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 (AD) who exhibit 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.
| 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 |
- 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
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 and microglia accumulate specifically in regions with tau pathology
- Genetic clearance of senescent cells prevents tau-dependent pathology and cognitive decline
- Tau-bearing neurons display senescence-associated transcriptomic signatures
Selecting participants with established tau pathology ensures the study population has a biological rationale for senolytic intervention.
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 (BBB) in the SToMP-AD trial (CSF:plasma ratio 0.42–0.92%)
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
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.
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 dysfunction
In AD, tau pathology directly drives senescence — tau-bearing neurons upregulate p16INK4a and p21, adopt SASP, and create a pro-inflammatory microenvironment.
Senescent cells are protected from 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.
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
- Safety and Tolerability: Assessment of adverse events, serious adverse events, and laboratory abnormalities
- Feasibility: Ability to complete the full treatment course
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, tau)
- Senescence markers (p16INK4a expression in peripheral blood mononuclear cells)
- Physical function: Gait speed, grip strength
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 |
- 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 monitoring
¶ Challenges and Limitations
- 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
- 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
- No validated biomarker exists for in vivo senescent cell burden
- Surrogate markers (p16 expression, SASP factors) may not accurately reflect brain senescence
- 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 indications
- 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