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.
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
No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for HCRT yet. Search RCSB →
Median TPM across 13 brain regions for HCRT from GTEx v10.
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.
No resource usage or linked notebooks recorded for this hypothesis yet.