Overview
Cross-system analysis of neurodegenerative diseases has generated hypotheses about disease connections, drug repurposing, and prevention strategies. These build on foundational work in neuroscience and geriatric medicine spanning decades.
The Challenge
Neurodegenerative diseases remain largely incurable. Even modest improvements in prevention or treatment could transform public health, given the scale of the aging population.
The Hypotheses
1
CV-Alzheimer's Inflammation Connection
Observation: Major CV and AD risk genes share biological characteristics related to inflammation.
Prediction: CV inflammation treatments may reduce AD risk or slow progression.
Testable: Analyze AD incidence in patients on PCSK9 inhibitors or anti-inflammatory CV drugs.
2
Protein Aggregation Convergence
Observation: Alzheimer's (tau) and Parkinson's (synuclein) both involve protein aggregation.
Prediction: Therapies targeting aggregation in one disease may help the other.
Testable: Test anti-tau antibodies in Parkinson's models; anti-synuclein in AD models.
3
Anti-Amyloid Antibody Response Prediction
Observation: Lecanemab, aducanumab, and donanemab show varying efficacy.
Prediction: Baseline biomarkers can predict which patients respond to which antibody.
Testable: Stratify trial data by inflammation, APOE status, and amyloid burden.
4
Microglial-Targeted Therapy
Observation: TREM2 and APOE both affect microglial function and share characteristics.
Prediction: TREM2 agonists may show different efficacy in APOE4 vs non-carriers.
Testable: Stratify TREM2-targeted trials by APOE genotype.
5
Statin-Dementia Connection
Observation: Epidemiological studies show mixed results on statins and dementia.
Prediction: Specific statins may be protective based on their biological characteristics.
Testable: Compare dementia incidence across different statins in registry data.
6
ALS Drug Repurposing
Observation: Tofersen (SOD1-ALS) shares characteristics with drugs from other fields.
Prediction: Some cancer or CV drugs may show unexpected ALS benefit.
Testable: Screen approved drugs with similar characteristics in ALS models.
7
PD-AD Comorbidity
Observation: Parkinson's and Alzheimer's share protein aggregation characteristics.
Prediction: Patients with one disease are at elevated risk for the other.
Testable: Analyze comorbidity rates and shared genetic risk.
Research Priority Matrix
| Hypothesis | Data Required | Feasibility | Impact |
|---|---|---|---|
| H1: CV-AD inflammation | Registry data | High | Very High |
| H2: Aggregation convergence | Preclinical | Moderate | Very High |
| H3: Anti-amyloid prediction | Trial data | High | High |
| H4: Microglial therapy | Stratified trials | Moderate | High |
| H5: Statin-dementia | Registry data | High | High |
| H6: ALS repurposing | Drug screening | Moderate | Very High |
| H7: PD-AD comorbidity | Epidemiology | High | Moderate |
Potential Impact
65+ million people live with neurodegenerative disease. These conditions are currently incurable.
If these hypotheses lead to even modest improvements:
- Delay onset by 5 years = 50% reduction in prevalence
- Slow progression = millions of quality life years
- Prevention strategies = transform public health
Collaboration Invitation
We seek partnerships with:
- AD/PD clinical trial networks
- Neuroimaging consortia
- Biobank databases with cognitive outcomes
- Drug repurposing platforms