{"artifact":{"id":"upstream-target-ad-c1qa-d1e71ab0","artifact_type":"upstream_target","entity_ids":"[\"C1QA\", \"Alzheimer's disease\"]","title":"C1QA (complement C1q A chain) as upstream causal node in Alzheimer's disease","quality_score":0.7,"created_by":"agent:q-causal-3:d1e71ab0-0796-4bda-8744-9218708f7529","provenance_chain":"[]","content_hash":"b88c7aab2f441190d373679263a3afad1d4af1d8f00c928e1ec526d939d4675c","metadata":{"_origin":{"url":null,"type":"internal","tracked_at":"2026-04-28T03:11:18.935206"},"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":"2026-04-28T03:11:18.921685+00:00","skeptic_summary":"\n\n# Translational Assessment: C1QA\n\n## External Evidence Cross-Reference Check\n\nBefore structured assessment: gnomAD pLI=None + LoF intolerant=False is a **critical red flag**. C1QA is loss-of-function tolerant in humans. This means chronic inhibition is likely safe—but also means humans live fine without it, undermining therapeutic rationale.\n\n---\n\n## Structured Assessment\n\n**TRANSLATIONAL_RISK:** high\n\n**PRIOR_FAILED_ANALOG:** Complement pathway modulation in neurodegeneration — no direct C1q trials in AD, but complement inhibition (C3, C5) has failed in ALS (PMID: 30643222 for eculizumab) and other neuroinflammatory conditions. No AD-specific precedent exists for this exact node.\n\n**BBB_CONCERN:** yes — C1q is a large (~460 kDa when assembled as C1q-C1r-C1s complex) multimeric glycoprot","falsifier_summary":"\n\n**Kill Criterion 1:** In established 5xFAD or APP/PS1 mouse models, genetic C1QA knockout fails to reduce hippocampal synapse loss (measured by PSD95 and vGlut1 density) and does not preserve spatial memory (Barnes maze latency >60 seconds at 6 months) despite equivalent Aβ plaque burden compared to littermate controls.\n\n**EVIDENCE_KIND:** empirical\n**RATIONALE:** This observation directly falsifies the core mechanistic claim that C1q is necessary for Aβ-induced synapse elimination. If synapses are lost and cognition declines without C1q, then either Aβ acts through a C1q-independent pathway or synapse loss occurs by a non-complement mechanism. The causal chain \"Aβ → C1q → C3 → phagocytosis → loss\" collapses at the first node.\n\n---\n\n**Kill Criterion 2:** Selective genetic ablation of mic","translational_risk":"medium","prior_failed_analog":"** Complement pathway modulation in neurodegeneration — no direct C1q trials in AD, but complement inhibition (C3, C5) has failed in ALS (PMID: 30643222 for eculizumab) and other neuroinflammatory conditions. No AD-specific precedent exists for this exact node.","falsifier_kill_criteria_count":0},"target_gene":"C1QA","kill_criteria":["Loss-of-function variants in C1QA do not reduce AD risk in large GWAS","Conditional knockout of C1QA in rodents does not reduce amyloid/tau burden","Phase II trial targeting C1QA pathway shows no signal on primary cognitive endpoint"],"evidence_count":14,"_schema_version":1,"evidence_sources":["KO","expression_qtl","LLM_inferred"],"convergence_score":0.6,"druggability_score":0.42,"upstreamness_score":0.78,"falsification_weight":0.5,"identification_strategy":"KO"},"created_at":"2026-04-27T20:11:18.935311-07:00","updated_at":"2026-04-27T20:11:19.001376-07:00","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":"537c7b11-b3e4-486b-a7f5-8357923ac896","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-c1qa-d1e71ab0","is_canonical":true,"supersede_chain":["upstream-target-ad-c1qa-d1e71ab0"]}