The gap can be tested by treating age-linked CpG drift as an upstream driver rather than a passive correlate. If true, perturbing locus-specific epigenome editing should shift cell-sorted methylomes before downstream neurodegeneration markers change.
Curated pathway from expert analysis
flowchart TD
A["Age-Linked CpG Drift<br/>Progressive Hypomethylation"]
B["DNMT1 Maintenance Failure<br/>Replication-Linked Fidelity Loss"]
C["Transposon Derepression<br/>LINE-1 and IAP Silencing Loss"]
D["cGAS-STING Innate Sensing<br/>Cytosolic DNA Detection"]
E["Heterochromatin Erosion<br/>H3K9me3 and H3K27me3 Loss"]
F["SASP Cytokine Secretion<br/>Senescence-Associated Phenotype"]
G["Glial Identity Drift<br/>Microglia and Astrocyte Dysregulation"]
A --> B
A --> C
B --> E
C --> D
D --> F
E --> G
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a

No curated PDB or AlphaFold mapping for AGE-LINKED yet. Search RCSB →
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 age-linked CpG drift.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF CpG drift is upstream, THEN baseline drift burden in aging brain organoids will predict subsequent neuronal-loss markers at r >=0.30 over 60 days. | CpG drift burden predicts later cleaved-caspase or synapse-loss module with r >=0.30. | — no observation — | pending | 0.51 |
| IF age-linked CpG drift is causal in neurodegeneration, THEN epigenome editing of top drift CpGs in human neurons will shift stress-response and synaptic gene expression by >=20% within 14 days. | Targeted CpG editing produces >=20% expression change in preregistered stress/synaptic modules versus scrambled guide controls. | — no observation — | pending | 0.55 |