Senolytic Therapy (D+Q) Phase IIa Trial in Early Alzheimer's Disease
Background and Rationale
This Phase IIa clinical trial evaluates the therapeutic potential of senolytic therapy using dasatinib plus quercetin (D+Q) in early Alzheimer's disease patients, targeting the senescence-associated secretory phenotype (SASP) that contributes to neuroinflammation and cognitive decline. Cellular senescence accumulates in the aging brain and is accelerated in AD, with senescent cells secreting pro-inflammatory cytokines, chemokines, and proteases that damage surrounding healthy neurons and promote tau and amyloid pathology. The D+Q combination has demonstrated selective elimination of senescent cells in preclinical models and shown promise in age-related conditions. This randomized, double-blind, placebo-controlled trial will assess the safety and preliminary efficacy of intermittent D+Q treatment in patients with mild cognitive impairment or mild AD dementia. The study incorporates comprehensive biomarker analysis including SASP factors (IL-6, TNF-α, IL-1β), neuroinflammation markers, and senescence indicators (p16INK4a, p21) in blood and cerebrospinal fluid.
...Senolytic Therapy (D+Q) Phase IIa Trial in Early Alzheimer's Disease
Background and Rationale
This Phase IIa clinical trial evaluates the therapeutic potential of senolytic therapy using dasatinib plus quercetin (D+Q) in early Alzheimer's disease patients, targeting the senescence-associated secretory phenotype (SASP) that contributes to neuroinflammation and cognitive decline. Cellular senescence accumulates in the aging brain and is accelerated in AD, with senescent cells secreting pro-inflammatory cytokines, chemokines, and proteases that damage surrounding healthy neurons and promote tau and amyloid pathology. The D+Q combination has demonstrated selective elimination of senescent cells in preclinical models and shown promise in age-related conditions. This randomized, double-blind, placebo-controlled trial will assess the safety and preliminary efficacy of intermittent D+Q treatment in patients with mild cognitive impairment or mild AD dementia. The study incorporates comprehensive biomarker analysis including SASP factors (IL-6, TNF-α, IL-1β), neuroinflammation markers, and senescence indicators (p16INK4a, p21) in blood and cerebrospinal fluid. Advanced neuroimaging including tau PET and structural MRI will assess treatment effects on AD pathology and brain atrophy. This groundbreaking study represents the first clinical application of senolytic therapy in neurodegenerative disease and could establish a new therapeutic paradigm for AD treatment by targeting fundamental aging mechanisms.
This experiment directly tests predictions arising from the following hypotheses:
- Senescent Microglia Resolution via Maresins-Senolytics Combination
- SASP-Mediated Complement Cascade Amplification
- Senescence-Activated NAD+ Depletion Rescue
- Senescent Cell Mitochondrial DNA Release
- Senescence-Associated Myelin Lipid Remodeling
Experimental Protocol
Phase 1: Screening and Baseline Assessment (Weeks -4 to 0)• Screen 200 potential participants aged 60-85 with mild cognitive impairment or early AD (CDR 0.5-1.0)
• Confirm amyloid positivity via PET imaging (Centiloid >20) or CSF Aβ42/40 ratio <0.067
• Obtain comprehensive neuropsychological battery (ADAS-Cog, MMSE, CDR-SB, FAQ)
• Collect baseline blood biomarkers: p16INK4a, p21, IL-6, TNF-α, SASP factors
• Perform baseline brain MRI with volumetric analysis and DTI sequences
• Lumbar puncture for CSF collection: Aβ40, Aβ42, tau, p-tau181, neurofilament light
• Randomize 120 eligible participants 1:1 to D+Q vs placebo arms (n=60 each)
Phase 2: Treatment Period (Weeks 1-24)
• Administer dasatinib 100mg + quercetin 1000mg orally for 2 consecutive days every 4 weeks (6 cycles total)
• Placebo group receives matched capsules on same schedule
• Safety monitoring every 2 weeks: CBC, comprehensive metabolic panel, liver enzymes
• Cognitive assessments at weeks 4, 8, 12, 18, and 24
• Blood biomarker collection at weeks 4, 12, and 24
• Brain MRI at week 12 and 24
• Adverse event monitoring throughout treatment period
Phase 3: Follow-up Assessment (Week 26)
• Final comprehensive neuropsychological testing
• CSF collection via lumbar puncture for biomarker analysis
• Final safety laboratory assessments
• Brain MRI with advanced sequences for volumetric and connectivity analysis
• Quality of life assessments (QoL-AD, EQ-5D-5L)
Phase 4: Extended Follow-up (Weeks 30, 38, 50)
• Telephone cognitive screening (TICS-M) and safety check-ins
• Blood biomarker collection at week 50
• Long-term safety and efficacy monitoring
Expected Outcomes
Cognitive Function Preservation: D+Q group will show 30% slower decline in ADAS-Cog scores compared to placebo (effect size Cohen's d ≥ 0.5) at 24 weeks
Senescence Biomarker Reduction: Significant decrease in circulating p16INK4a+ cells (≥40% reduction) and SASP factors (IL-6, TNF-α) in D+Q group vs placebo (p<0.05)
Neuroinflammation Suppression: CSF inflammatory markers (YKL-40, sTREM2) will decrease by ≥25% in D+Q group while remaining stable or increasing in placebo group
Amyloid Pathology Stabilization: CSF Aβ42/40 ratio will remain stable or improve (≥10% increase) in D+Q group vs continued decline in placebo group
Brain Volume Preservation: Hippocampal volume loss will be reduced by ≥50% in D+Q group compared to placebo as measured by MRI volumetrics
Safety Profile: Incidence of serious adverse events will remain <10% with no treatment-related deaths or permanent disabilitySuccess Criteria
•
Primary Efficacy Endpoint: Statistically significant difference (p<0.05) in ADAS-Cog change from baseline between D+Q and placebo groups at week 24, with effect size ≥0.4
• Biomarker Validation: ≥2 of 3 key biomarker categories (senescence markers, neuroinflammation, amyloid pathology) show significant improvement (p<0.05) in D+Q vs placebo
• Safety Threshold: Treatment-emergent serious adverse events <15% in D+Q group with no more than 2-fold increase vs placebo group
• Sample Size Achievement: Minimum 50 evaluable participants per group (83% retention rate) with complete primary endpoint data
• Dose Completion: ≥80% of D+Q participants complete at least 4 of 6 treatment cycles without dose-limiting toxicities
• Biomarker Response: ≥60% of D+Q participants show ≥20% reduction in at least one senescence biomarker (p16INK4a or SASP factors) by week 24