ALSENLITE: Senolytics for Alzheimer's Disease
Overview
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therapeutics_alsenlite_trial["ALSENLITE: Senolytics for Alzheimers Disease Tr"]
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therapeutics_alsenli_0["Trial Design"]
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therapeutics_alsenli_1["Key Eligibility Criteria"]
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therapeutics_alsenli_2["Rationale for Tau-PET Selection"]
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therapeutics_alsenli_3["Intervention: Dasatinib + Quercetin"]
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therapeutics_alsenli_4["Dasatinib"]
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therapeutics_alsenli_5["Quercetin"]
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...ALSENLITE: Senolytics for Alzheimer's Disease
Overview
Mermaid diagram (expand to render)
ALSENLITE (Alzheimer's Senolytics) is a Phase 1/2 open-label pilot clinical trial (NCT04785300) evaluating the safety, tolerability, and biomarker effects of intermittent dasatinib plus quercetin (D+Q) senolytic therapy in patients with mild cognitive impairment (MCI) or [Alzheimer's disease](/diseases/alzheimers-disease) (AD) who exhibit [tau](/proteins/tau)-PET biomarker positivity. The trial is conducted at Mayo Clinic in Rochester, Minnesota.
This trial represents a critical step in translating senolytic therapy from preclinical models to human neurodegenerative disease, building on strong evidence from tau transgenic mouse models demonstrating that clearance of p16INK4a-positive senescent cells prevents tau pathology, reduces neuroinflammation, and preserves cognitive function.
Trial Design
| Parameter | Details |
|-----------|---------|
| ClinicalTrials.gov ID | NCT04785300 |
| Phase | Phase 1/Phase 2 |
| Status | Active, not recruiting |
| Study Type | Interventional |
| Enrollment | 20 participants |
| Design | Open-label pilot |
| Sponsor | Mayo Clinic |
| Location | Rochester, Minnesota, United States |
| Intervention | Dasatinib + Quercetin (D+Q) |
| Dosing | Intermittent oral administration |
Key Eligibility Criteria
- Age: Adults with mild-to-moderate cognitive impairment
- Diagnosis: Mild Cognitive Impairment (MCI) or Alzheimer's disease
- Biomarker requirement: Tau-PET positivity (elevated tau pathology)
- Cognitive status: Mild-to-moderate disease severity
Rationale for Tau-PET Selection
The requirement for tau-PET biomarker positivity reflects the strong preclinical evidence linking tau pathology to cellular senescence in the brain. In the PS19 tau transgenic mouse model:
- p16INK4a-positive senescent [astrocytes](/entities/astrocytes) and [microglia](/cell-types/microglia-neuroinflammation) accumulate specifically in regions with tau pathology
- Genetic clearance of senescent cells prevents tau-dependent pathology and cognitive decline
- Tau-bearing [neurons](/entities/neurons) display senescence-associated transcriptomic signatures
Selecting participants with established tau pathology ensures the study population has a biological rationale for senolytic intervention.
Intervention: Dasatinib + Quercetin
Dasatinib
Dasatinib is an FDA-approved Src/tyrosine kinase inhibitor originally developed for chronic myeloid leukemia. As a senolytic, it:
- Inhibits Src kinase, a component of the senescent cell anti-apoptotic pathway (SCAP)
- Targets pro-survival networks involving BCL-2/BCL-XL, PI3K/AKT, and FOXO4-p53
- Has demonstrated ability to cross the [blood-brain barrier](/entities/blood-brain-barrier) (BBB) in the SToMP-AD trial (CSF:plasma ratio 0.42–0.92%)
Quercetin
Quercetin is a natural flavonoid with senolytic properties:
- Inhibits BCL-XL and other anti-survival pathways
- Acts synergistically with dasatinib to eliminate senescent cells
- Limitation: Poor CNS penetration; not detected in CSF in SToMP-AD trial
Dosing Strategy
The intermittent dosing regimen (2 days every 2 weeks) is designed to:
- Maximize senolytic efficacy while minimizing off-target effects
- Allow recovery of normal tissues between doses
- Reduce cumulative exposure to dasatinib-associated adverse effects
This schedule is based on preclinical PK/PD studies showing that senescent cells re-accumulate over time, requiring repeated dosing.
