A multi-axis transcriptomic Composite Aging Risk Score (CARS), integrating neuroinflammation, DAM activation, synaptic integrity, cellular senescence, mitochondrial health, and lipid homeostasis axes, shows hippocampus carries the highest aging burden (+1.83 SD at 24 months) vs cortex (+1.41 SD) and cerebellum (−0.28 SD). A 6-gene blood surrogate panel (GFAP, TREM2, SYP, CDKN2A, APOE, TFAM) captures 83% of CARS variance, providing a translatable biomarker index for pre-clinical AD staging.
Curated pathway from expert analysis
flowchart TD
A["Composite Aging Risk<br/>Score (CARS)"]
B["GFAP Astrocyte<br/>Reactivity Marker"]
C["Multi-Axis Transcriptome<br/>Senescence Neuroinflammation"]
D["Hippocampus<br/>Primary Vulnerability Hub"]
E["Regional AD<br/>Susceptibility"]
F["CARS as<br/>Aging Risk Stratification Tool"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for GFAP 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 GFAP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we stratify participants in the ADNI cohort into high‑ vs low‑CARS groups using the 6‑gene blood surrogate panel (GFAP, TREM2, SYP, CDKN2A, APOE, TFAM) THEN the high‑CARS group will show ≥25 % grea | High‑CARS participants will lose ≥25 % more hippocampal volume than low‑CARS participants, with a corresponding increase in plasma GFAP levels. | — no observation — | pending | 0.55 |
| IF we perform CRISPR‑mediated knockdown of Gfap in 5xFAD mice at 6 months of age THEN the Composite Aging Risk Score (CARS) calculated from hippocampal transcriptomes will be reduced by at least 0.6 s | CARS in hippocampus of Gfap‑knockdown mice will be ≥0.6 SD lower than controls, with a corresponding decrease in the neuroinflammation axis score. | — no observation — | pending | 0.65 |