ALSENLITE: Senolytics for Alzheimer's Disease Trial

ALSENLITE: Senolytics for Alzheimer's Disease

Overview

ALSENLITE: Senolytics for Alzheimer's Disease

Overview

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

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

Mechanism of Action

Cellular Senescence in AD

Senescent cells accumulate in the aging brain and in neurodegenerative disease contexts through multiple mechanisms:

In 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

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

Primary and Secondary Endpoints

Primary Endpoints

Secondary/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

Challenges 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

Planned/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

Related Hypotheses

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
• [Prefrontal sensory gating circuit restoration via PV interneuron enhancement](/hypothesis/h-62f9fc90) — <span style="color:#81c784;font-weight:600">0.72</span> · Target: PVALB
• [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
• [Excitatory Neuron Vulnerability via SLC17A7 Downregulation](/hypothesis/h-seaad-7f15df4c) — <span style="color:#81c784;font-weight:600">0.63</span> · Target: SLC17A7
• [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

Related Analyses:

• [Neuroinflammation resolution mechanisms and pro-resolving mediators](/analysis/SDA-2026-04-01-gap-014) &#x1f504;
• [Circuit-level neural dynamics in neurodegeneration](/analysis/SDA-2026-04-02-26abc5e5f9f2) &#x1f504;
• [Cell type vulnerability in Alzheimers Disease (SEA-AD transcriptomic data)](/analysis/SDA-2026-04-02-gap-seaad-v4-20260402065846) &#x1f504;
• [Tau propagation mechanisms and therapeutic interception points](/analysis/SDA-2026-04-02-gap-tau-prop-20260402003221) &#x1f504;
• [SEA-AD Gene Expression Profiling — Allen Brain Cell Atlas](/analysis/analysis-SEAAD-20260402) &#x1f504;