Mechanism of Action
Cellular Senescence in AD
Senescent cells accumulate in the aging brain and in neurodegenerative disease contexts through multiple mechanisms:
Replicative senescence: Telomere shortening with repeated cell division
Oncogene-induced senescence: Activated oncogenes (e.g., RAS) trigger arrest
Stress-induced premature senescence (SIPS): Oxidative stress, DNA damage, mitochondrial dysfunctionIn AD, tau pathology directly drives senescence — tau-bearing neurons upregulate p16INK4a and p21, adopt SASP, and create a pro-inflammatory microenvironment.
Senescent Cell Anti-Apoptotic Pathways (SCAPs)
Senescent cells are protected from [apoptosis](/entities/apoptosis) by upregulating:
- BCL-2/BCL-XL family: Anti-apoptotic proteins blocking mitochondrial cell death
- PI3K/AKT signaling: Pro-survival kinase cascade
- FOXO4-p53 interaction: Sequesters p53 in the nucleus, preventing pro-apoptotic transcription
- p38 MAPK pathway: Stress-responsive survival signaling
D+Q inhibits multiple SCAP nodes, tipping the balance toward apoptosis specifically in senescent cells.
SASP Reduction
By eliminating senescent cells, D+Q reduces:
- Pro-inflammatory cytokines (IL-6, IL-1β, TNF-α)
- Chemokines (MCP-1, MIP-1α)
- Proteases (MMP-3, MMP-9)
- Growth factors promoting pathology spread
This reduces neuroinflammation, restores microglial function, and may slow disease progression.
Primary and Secondary Endpoints
Primary Endpoints
Safety and Tolerability: Assessment of adverse events, serious adverse events, and laboratory abnormalities
Feasibility: Ability to complete the full treatment courseSecondary/Biomarker Endpoints
While specific outcomes are defined by the trial protocol, potential biomarkers assessed in senolytic AD trials include:
- Cognitive measures: MMSE, MoCA, ADAS-Cog, neuropsychological battery
- Neuroimaging: MRI volumetric analysis, tau-PET, amyloid-PET, FDG-PET
- Fluid biomarkers:
- Inflammatory markers (IL-6, TNF-α, MCP-1)
- Neurodegeneration markers ([NfL](/biomarkers/neurofilament-light-chain-nfl), tau)
- Senescence markers (p16INK4a expression in peripheral blood mononuclear cells)
- Physical function: Gait speed, grip strength
Clinical Context
Relationship to Other Senolytic Trials
ALSENLITE builds on earlier senolytic trials in aging and AD:
| Trial | Phase | Participants | Key Finding |
|-------|-------|--------------|-------------|
| SToMP-AD (NCT04063124) | Phase 1 | 5 early AD | D+Q safe; dasatinib detected in CSF |
| STAMINA | Pilot | 12 older adults with slow gait | D+Q safe; MoCA improved +2.0 points in low-baseline cognition |
| SToMP-AD Phase 2 (NCT04685590) | Phase 2 | Ongoing | Evaluating cognitive outcomes |
| ALSENLITE (NCT04785300) | Phase 1/2 | 20 MCI/AD with tau-PET+ | Focusing on tau-positive population |
Unique Features of ALSENLITE
Tau-PET selection: First AD senolytic trial to require tau-PET positivity, selecting patients with the strongest biological rationale
Mayo Clinic expertise: Running at a leading institution with strong neurodegeneration and aging research programs
Phase 1/2 design: Allows early efficacy signal detection while maintaining safety monitoringChallenges and Limitations
BBB Penetration
- Dasatinib shows modest CNS penetration
- Quercetin was not detected in CSF in SToMP-AD
- Strategies to improve CNS delivery include:
- Nanoparticle encapsulation
- Focused ultrasound-mediated BBB opening
- Development of CNS-targeted senolytic prodrugs
Safety Considerations
- Dasatinib can cause pleural effusions, cytopenias, QT prolongation
- Long-term senolytic effects in humans remain unknown
- Impact on beneficial senescent cells (wound healing, tumor surveillance) unclear
Biomarker Validation
