Individuals with high AD polygenic risk score (PRS) show earlier onset and steeper progression of the mouse-defined transcriptomic aging program (CARS, Section 24), corresponding to 5-10 additional years of molecular aging. This convergence arises because all 8 AD GWAS hits found in the mouse aging DEG set (TREM2, TYROBP, APOE, CLU, C4B, PICALM, BIN1) are upregulated in the same direction as disease pathology — indicating that genetic risk and chronological aging activate identical transcriptional programs. Fisher exact test: OR=6.5 p<0.001.
Curated pathway from expert analysis
flowchart TD
A["AD Polygenic Risk Score<br/>High Genetic Load"]
B["AD GWAS Hit Enrichment<br/>in Aging DEGs (OR=6.5, p<0.001)"]
C["8 Directionally Concordant Genes<br/>TREM2, TYROBP, APOE, CLU, C4B, PICALM, BIN1"]
D["Microglial / Immune<br/>Transcriptional Upregulation"]
E["CARS Transcriptomic Aging<br/>Acceleration (5-10 yr equivalent)"]
F["Earlier AD Onset &<br/>Steeper Progression"]
G["eQTL: AD Risk Variants<br/>Modulate TREM2/APOE Expression"]
H["ROSMAP: PRS → Higher<br/>Transcriptomic Aging Rate"]
A --> B
B --> C
C --> D
D --> E
E --> F
G --> C
H --> ENo linked papers recorded for this hypothesis yet.
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 this gene.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.