The most defensible synthesis is that AD contains at least two trajectory classes: an amyloid-clearance/endosomal class and a trophic-transport/cholinergic-vulnerability class. This is less a single mechanism than a framework that can reconcile heterogeneous human biomarker sequences and guide stratified trials.
Curated pathway from expert analysis
flowchart TD
A["NTRK1/TrkA Receptor<br/>Neurotrophin Tyrosine Kinase"]
B["NGF Binding<br/>Dimerization and Autophosphorylation"]
C["PI3K/AKT Pathway<br/>Survival Signal Cascade"]
D["MAPK/ERK Pathway<br/>Neuronal Differentiation"]
E["PLCgamma1 Activation<br/>Calcium Signaling Cascade"]
F["TrkA Internalization<br/>Endosomal Signaling"]
G["Sustained AKT Signaling<br/>Pro-Survival Outcome"]
H["Tau Phosphorylation<br/>ERK-Mediated GSK3B"]
I["Neuronal Apoptosis<br/>Survival Signal Loss"]
A --> B
B --> C
B --> D
B --> E
C --> F
F --> G
D --> H
G -->|"blocks"| I
H -.->|"contributes"| I
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style I fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for APOE, SORL1, NTRK1, BIN1, PICALM 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 APOE, SORL1, NTRK1, BIN1, PICALM.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF late-onset AD cases are stratified by APOE4/SORL1 burden versus NTRK1/cholinergic expression markers at baseline, THEN the amyloid-clearance/endosomal subtype will show CSF Aβ42 abnormalities prece | At least 35% of AD cases will cluster into each of two distinct temporal biomarker orderings, with <10% showing intermediate/universal ordering patterns | — no observation — | pending | 0.55 |
| IF AD cases are stratified into amyloid-clearance/endosomal versus trophic-transport subtypes using the two-class framework, THEN anti-amyloid immunotherapy (anti-Aβ monoclonal antibodies) will demons | Significant treatment-by-subtype interaction (p<0.01) with opposite directional effects matching subtype mechanism predictions | — no observation — | pending | 0.45 |