This experiment addresses the AD Knowledge Gap: "How do vascular factors contribute to AD?" (ranked in top 15 AD gaps). Vascular dysfunction interacts with amyloid pathology and may be an independent driver of cognitive decline.
Related: AD Knowledge Gap #12 | AD Cure Roadmap | Neurovascular Unit
What is the independent contribution of vascular dysfunction to AD pathogenesis? Can targeting vascular pathways provide additive benefits beyond anti-amyloid therapy?
Vascular dysfunction contributes to AD through:
Recruit 600 participants with:
| Group | N | Characteristics |
|---|---|---|
| AD + CVD | 200 | AD with confirmed cerebrovascular disease |
| AD only | 200 | AD without significant vascular disease |
| CVD only | 100 | Vascular cognitive impairment, no AD |
| Control | 100 | Normal cognition, no vascular disease |
Primary measures:
Follow-up: 24 months, 4 timepoints
Key questions:
Trial design: 2x2 factorial
| Arm | Intervention |
|---|---|
| A | Standard of care |
| B | Intensive vascular risk control |
| C | Anti-amyloid (lecanemab) |
| D | Intensive vascular + anti-amyloid |
Primary endpoint: Cognitive decline rate (CDR-SB slope)
| System | Use | Strength |
|---|---|---|
| Human cohort | Primary data | Direct relevance |
| 5xFAD x cerebral ischemia model | In vivo | Combined pathology |
| iPSC brain microvascular organoids | Mechanism | Human BBB model |
| Rodent chronic hypoperfusion model | Vascular | Established model |
| Factor | Assessment |
|---|---|
| Technical Feasibility | High — MRI, biomarkers established |
| Recruitment Feasibility | Moderate — stroke clinics, memory clinics |
| Cost Estimate | $12-18M over 4 years |
| Timeline | 48 months |
| Cross-Disease Value | High — applies to vascular dementia, PD |
| Component | Cost (USD) |
|---|---|
| Clinical operations | $6M |
| MRI (2500 scans) | $3M |
| Biomarker assays | $3M |
| Data analysis | $2M |
| Intervention supplies | $2M |
| Risk | Mitigation |
|---|---|
| Confounding by comorbidities | Careful exclusion criteria |
| Variable vascular assessment | Standardized protocols |
| Intervention interactions | Factorial design |