{"artifact":{"id":"upstream-target-ad-trem2-d1e71ab0","artifact_type":"upstream_target","entity_ids":"[\"TREM2\", \"Alzheimer's disease\"]","title":"TREM2 (triggering receptor expressed on myeloid cells-2) as upstream causal node in AD","quality_score":0.7,"created_by":"agent:q-causal-3:d1e71ab0-0796-4bda-8744-9218708f7529","provenance_chain":"[]","content_hash":"d2137e62531f3f49b54fdc112dad1356bae267c1bd2737373c7ccc4ed22fdd99","metadata":{"_origin":{"url":null,"type":"internal","tracked_at":"2026-04-28T03:08:22.499413"},"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":"2026-04-28T03:08:22.487515+00:00","skeptic_summary":"\n\n**TRANSLATIONAL_RISK: medium**\n\n**PRIOR_FAILED_ANALOG:** AL002 (anti-TREM2 agonistic antibody, Alector) — completed Phase 1b/2 (INVOKE-2, NCT05135082) with interim signals reported but no Phase 3 completion or validation. Not a failure per se, but mechanism remains **clinically unvalidated** rather than a prior success. No oral small-molecule TYROBP/TREM2 modulator has advanced to human trials as of my knowledge cutoff.\n\n**BBB_CONCERN: yes** — TREM2 is a microglial surface receptor; antibody-based approaches (the primary tractable modality) do not cross the BBB. Peripheral agonism requires sufficient target engagement at the vascular interface of the CNS. The effect size from genetic loss-of-function (OR 2–4×) does not guarantee that pharmacologic agonism will translate proportionally, e","falsifier_summary":"\n\n**KILL_CRITERION_1:** Fine-mapping and conditional analysis reveals the AD association signal at the TREM2 locus is fully explained by a distinct causal variant in linkage disequilibrium (r² > 0.8) that does not alter TREM2 protein function, expression, or splicing, and Mendelian randomization using loss-of-function-proxy variants shows no causal effect on AD risk (IVW-OR = 1.0, 95% CI: 0.92–1.08).\n\n**EVIDENCE_KIND:** empirical\n\n**RATIONALE:** TREM2 is currently nominated based on rare coding variants (R47H, R62H, D87N) linked to AD risk. If the GWAS signal is actually driven by a non-functional proxy variant, the causal chain from TREM2 dysfunction to AD pathogenesis is broken. This would mean TREM2 is a bystander rather than a causal node, making it unsuitable as a therapeutic target r","translational_risk":"medium","prior_failed_analog":"** AL002 (anti-TREM2 agonistic antibody, Alector) — completed Phase 1b/2 (INVOKE-2, NCT05135082) with interim signals reported but no Phase 3 completion or validation. Not a failure per se, but mechanism remains **clinically unvalidated** rather than a prior success. No oral small-molecule TYROBP/TREM2 modulator has advanced to human trials as of my knowledge cutoff.","falsifier_kill_criteria_count":3},"effect_size":2.9,"target_gene":"TREM2","kill_criteria":["** Fine-mapping and conditional analysis reveals the AD association signal at the TREM2 locus is fully explained by a distinct causal variant in linkage disequilibrium (r² > 0.8) that does not alter TREM2 protein function, expression, or splicing, and Mendelian randomization using loss-of-function-proxy variants shows no causal effect on AD risk (IVW-OR = 1.0, 95% CI: 0.92–1.08).","** In multiple independent TREM2 loss-of-function models (CRISPR-Cas9 knockout in iPSC-derived microglia, Trem2−/− × 5×FAD or APP/PS1 crosses), amyloid plaque burden, soluble Aβ40/42 levels, microglial cluster density, and cognitive performance are indistinguishable from wild-type controls at 12+ months of age, with no significant effect on disease progression trajectory.","** Human genetic analysis of TREM2 loss-of-function carriers (nonsense, frameshift, or essential splice variants with >50% expected reduction in functional protein) shows no significant association with Alzheimer's disease risk (OR = 0.95, 95% CI: 0.88–1.03, p = 0.28), cognitive decline, or age at AD onset compared to non-carriers in cohorts >10,000 AD cases and >15,000 controls."],"evidence_count":32,"_schema_version":1,"evidence_sources":["GWAS","KO","eQTL","LLM_inferred"],"convergence_score":0.8,"druggability_score":0.58,"upstreamness_score":0.85,"falsification_weight":0.5,"identification_strategy":"MR"},"created_at":"2026-04-27T20:08:22.499485-07:00","updated_at":"2026-04-27T20:08:22.553642-07:00","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":"57d99b66-fee3-4169-b0b3-66faa6c36cc6","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-trem2-d1e71ab0","is_canonical":true,"supersede_chain":["upstream-target-ad-trem2-d1e71ab0"]}