Description
While the abstract states that increased ADAM10 activity protects against β-amyloid deposition, ADAM10 cleaves many substrates beyond APP including cytokines and adhesion molecules. The challenge of selectively enhancing beneficial APP cleavage without disrupting other essential ADAM10 functions remains unresolved.
Gap type: open_question Source paper: Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer’s Disease Treatment. (2018, Pharmaceuticals (Basel, Switzerland), PMID:29382156)
Evidence summary
{“resolution_pipeline”: “scidex.atlas.gap_closure_pipeline”, “task_id”: “f4f7b129-0f43-4c84-abd8-20d4e701842d”, “evaluated_at”: “2026-04-28T19:10:41.726341+00:00”, “resolution_summary”: “Resolved by hypothesis h-trem2-fe8c644a: Soluble TREM2 (sTREM2) as Therapeutic Mimic — Decoupling Phagocytosis from Inflammation. Supporting evidence includes debate sess_SDA-2026-04-15-gap-pubmed-20260411-083737-59771b32_20260416-033540.”, “match_counts”: {“hypothesis_matches”: 1, “debate_matches”: 5, “paper_matches”: 0}, “hypothesis_matches”: [{“id”: “h-trem2-fe8c644a”, “title”: “Soluble TREM2 (sTREM2) as Therapeutic Mimic — Decoupling Phagocytosis from Inflammation”, “score”: 0.25, “reason”: “23 token overlaps; entity overlap: adam10”, “analysis_id”: “SDA-2026-04-02-gap-001”, “target_gene”: “TREM2, ADAM10, ADAM17”, “target_pathway”: “ectodomain shedding, microglial survival signaling”, “disease”: “Alzheimer’s disease”, “composite_score”: 0.71429, “confidence_score”: 0.65, “status”: “proposed”, “pubmed_evidence_ids”: [“27986010”, “29695715”, “33483491”, “41509917”]}], “debate_matches”: [{“id”: “sess_SDA-2026-04-15-gap-pubmed-20260411-083737-59771b32_20260416-033540”, “title”: “The study demonstrates that SGMS1 elevation correlates with increased Aβ and that SGMS inhibition reduces Aβ production, but the specific biochemical pathways connecting sphingomyelin metabolism to APP processing remain unexplained. Understanding this mechanism is critical for developing targeted therapeutic interventions.\n\nGap type: unexplained_observation\nSource paper: Elevation in sphingomyelin synthase activity is associated with increases in amyloid-beta peptide generation. (None, None, PMID:23977395)”, “score”: 0.43, “reason”: “8 token overlaps; entity overlap: app, pmid”, “analysis_id”: “SDA-2026-04-15-gap-pubmed-20260411-083737-59771b32”, “quality_score”: 0.75, “status”: “completed”, “target_artifact_id”: null, “target_artifact_type”: null}, {“id”: “sess_SDA-2026-04-16-gap-pubmed-20260411-082446-2c1c9e2d”, “title”: “The abstract explicitly questions whether AD’s hallmark pathologies induce cholinergic dysfunction or vice versa. This fundamental causality question is critical for determining therapeutic targets but remains unresolved despite evidence that β-amyloid affects cholinergic receptors.\n\nGap type: open_question\nSource paper: The cholinergic system in aging and neuronal degeneration. (2011, Behavioural brain research, PMID:21145918)”, “score”: 0.361, “reason”: “10 token overlaps; entity overlap: pmid”, “analysis_id”: “SDA-2026-04-16-gap-pubmed-20260411-082446-2c1c9e2d”, “quality_score”: 0.95, “status”: “completed”, “target_artifact_id”: null, “target_artifact_type”: null}, {“id”: “sess_SDA-2026-04-12-20260411-082446-2c1c9e2d_20260412-210950”, “title”: “The abstract explicitly questions whether AD’s hallmark pathologies induce cholinergic dysfunction or vice versa. This fundamental causality question is critical for determining therapeutic targets but remains unresolved despite evidence that β-amyloid affects cholinergic receptors.\n\nGap type: open_question\nSource paper: The cholinergic system in aging and neuronal degeneration. (2011, Behavioural brain research, PMID:21145918)”, “score”: 0.361, “reason”: “10 token overlaps; entity overlap: pmid”, “analysis_id”: “SDA-2026-04-12-20260411-082446-2c1c9e2d”, “quality_score”: 0.79, “status”: “completed”, “target_artifact_id”: null, “target_artifact_type”: null}, {“id”: “sess_SDA-2026-04-14-gap-pubmed-20260410-185318-186b0446”, “title”: “The abstract explicitly states the critical need to identify genetic risk factors for CTE, but these remain unknown. Understanding genetic susceptibility could enable risk stratification and personalized prevention strategies for athletes and military personnel.\n\nGap type: open_question\nSource paper: The neuropathology of chronic traumatic encephalopathy. (2015, Brain pathology (Zurich, Switzerland), PMID:25904048)”, “score”: 0.344, “reason”: “9 token overlaps; entity overlap: pmid”, “analysis_id”: “SDA-2026-04-14-gap-pubmed-20260410-185318-186b0446”, “quality_score”: 0.58, “status”: “completed”, “target_artifact_id”: null, “target_artifact_type”: null}, {“id”: “sess_SDA-2026-04-15-gap-pubmed-20260411-093843-0a9326c2_20260416-032731”, “title”: “The abstract identifies BACE1 as an attractive drug target but doesn’t address its normal physiological roles. Understanding these functions is critical to predict potential adverse effects of BACE1 inhibitors in therapeutic development.\n\nGap type: open_question\nSource paper: BACE1: the beta-secretase enzyme in Alzheimer’s disease. (2004, Journal of molecular neuroscience : MN, PMID:15126696)”, “score”: 0.34, “reason”: “8 token overlaps; entity overlap: pmid”, “analysis_id”: “SDA-2026-04-15-gap-pubmed-20260411-093843-0a9326c2”, “quality_score”: 0.76, “status”: “completed”, “target_artifact_id”: null, “target_artifact_type”: null}], “paper_matches”: []}