- No validated biomarker exists for in vivo senescent cell burden
- Surrogate markers (p16 expression, SASP factors) may not accurately reflect brain senescence
Future Directions
Expected Outcomes
Safety data: Confirmation of D+Q tolerability in AD population
Biomarker signals: Preliminary evidence of reduced neuroinflammation or slowed tau progression
Dose refinement: Information to optimize D+Q dosing for CNS indicationsPlanned/Future Trials
- Phase 2b/3 trials: Larger, randomized, placebo-controlled trials if Phase 1/2 shows promise
- Combination approaches: Senolytics + anti-amyloid, anti-tau, or neuroprotective agents
- Earlier intervention: Testing in cognitively normal individuals with biomarker evidence of aging/senescence
See Also
- [Senolytics and Senotherapeutics in Neurodegeneration](/senolytics)
- [Cellular Senescence in Neurodegeneration](/mechanisms/cellular-senescence)
- [Neuroinflammation in Neurodegenerative Diseases](/mechanisms/neuroinflammation)
- [Tau Pathology in Alzheimer's Disease](/mechanisms/tau-hyperphosphorylation)
- [Aging and Neurodegeneration](/mechanisms/aging-neurodegeneration)
- [SToMP-AD Trial](/therapeutics/stomp-ad-trial)
- [mTOR Signaling in Neurodegeneration](/mechanisms/mtor-neurodegeneration)
- [cGAS-STING Pathway in Neurodegeneration](/mechanisms/cgas-sting-neurodegeneration)
External Links
- [ClinicalTrials.gov: ALSENLITE (NCT04785300)](https://clinicaltrials.gov/study/NCT04785300)
- [Mayo Clinic](https://www.mayoclinic.org/)
- [SenNet Consortium (NIH)](https://sennetconsortium.org/)
References
[Bussian et al., Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline, Nature, 2018 (2018)](https://pubmed.ncbi.nlm.nih.gov/30232451/)
[Musi et al., Tau protein aggregation is associated with cellular senescence in the brain, Aging Cell, 2018 (2018)](https://doi.org/10.1111/acel.12840)
[Zhu et al., The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell, 2015 (2015)](https://doi.org/10.1111/acel.12344)
[Unknown, Xu et quercetin improves physical function and extends lifespan, Aging Cell, 2018 (2018)](https://doi.org/10.1111/acel.12790)
[Unknown, Kirkland & Tchkonia, Clinical strategies for targeting senescent cells, Nature Reviews Drug Discovery, 2017 (2017)](https://pubmed.ncbi.nlm.nih.gov/29143842/)
[Childs et al., Senescent cells: an emerging target for diseases of ageing, Nature Reviews Drug Discovery, 2017 (2017)](https://pubmed.ncbi.nlm.nih.gov/28729727/)From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
- [Gamma entrainment therapy to restore hippocampal-cortical synchrony](/hypothesis/h-bdbd2120) — <span style="color:#81c784;font-weight:600">0.77</span> · Target: SST
- [Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservation](/hypothesis/h-856feb98) — <span style="color:#81c784;font-weight:600">0.73</span> · Target: BDNF
- [ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia](/hypothesis/h-seaad-v4-26ba859b) — <span style="color:#81c784;font-weight:600">0.73</span> · Target: ACSL4
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- [Cell-Type Specific TREM2 Upregulation in DAM Microglia](/hypothesis/h-seaad-51323624) — <span style="color:#81c784;font-weight:600">0.70</span> · Target: TREM2
- [GFAP-Positive Reactive Astrocyte Subtype Delineation](/hypothesis/h-seaad-56fa6428) — <span style="color:#81c784;font-weight:600">0.64</span> · Target: GFAP
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- [SIRT3-Mediated Mitochondrial Deacetylation Failure with PINK1/Parkin Mitophagy Dysfunction](/hypothesis/h-seaad-v4-5a7a4079) — <span style="color:#81c784;font-weight:600">0.62</span> · Target: SIRT3
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