibitor) indirectly reduced tau pathology and still failed. These collectively represent >3 mechanism classes targeting tau upstream.\n\n**BBB_CONCERN:** yes — Glymphatic clearance is CSF-interstitial fluid bulk flow; targeting *upstream* tau synthesis via MAPT KO would require CNS penetration of whichever modality delivers the intervention. ASOs achieve ~0.1-1% BBB penetration with active transport; viral vectors have localization const","falsifier_summary":"\n\n**KILL_CRITERION_1**: Human loss-of-function variants in MAPT (nonsense/frameshift causing <50% normal protein levels) show no significant reduction in AD risk (OR ≥ 0.90) or age-at-onset delay (>1 year) in GWAS meta-analysis of >50,000 AD cases vs. controls.\n\n**EVIDENCE_KIND**: empirical\n\n**RATIONALE**: This would directly contradict the premise that reducing tau is sufficient to prevent AD neurodegeneration. If heterozygous loss-of-function alleles—the strongest possible pharmacological proxy for chronic \"tau reduction therapy\"—confer no protection, therapeutic reduction of tau protein levels would be ineffective. The existence of tauopathies like FTDP-17 establishing that tau dysfunction causes neurodegeneration does not establish that reducing wild-type tau prevents AD; these are mec","translational_risk":"high","prior_failed_analog":"** Multiple. ABBV-8E12 (tilavonemab) Phase II NCT02880956 — anti-tau antibody failed to meet primary endpoint. BIIB080 (tau ASO) Phase I/II completed, data awaited but previous ASO programs have shown modest effects. Semagacestat (BACE-1 inhibitor) indirectly reduced tau pathology and still failed. These collectively represent >3 mechanism classes targeting tau upstream.","falsifier_kill_criteria_count":3},"target_gene":"MAPT","kill_criteria":["or age-at-onset delay (>1 year) in GWAS meta-analysis of >50,000 AD cases vs. controls.\n\n**EVIDENCE_KIND**: empirical\n\n**RATIONALE**: This would directly contradict the premise that reducing tau is su","and no enrichment for AD risk alleles among expression-increasing variants (permutation p >","appears derived from MR/expression_qtl sources, but without colocalization, these relationships may reflect confounding, linkage, or downstream consequences of neurodegeneration rather than causal ups"],"evidence_count":21,"_schema_version":1,"evidence_sources":["KO","MR","expression_qtl","LLM_inferred"],"convergence_score":0.8,"druggability_score":0.55,"upstreamness_score":0.8,"falsification_weight":1.0,"identification_strategy":"KO"},"created_at":"2026-04-27T20:12:48.036365-07:00","updated_at":"2026-04-27T20:12:48.100034-07:00","version_number":5,"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":"1e12cc9d-07d1-4239-9ea4-d95f72c16cc3","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":"agent:q-causal-3:d1e71ab0-0796-4bda-8744-9218708f7529"}]},"epistemic_tier":"T3_provisional","created_by_agent_id":null},"outgoing_links":[],"incoming_links":[],"current_artifact_id":"upstream-target-ad-mapt-d1e71ab0","is_canonical":true,"supersede_chain":["upstream-target-ad-mapt-d1e71ab0"]}