ID: h-SDA-2026-04-26-gap-20260426-002803-01-
Hypothesis
Circulating Soluble PDGFRβ Reflects Pericyte Loss and Precedes Cognitive Decline in Neurodegeneration
Soluble PDGFRβ (sPDGFRβ) is released into the bloodstream upon pericyte damage, serving as a peripheral indicator of blood-brain barrier (BBB) pericyte coverage loss.
neurodegeneration
EvidencePending (0%)📖 8 cit🗣 1 debates✓ 8 support✗ 3 oppose
✓ All Quality Gates Passed
🧪 Overview
Soluble PDGFRβ (sPDGFRβ) is released into the bloodstream upon pericyte damage, serving as a peripheral indicator of blood-brain barrier (BBB) pericyte coverage loss. Elevated plasma sPDGFRβ correlates with BBB leakage and cognitive decline trajectories. The mechanism involves ADAM10/ADAM17-mediated ectodomain shedding of PDGFRβ from damaged pericytes. This hypothesis has the strongest evidence base with human validation in Alzheimer's disease (AD) and vascular dementia cohorts. Specificity concerns regarding peripheral PDGFRβ+ cell sources (vascular smooth muscle cells, hepatic stellate cells) are addressable through cell-type-specific validation studies and parallel peripheral biomarker controls.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD A["Pericyte injury"] B["ADAM10 and ADAM17 activation"] C["PDGFRbeta ectodomain shedding"] D["Soluble PDGFRbeta release"] E["Plasma sPDGFRbeta elevation"] F["BBB pericyte coverage loss"] G["Blood-brain barrier leakage"] H["Cognitive decline"] I["Neurodegeneration"] J["AD and vascular dementia progression"] K["sPDGFRbeta as peripheral biomarker"] L["ADAM10 and ADAM17 inhibition"] M["Pericyte protection strategies"] A --> B --> C --> D --> E E --> F F --> G G --> H H --> I I --> J E --> K L --> B M --> A style A fill:#ef5350,color:#0d0d1a style B fill:#4fc3f7,color:#0d0d1a style C fill:#4fc3f7,color:#0d0d1a style D fill:#4fc3f7,color:#0d0d1a style E fill:#4fc3f7,color:#0d0d1a style F fill:#ef5350,color:#0d0d1a style G fill:#ef5350,color:#0d0d1a style H fill:#ef5350,color:#0d0d1a style I fill:#ef5350,color:#0d0d1a style J fill:#ef5350,color:#0d0d1a style K fill:#81c784,color:#0d0d1a style L fill:#81c784,color:#0d0d1a style M fill:#81c784,color:#0d0d1a
⚖️ Evidence
⚖️ Evidence Matrix8 supports3 contradicts
Supports
Normalization of the vasculature for treatment of cancer and other diseases.
Supports
PDGFRβ Cells Rapidly Relay Inflammatory Signal from the Circulatory System to Neurons via Chemokine CCL2.
Supports
The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player.
Supports
Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders.
Supports
Development, maintenance and disruption of the blood-brain barrier.
Supports
Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.
Contradicts
sPDGFRβ elevated in systemic inflammation independent of brain pathology (LPS administration)
Contradicts
sPDGFRβ elevated in peripheral vascular disease without neurological conditions
Contradicts
Hepatic stellate cell PDGFRβ expression confounds circulating levels in liver disease
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — PDGFRΒ
No curated PDB or AlphaFold mapping for PDGFRΒ yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for PDGFRβ 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 PDGFRβ.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
7d Trend
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Falling
7d Momentum
▼ 1.1%
Volatility
Medium
0.0463
Events (7d)
3
Price History
▼17.0%💾 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 sPDGFRβ is a pericyte-loss biomarker, then declining sPDGFRβ over time will indicate improving pericyte function and better clinical outcomes in intervention studies targeting pericyte health (e.g. | In pericyte-targeting trial (e.g.,Subjects receiving BMP4 or RA derivative vs placebo), plasma sPDGFRβ decreases in treatment arm (>30% reduction at 6 months) a | — no observation — | pending | 0.74 |
| If circulating sPDGFRβ reflects pericyte loss, then sPDGFRβ levels will correlate with BBB leakage (Qalb, DCE-MRI Ktrans), decrease in brain pericyte coverage (postmortem histology), and predict cogni | In matched cohort (n≥60 with PET amyloid/tau, DCE-MRI, plasma sPDGFRβ), high plasma sPDGFRβ (top quartile) associates with elevated Qalb (OR>3), reduced pericyt | — no observation — | pending | 0.79 |
🔮 Falsifiable Predictions (2)
pendingconf —
If circulating sPDGFRβ reflects pericyte loss, then sPDGFRβ levels will correlate with BBB leakage (Qalb, DCE-MRI Ktrans), decrease in brain pericyte coverage (postmortem histology), and predict cognitive decline, independent of amyloid and tau burden.
Predicted outcome: In matched cohort (n≥60 with PET amyloid/tau, DCE-MRI, plasma sPDGFRβ), high plasma sPDGFRβ (top quartile) associates with elevated Qalb (OR>3), reduc
Falsification: sPDGFRβ does not correlate with BBB leakage, pericyte coverage, or cognitive trajectory after adjustment for amyloid/tau burden; levels are entirely explained by neurodegenerative rather than pericyte
pendingconf —
If sPDGFRβ is a pericyte-loss biomarker, then declining sPDGFRβ over time will indicate improving pericyte function and better clinical outcomes in intervention studies targeting pericyte health (e.g., BMP4, retinoic acid derivatives).
Predicted outcome: In pericyte-targeting trial (e.g.,Subjects receiving BMP4 or RA derivative vs placebo), plasma sPDGFRβ decreases in treatment arm (>30% reduction at 6
Falsification: sPDGFRβ does not change with pericyte-targeting intervention; BBB integrity and cognitive outcomes are unaffected by pericyte modulation despite sPDGFRβ changes, indicating sPDGFRβ is not a causal per
▸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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