This experiment addresses the critical AD knowledge gap: "What triggers the switch from normal aging to AD?" (ranked #2 in AD Knowledge Gaps with 30 points). Identifying this trigger point could enable prevention rather than treatment.
Related: AD Knowledge Gap #2 | AD Cure Roadmap | Aging Mechanisms
What is the molecular event that transforms age-related cognitive decline into Alzheimer's disease pathology? Is there a specific threshold or cascade that constitutes the "point of no return"?
The transition from normal aging to AD is triggered by one or more of the following:
Recruit participants from three complementary cohorts:
| Cohort | N | Purpose | Timeline |
|---|---|---|---|
| Preclinical AD | 500 | Biomarker trajectory before symptoms | 5 years |
| Early MCI | 300 | Identify transition events | 3 years |
| Normal Aging Control | 200 | Baseline comparison | 5 years |
Primary Measures:
Sampling: Baseline, 6, 12, 24 months
Approach: Use systems biology to identify cascade events
In vitro validation:
In vivo validation:
| System | Use | Strength |
|---|---|---|
| Human longitudinal cohorts | Primary data | Direct relevance |
| iPSC neurons | Mechanism testing | Patient-specific |
| 5xFAD/APP/PS1 mice | In vivo validation | Established models |
| Cerebral organoids | Developmental context | Human-relevant |
| Factor | Assessment |
|---|---|
| Technical Feasibility | High — all biomarkers available |
| Recruitment Feasibility | Moderate — ADNI, local registries |
| Cost Estimate | $15-20M over 5 years |
| Timeline | 60 months for initial results |
| Cross-Disease Value | High — applicable to other neurodegenerative diseases |
| Component | Cost (USD) |
|---|---|
| Clinical operations (3 cohorts, n=1000) | $8M |
| PET imaging (4000 scans) | $4M |
| MRI (5000 scans) | $2M |
| Biomarker assays | $3M |
| Multi-omics | $2M |
| Data analysis | $1M |
| Risk | Mitigation |
|---|---|
| Insufficient converters | Enrich with MCI participants |
| Biomarker variability | Use multiple platforms |
| Irreversible damage | Focus on pre-symptomatic detection |