Targeted elimination of senescent brain cells using dasatinib + quercetin (D+Q) senolytic therapy will reduce neuroinflammation, slow amyloid-beta accumulation, and preserve cognitive function in early-stage Alzheimer's disease patients.
Core mechanistic prediction: Senolytic clearance of senescent astrocytes and microglia will reduce CSF SASP factors by >40% at 12 weeks — demonstrating proof of mechanism — which will correlate with reduced amyloid PET progression at 24 weeks.
No completed Phase II RCT has evaluated whether senolytic therapy modifies AD pathophysiology in humans. The completed NCT03415087 Phase I trial established safety but was not powered for efficacy endpoints[1]. This experiment addresses the critical gap between preclinical proof and clinical validation.
The mechanistic rationale rests on four converging lines of evidence:
Phase IIa rather than Phase I: Safety of D+Q is already established from oncology (dasatinib) and aging trials (D+Q in NCT02848131). Proceeding directly to Phase IIa allows efficacy signal detection with a small 60-patient cohort.
SASP composite as primary endpoint: Measuring SASP biomarkers (IL-6, IL-8, TNF-α, CXCL1, MMP-3) in plasma and CSF provides a mechanistic read-out that directly tests the hypothesized mechanism. This is more proximal to the drug's action than cognitive endpoints.
Early AD population: Patients with MCI due to AD or mild AD dementia (CDR 0.5-1) have moderate amyloid burden and functional reserve — optimal for senolytic intervention. Advanced AD patients have floor effects and overwhelming pathology.
| Parameter | Value |
|---|---|
| Total sample size | 60 participants (30 active, 30 placebo) |
| Randomization | 1:1, stratified by age (60-70, 71-80) and baseline amyloid PET |
| Duration | 24 weeks treatment, 12-week follow-off |
| Setting | 4 academic memory clinics in US |
| Target enrollment | 15 months |
| Arm | Intervention | Dose | Schedule |
|---|---|---|---|
| Active | Dasatinib + Quercetin | 100mg + 1000mg | Oral, 3 consecutive days/week |
| Placebo | Matching placebo | — | Same schedule |
Dosing rationale: The 3-days/week intermittent schedule was chosen based on:
Measurement: Composite of plasma and CSF SASP factors at baseline, week 12, and week 24.
| Biomarker | Matrix | Assay |
|---|---|---|
| IL-6 | Plasma + CSF | Simoa |
| IL-8 | Plasma + CSF | Simoa |
| TNF-α | Plasma + CSF | Simoa |
| IL-1β | Plasma + CSF | Simoa |
| CXCL1 | Plasma | Simoa |
| MMP-3 | Plasma | ELISA |
Primary analysis: Percent change from baseline to week 12 in composite z-score. Week 12 (mid-treatment) is the primary timepoint because it captures peak senolytic effect before potential compensatory upregulation.
Hypothesis: D+Q will reduce composite SASP by ≥40% at week 12 vs. placebo.
Measurement: [^11C]PiB or [^18F]florbetapir PET at baseline and week 24.
Primary analysis: Change in global cortical SUVR from baseline to week 24.
Hypothesis: D+Q will reduce amyloid PET progression by ≥25% vs. placebo (reduced slope).
Primary endpoint (SASP composite):
Secondary endpoint (amyloid PET):
| Endpoint | Test | Model |
|---|---|---|
| SASP composite (primary) | ANCOVA | Change from baseline ~ treatment + baseline + stratification vars |
| Amyloid PET (primary) | Mixed model | Repeated measures with time × treatment interaction |
| CDR-SB (secondary) | MMRM | As above |
| Safety | Descriptive | AE incidence, lab abnormality rates |
| Biomarker correlation | Pearson/Spearman | SASP change vs. amyloid PET change |
Multiplicity control: Two primary endpoints evaluated at α=0.025 (one-sided). Secondary endpoints at α=0.05 with Hochberg correction.
| Milestone | Estimated Time |
|---|---|
| Protocol finalization and IRB approval | Month 0-3 |
| Site activation and enrollment start | Month 3-4 |
| First patient enrolled | Month 4 |
| Last patient enrolled | Month 18 |
| Primary endpoint readout (week 24) | Month 22 |
| Data lock and primary analysis | Month 24 |
| Follow-off completion | Month 27 |
| Final clinical report | Month 30 |
Total duration: ~30 months from protocol to final report
| Risk | Likelihood | Mitigation |
|---|---|---|
| D+Q insufficient BBB penetration | Moderate | Use highest tolerable dose; include CSF sampling to measure exposure |
| Thrombocytopenia | Low-Moderate | Biweekly CBC monitoring; dose hold criteria |
| Placebo response confounding | Moderate | Stratified randomization; objective biomarker co-primary |
| Slow enrollment | Moderate | 4 high-volume memory clinics; pre-screened patient pools |
| Insufficient mechanistic effect | Moderate | SASP endpoint designed to detect even partial senolytic activity |
Dasatinib+Quercetin in Alzheimer's Disease (D+Q AD). 2022. ↩︎ ↩︎
Musi N, Valentine JM, Sickora KR, et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018. ↩︎
Bussian TJ, Aziz A, Meyer CF, et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature. 2018. ↩︎ ↩︎
Chen X, Liu Y, Zhang P, et al. Senolytic targeting of microglia reduces amyloid-beta burden in 5xFAD mice. Nat Neurosci. 2024. ↩︎ ↩︎
Dasatinib+Quercetin in Parkinson's Disease (D+Q PD). 2022. ↩︎