Excess orexin-A worsens AD cognition through wake-driven amyloid production
🧪 Overview
Chronic orexin-A elevation may aggravate AD by extending wakefulness, fragmenting circadian rhythms, and increasing activity-dependent amyloid/tau release. Lowering orexin tone should improve pathology only when it normalizes sleep rather than causing broad hypoarousal.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD A["Orexin-A (HCRT) Elevation"] -->|"extends wakefulness"| B["Chronic Wakefulness Duration"] A -->|"fragmented"| C["Circadian Rhythm Dysregulation"] B -->|"increases"| D["Activity-Dependent Amyloid Production"] C -->|"enhances"| D B -->|"increases"| E["Activity-Dependent Tau Release"] C -->|"enhances"| E A -->|"direct effect"| F["Wake-Active Neuronal Activity"] F -->|"promotes"| D F -->|"promotes"| E D -->|"drives"| G["Amyloid Pathology Accumulation"] E -->|"drives"| G G -->|"worsens"| H["Cognitive Deficits in AD"] I["Lowering Orexin Tone"] -->|"restores"| J["Normalized Sleep Duration"] J -->|"reduces"| D J -->|"reduces"| E J -->|"stabilizes"| C I -->|"indirect suppression"| A K["Broad Hypoarousal State"] -.->|"fails to improve"| H
⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — HCRT
No curated PDB or AlphaFold mapping for HCRT yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for HCRT from GTEx v10.
💉 Clinical Trials (5)Relevance: 72%
Active
Completed
Total Enrolled
Highest Phase
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for HCRT.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |