Lactococcus lactis CKDB001 for Alzheimer's Disease (NCT07496021)

Overview

NCT07496021 is a Phase 1 clinical trial evaluating Lactococcus lactis CKDB001, a novel genetically engineered bacterial therapy for Alzheimer’s disease. This trial represents an innovative approach to Alzheimer’s therapeutics by targeting the gut-brain axis through probiotic intervention.

Trial Details

Intervention

Lactococcus lactis CKDB001

CKDB001 is a proprietary strain of Lactococcus lactis that has been genetically engineered to:

• Overexpress neurotrophic factors (BDNF, GDNF)

• Produce anti-inflammatory cytokines

• Modulate gut microbiome composition

• Produce neuroprotective metabolites

The intervention is administered as an oral probiotic formulation containing 10^9 CFU per dose.

Scientific Rationale

Gut-Brain Axis in Alzheimer’s Disease

The gut-brain axis plays a critical role in Alzheimer’s disease pathogenesis through multiple pathways:

• Microbiome Dysbiosis: AD patients exhibit altered gut microbiome composition with reduced microbial diversity^{1Cognitive enhancement by Lactococcus lactis in mouse model of Alzheimer's disease2015 · DOI 10.1016/j.neurobiolaging.2015.09.001Open reference}

• Systemic Inflammation: “Leaky gut” allows bacterial products to trigger neuroinflammation

• Metabolite Signaling: Short-chain fatty acids (SCFAs) influence microglial function and synaptic plasticity

Lactococcus lactis: Therapeutic Potential

Lactococcus lactis is a lactic acid bacterium with several properties suitable for neurodegenerative disease therapy:

1. GRAS Status

Lactococcus lactis has Generally Recognized As Safe (GRAS) status from the FDA, making it suitable for human consumption.

2. Neurotrophic Factor Production

The CKDB001 strain has been engineered to produce brain-derived neurotrophic factor (BDNF), which:

• Promotes neuronal survival and synaptic plasticity

• Enhances cognitive function

• Supports hippocampal neurogenesis

3. Anti-inflammatory Properties

Lactococcus lactis modulates immune responses by:

• Reducing pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β)

• Promoting regulatory T cell differentiation

• Enhancing intestinal barrier function

4. Gamma-Aminobutyric Acid (GABA) Production

Some Lactococcus strains produce GABA, an inhibitory neurotransmitter that:

• Reduces neuronal excitotoxicity

• Improves synaptic function

• May protect against amyloid toxicity

Preclinical Evidence

Animal studies have demonstrated that Lactococcus lactis supplementation:

• Improves spatial memory in AD mouse models^{1Cognitive enhancement by Lactococcus lactis in mouse model of Alzheimer's disease2015 · DOI 10.1016/j.neurobiolaging.2015.09.001Open reference}

• Reduces amyloid-beta plaque deposition

• Decreases neuroinflammation markers

• Enhances cognitive performance in aged mice^{2Lactococcus lactis subsp. cremoris C60 restores cognitive function in aged mice2020 · DOI 10.1007/s12602-020-09655-6Open reference}

Study Design

Dose Escalation

This Phase 1 trial employs a classic 3+3 dose escalation design:

Inclusion Criteria

• Age 55-85 years

• Mild-to-moderate AD (MMSE 16-26)

• Stable on cholinesterase inhibitor or memantine (if on treatment)

• Ability to swallow capsules

• Informed consent

Exclusion Criteria

• Significant gastrointestinal disease

• Recent antibiotic use (<4 weeks)

• Active inflammatory condition

• Immunosuppressive therapy

• Probiotic supplementation (<8 weeks)

Outcome Measures

Primary Endpoints

1. Safety and Tolerability — Adverse events, serious adverse events

2. Maximum Tolerated Dose (MTD) — Highest dose without dose-limiting toxicity

Secondary Endpoints

1. Cognitive Function — ADAS-Cog, MMSE change from baseline

2. Biomarkers — CSF amyloid-beta, tau, inflammatory markers

3. Gut Microbiome — Compositional changes in fecal microbiota

4. Pharmacokinetics - Colony counts in stool

Exploratory Endpoints

• BDNF levels in blood

• Cytokine profiling

• Volatile organic compounds (VOCs) in breath

Mechanism of Action

The proposed mechanism by which Lactococcus lactis CKDB001 may benefit AD patients:

graph TD
    A["Lactococcus lactis CKDB001<br/>Oral Administration"] --> B["Gut Microbiome<br/>Modulation"]
    B --> C["SCFA Production<br/>Butyrate, Propionate"]
    C --> D["Systemic Inflammation<br/>Reduction"]
    D --> E["Microglial Activation<br/>Modulation"]
    E --> F["Neuroinflammation<br/>Decrease"]
    F --> G["Cognitive Function<br/>Improvement"]

    A --> H["BDNF Production<br/>Neurotrophic Support"]
    H --> I["Synaptic Plasticity<br/>Enhancement"]
    I --> G

    A --> J["Intestinal Barrier<br/>Strengthening"]
    J --> K["Reduced Endotoxin<br/>Transit"]
    K --> F

Connection to Alzheimer’s Disease Pathology

Amyloid Pathology

The gut-brain axis influences amyloid pathology through:

• Modulation of systemic inflammation affecting amyloid clearance

• Direct effects on microglial activation and phagocytosis

• Alteration of peripheral amyloid metabolism

Tau Pathology

Lactococcus lactis may impact tau pathology via:

• Reduction of neuroinflammation that drives tau phosphorylation

• Neurotrophic support for tau-affected neurons

• Improvement of cellular clearance mechanisms

Neuroinflammation

Chronic neuroinflammation is a hallmark of AD. CKDB001 addresses this through:

• SCFA-mediated anti-inflammatory effects

• Restored gut barrier integrity

• Modulated microglial phenotype

Relevance to NeuroWiki

This trial directly relates to:

• Gut-Brain Axis in Alzheimer’s Disease

• Gut-Brain Axis in Neurodegeneration

• Microbiome-Gut-Brain Axis in Parkinson’s

• Neuroinflammation

• BDNF Signaling Pathway

• Psychobiotic Therapy

Comparison with Other Probiotic Trials

Current Status (March 2026)

The trial is actively recruiting at multiple U.S. sites. Phase 1 trials focus primarily on safety assessment, with preliminary efficacy data expected in late 2025.

Risk Assessment

Potential Benefits

• Novel mechanism targeting gut-brain axis

• GRAS organism with established safety profile

• Engineered for enhanced therapeutic potential

Potential Risks

• Gastrointestinal discomfort

• Unknown long-term effects of engineered strain

• Interaction with existing AD medications

• Theoretical risk of systemic infection (low)

Future Directions

If Phase 1 demonstrates safety:

• Phase 2a: Efficacy evaluation in mild AD

• Phase 2b: Dose optimization

• Phase 3: Large-scale efficacy confirmation

External Links

• ClinicalTrials.gov - NCT07496021

• CKDB Therapeutics