Concise Statement: Progressive failure of autophagy flux in AD neurons produces a cascading epigenetic feedback loop — as autophagy declines, damaged organelles accumulate, generating ROS-driven methylation drift at autophagy regulatory genes, which further suppresses autophagy in a self-reinforcing cycle that is quantifiable as a disease-stage-specific methylation "chronometer."
Curated pathway from expert analysis
flowchart TD
A["Target Gene: AD ROS BECN1 ATG5 ATG7"]
B["Molecular Mechanism<br/>Pathway Activation"]
C["Cellular Phenotype<br/>Neuronal / Glial Response"]
D["Network Effect<br/>Circuit-Level Consequence"]
E["Disease Relevance<br/>Neurodegeneration Link"]
A --> B --> C --> D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784No curated PDB or AlphaFold mapping for AD yet. Search RCSB →
Median TPM across 13 brain regions for AD, ROS, BECN1, ATG5, ATG7 from GTEx v10.
No clinical trials data linked to this hypothesis yet.
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 AD, ROS, BECN1, ATG5, ATG7.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF autophagy-flux methylation is an AD stage chronometer, THEN BECN1/ATG5/ATG7 methylation module scores will increase monotonically from cognitively normal amyloid-negative to amyloid-positive MCI to | Autophagy methylation module shows ordered stage increase with Jonckheere trend p <0.01 and >=0.5 SD difference between endpoints. | — no observation — | pending | 0.61 |
| IF autophagy-epigenetic feedback compounds AD stress, THEN restoring autophagy flux in amyloid/tau iPSC neurons will reduce ROS markers by >=25% and partially normalize ATG methylation within 28 days. | Autophagy rescue lowers ROS readouts by >=25% and shifts ATG methylation module >=0.3 SD toward control values. | — no observation — | pending | 0.54 |