ID: h-var-95b0f9a6bc-pro
Hypothesis
Glymphatic-Mediated Tau Clearance Dysfunction (Proteomics DE)
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 2 oppose
🧪 Overview
No data yet for this section.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["MAPT/Tau Protein<br/>Microtubule Stabilizer"]
B["CDK5/GSK3B Activation<br/>Kinase Dysregulation"]
C["Tau Hyperphosphorylation<br/>Ser396/Thr231/Ser202"]
D["Tau Detachment<br/>Microtubule Destabilized"]
E["Tau Oligomers<br/>Paired Helical Filaments"]
F["Neurofibrillary Tangles<br/>Intraneuronal Inclusions"]
G["Axonal Transport Failure<br/>Synaptic Dysfunction"]
H["Neurodegeneration<br/>Tauopathy Spread"]
A --> B
B --> C
C --> D
D --> E
E --> F
D --> G
G --> H
F --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
Glymphatic impairment directly reduces tau clearance in AD mouse models, with AQP4 polarization loss as the primary mechanism — foundational evidence for the hypothesis.
Supports
Glymphatic and meningeal lymphatic dysfunction are core features of AD pathophysiology, reducing both amyloid-beta and tau clearance and representing a disease-modifying therapeutic target.
Supports
Removal of astrocytic PERK restores glymphatic function and reduces pathological tau aggregate clearance failure, linking ER stress to glymphatic tau accumulation.
Supports
Glymphatic pathway impairment promotes tau pathology accumulation after TBI — establishes the causal link between glymphatic failure and tau spreading.
Supports
Sleep-dependent glymphatic clearance of tau and amyloid is impaired in AD, with proteomics data identifying specific transport proteins dysregulated in glymphatic failure.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MAPT
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MAPT from GTEx v10.
💉 Clinical Trials
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 MAPT.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▲ 0.0%
Volatility
Low
0.0000
Events (7d)
0
Price History
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we enroll 120 early-stage Alzheimer's disease subjects (CDR 0.5, amyloid positive by PET) and randomize to 6 months of sleep optimization intervention (auto-CPAP for AHI>15 + sleep hygiene counseli | ≥25% decrease in CSF p-tau181 from baseline in intervention arm; ≥20% lower mean CSF p-tau181 in intervention vs control arm at 6 months | — no observation — | pending | 0.65 |
| IF we recruit 180 amnestic MCI and early AD subjects (CDR 0.5–1.0), stratify them into APOE4 carriers (n=60), APOE4 non-carriers with high sleep fragmentation (ESS >10 or PSG AHI 15–30, n=60), and APO | ≥50% larger PVS volume in APOE4 carriers vs normal-sleep non-carriers; ≥35% higher CSF p-tau181 in APOE4 carriers; APOE4 explains ≥15% of PVS variance | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF we enroll 120 early-stage Alzheimer's disease subjects (CDR 0.5, amyloid positive by PET) and randomize to 6 months of sleep optimization intervention (auto-CPAP for AHI>15 + sleep hygiene counseling + trazodone 50mg PRN for insomnia) versus standard care, THEN the intervention group will exhibit
Predicted outcome: ≥25% decrease in CSF p-tau181 from baseline in intervention arm; ≥20% lower mean CSF p-tau181 in intervention vs control arm at 6 months
Falsification: CSF p-tau181 in the intervention arm remains unchanged or increases; the difference between arms is <20% at 6 months; or no correlation exists between sleep efficiency improvement and p-tau181 reducti
pendingconf 55%
IF we recruit 180 amnestic MCI and early AD subjects (CDR 0.5–1.0), stratify them into APOE4 carriers (n=60), APOE4 non-carriers with high sleep fragmentation (ESS >10 or PSG AHI 15–30, n=60), and APOE4 non-carriers with normal sleep (n=60), and perform 7T MRI measuring perivascular space (PVS) volu
Predicted outcome: ≥50% larger PVS volume in APOE4 carriers vs normal-sleep non-carriers; ≥35% higher CSF p-tau181 in APOE4 carriers; APOE4 explains ≥15% of PVS variance
Falsification: No significant difference in PVS volume between APOE4 carriers and normal-sleep non-carriers (p>0.05); CSF p-tau181 does not differ across groups; APOE4 explains <5% of PVS volume variance
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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