Last Updated: 2026-03-25
**Verification (slot-7, 2026-03-25 03:50 PT): Research gap review - 48 pages reviewed
- All gap pages have proper YAML frontmatter with refs section
- 48/48 pages have pageId assigned (no orphans)
- All pages contain 2024-2026 references in refs section
- 41 pages have explicit 2024-2026 research updates in body text
- Pages with outdated references (2020-2022) verified to have more recent refs in frontmatter
- Overview page confirms active maintenance with 45+ gap pages tracked
- Status: All research gap pages up-to-date ✓
- ALS Motor Neuron Vulnerability: Added single-cell RNAseq advances, iPSC phenotypic screening, biomarker developments, gene therapy pipeline
- ALS Immune Signature Stratification: Added multi-modal immune profiling, CNS-peripheral immune axis, clinical trial endpoints, therapeutic implications
- C9orf72 ALS-FTD Phenotype Divergence: Added repeat length/phenotype correlation, DPR toxicity, therapeutic development, biomarker correlates
**Verification (slot-12, 2026-03-25 22:16 PT): Research gap review - cross-verification
- Confirmed 45+ gap pages exist in content/gaps/
- All major gap pages (AD, PD, ALS, FTD) have 2025-2026 Research Updates sections
- Overview page has YAML frontmatter with pageId and proper tags
- Last updated timestamp verified as current
- Status: All research gap pages verified up-to-date
Gap analysis index date updated.
This page provides an overview of knowledge gaps in neurodegenerative disease research, highlighting areas where evidence is lacking or insufficient.
¶ Mechanistic Understanding
| Gap | Disease | Evidence Status | Priority |
|-----|---------|----------------|----------|
| Protein spreading mechanisms | AD, PD, ALS | Limited | High |
| Cell-type vulnerability | All | Moderate | High |
| Genetic modifiers | AD, PD | Limited | Moderate |
| Early disease biology | All | Very limited | Very High |
| Gap |
Disease |
Impact |
Priority |
| Blood-brain barrier delivery |
All |
Major |
Very High |
| Combination therapy design |
AD, PD |
Major |
High |
| Genetic subtype targeting |
FTD, ALS |
Significant |
High |
| Repurposing screen |
All |
Moderate |
Moderate |
| Gap |
Disease |
Current State |
Priority |
| Early detection biomarkers |
All |
Emerging |
Very High |
| Patient stratification |
AD, PD |
Limited |
High |
| Long-term outcomes |
All |
Limited |
Moderate |
| Real-world evidence |
All |
Sparse |
Moderate |
- Preclinical detection: Biomarkers for preclinical AD
- Mechanism of progression: How disease spreads
- Resilience factors: Why some resist disease
- Therapeutic targets: Novel mechanisms beyond amyloid
| Area |
Evidence Level |
| Amyloid biology |
Strong |
| Tau biology |
Moderate |
| Neuroinflammation |
Limited |
| Metabolic dysfunction |
Emerging |
- Alpha-synuclein biology: Normal function, aggregation
- Genetic modifiers: Risk genes beyond LRRK2, GBA
- Non-motor biomarkers: Early detection
- Disease modification: Proven approaches
| Area |
Evidence Level |
| Dopaminergic system |
Strong |
| Alpha-synuclein |
Moderate |
| Glial involvement |
Limited |
| Circuit dysfunction |
Emerging |
- Sporadic ALS mechanisms: 90% of cases
- Biomarkers: Diagnosis, progression
- Combination therapies: Multi-target approaches
- Resilience factors: Why some progress slowly |
| Area |
Evidence Level |
| Genetic forms (SOD1, C9orf72) |
Strong |
| Sporadic ALS |
Very limited |
| Neuroinflammation |
Moderate |
| Metabolism |
Emerging |
- Blood-based biomarker validation
- Genetic risk score development
- Repurposing clinical trials
- Patient registry expansion
- Early intervention trials
- Combination therapy studies
- Precision medicine trials
- Digital biomarker validation
- Prevention trials
- Disease modification proofs
- Regenerative approaches
- Curative strategies
¶ Funding Landscape
| Area |
Funding Level |
Trend |
| Biomarkers |
High |
Increasing |
| Genetics |
Moderate |
Stable |
| Clinical trials |
High |
Stable |
| Basic mechanisms |
Low |
Decreasing |