Senolytic Therapy (D+Q) Phase IIa Trial in Early Alzheimer's Disease

Hypothesis

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.

Hypothesis

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](/entities/astrocytes) and [microglia](/entities/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.

Rationale for Design

Knowledge Gap

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[@nct03415087]. This experiment addresses the critical gap between preclinical proof and clinical validation.

Preclinical Foundation

The mechanistic rationale rests on four converging lines of evidence:

Design Decisions

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.

Experimental Design

Phase IIa Randomized, Double-Blind, Placebo-Controlled Trial

| 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 |

Treatment Arms

| 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:

• Preclinical data showing maximum senolytic effect with intermittent exposure
• Human aging trials (NCT02848131) establishing safety at this regimen
• Pharmacokinetic modeling: dasatinib half-life 3-5h, quercetin 11-16h — 3 consecutive days on, 4 days off allows "off-target" recovery

Inclusion Criteria

• Age 60-80 years
• Clinical diagnosis: MCI due to AD or mild AD dementia (NIA-AA criteria)
• MMSE score 20-28
• [Amyloid-beta](/proteins/amyloid-beta) PET positive (Centiloid ≥ 40)](/proteins)
• [Tau](/proteins/tau) PET positive (Braak I-III) — ensures AD pathology
• Stable on acetylcholinesterase inhibitor for ≥3 months (if applicable)
• No recent (6-month) immunotherapy or antineoplastic treatment
• MRI with no prohibited lesions ( Strategically acquired hippocampal sclerosis, tumor, etc.)

Exclusion Criteria

• Prior senolytic, anti-amyloid, or anti-tau immunotherapy
• Active malignancy within 3 years
• Hematologic disorder (platelets < 100,000/μL)
• Severe liver or renal disease
• Current anticoagulant or antiplatelet therapy (increased bleeding risk with dasatinib)
• Active infection or inflammatory disease
• Known hypersensitivity to dasatinib or quercetin
• BRCA mutation or BRCA1/2-related cancer history

Key Safety Monitoring

• Platelet count every 4 weeks (dasatinib thrombocytopenia risk)
• Complete blood count biweekly for first 8 weeks, then monthly
• Adverse events reviewed by independent data safety monitoring board (DSMB) at 8-week intervals

Endpoints

Primary Endpoints

1. SASP Biomarker Composite (Mechanistic)

| 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.

2. Amyloid PET SUVR (Disease Modification)

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).

Secondary Endpoints

Clinical Measures

• CDR-SB at weeks 0, 12, 24, 36: Global cognition and function
• ADAS-Cog14 at weeks 0, 12, 24, 36: Detailed cognitive battery
• MMSE at weeks 0, 12, 24, 36: Screening cognitive measure
• ADCS-MCI-ADL at weeks 0, 12, 24, 36: Daily living function

Biomarker Measures

• CSF Aβ42/40 ratio: Amyloid pathway
• CSF p-tau181, p-tau217: Tau pathology
• CSF neurofilament light chain (NfL): Neurodegeneration
• Plasma GFAP: Astrocyte activation
• Plasma NfL: Neurodegeneration
• 18F-MK-6240 tau PET: Regional tau burden (subset, n=20)

Mechanistic Biomarkers

• Peripheral blood senescent cell burden: p16^INK4a mRNA in PBMCs (qPCR)
• Senescence-associated secretory phenotype: as primary
• Cellular senescence PET tracer: [18F]DMF pilot sub-study (n=10, optional)

Exploratory Endpoints

• CSF proteomics (Olink) at baseline and week 24: Systems-level pathway changes
• Neuroimaging: Structural MRI (hippocampal volume), FDG-PET (glucose metabolism)
• Gut microbiome: Fecal sample analysis at baseline and week 24

Statistical Analysis

Sample Size Justification

Primary endpoint (SASP composite):

• Assuming 40% reduction in active vs. 10% reduction in placebo (30% difference)
• Standard deviation: 0.5 (standardized effect size d = 0.6)
• α = 0.025 (one-sided, Bonferroni for two primary endpoints)
• Power = 80%
• Required n = 27 per arm; enrolling 30 per arm (60 total) for 10% dropout buffer

• Detectable effect size with n=60: ≥25% reduction in progression slope
• Will be interpreted as supportive rather than confirmatory given Phase IIa scope

Analysis Plan

| 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.

Timeline

| 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 Assessment

| 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 |

Connection to Prior and Ongoing Work

• NCT03415087 (D+Q AD Phase I): Established safety in 32 AD patients — this trial builds on safety data[@nct03415087]
• NCT04685590 (D+Q PD Phase I/II): Parallel senolytic AD trial in Parkinson's[@nct04685590]
• Bussian et al. 2018: Preclinical proof that senolytic clearance prevents tau pathology[@bussian2018]
• Chen et al. 2024: Preclinical evidence that D+Q reduces amyloid burden in 5xFAD mice[@chen2024]

Related Pages

• [Cellular Senescence as AD Driver (Hypothesis)](/hypotheses/cellular-senescence-alzheimers)](/hypotheses)
• [Dasatinib + Quercetin (D+Q) for Neurodegeneration](/therapeutics/dasatinib-quercetin-senolytic)](/therapeutics)
• [Senolytic Therapies for Neurodegeneration](/therapeutics/senolytic-therapies-neurodegeneration)](/therapeutics)
• [AD Combination Therapy Trial: Anti-Aβ + Anti-Tau](/experiments/ad-combination-therapy-trial)

Pathway Diagram

The following diagram shows the key molecular relationships involving Senolytic Therapy (D+Q) Phase IIa Trial in Early Alzheimer's Disease discovered through SciDEX knowledge graph analysis: