Probiotics in Mild Alzheimer's Disease (NCT06181513)

Overview

This clinical trial investigates whether probiotic supplementation can improve cognitive function and reduce neuroinflammation in patients with mild Alzheimer's disease (AD). The study targets the gut-brain axis as a modifiable pathway for neurodegeneration, based on emerging evidence that gut microbiota composition influences brain function and neuroinflammation[@Sampson2016][@bonfili2020].

The gut-brain axis is a bidirectional communication network connecting the gastrointestinal tract to the central nervous system. This communication occurs through multiple pathways including the vagus nerve, immune system signaling, microbial metabolites, and endocrine pathways. In neurodegenerative diseases, dysbiosis (imbalance in gut microbiota) has been associated with increased intestinal permeability ("leaky gut"), systemic inflammation, and neuroinflammation[@kim2021][@paoli2020].

Trial Details

Overview

This clinical trial investigates whether probiotic supplementation can improve cognitive function and reduce neuroinflammation in patients with mild Alzheimer's disease (AD). The study targets the gut-brain axis as a modifiable pathway for neurodegeneration, based on emerging evidence that gut microbiota composition influences brain function and neuroinflammation[@Sampson2016][@bonfili2020].

The gut-brain axis is a bidirectional communication network connecting the gastrointestinal tract to the central nervous system. This communication occurs through multiple pathways including the vagus nerve, immune system signaling, microbial metabolites, and endocrine pathways. In neurodegenerative diseases, dysbiosis (imbalance in gut microbiota) has been associated with increased intestinal permeability ("leaky gut"), systemic inflammation, and neuroinflammation[@kim2021][@paoli2020].

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT06181513 |
| Phase | Early Phase 1 |
| Status | Recruiting |
| Sponsor | University of Nicosia |
| Collaborator | Cyprus Institute of Neurology and Genetics |
| Principal Investigator | Nicoletta Nicolaou, Associate Professor |
| Enrollment | 40 patients |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel |
| Masking | Triple (Participant, Care Provider, Investigator) |
| Start Date | December 19, 2022 |
| Primary Completion | July 1, 2025 (Estimated) |
| Completion Date | December 1, 2025 (Estimated) |
| Duration | 16 weeks |
| Location | Nicosia, Cyprus |

Mechanism of Action

Gut-Brain Axis in Alzheimer's Disease

The probiotic intervention in this trial aims to modulate the gut-brain axis through multiple mechanisms:

Probiotic Strains

The trial uses Ultrabiotique Equilibre 30 Vitavea, containing:

• Lactobacillus paracasei: Supports immune regulation and may reduce pro-inflammatory cytokines
• Lactobacillus plantarum: Produces SCFAs (short-chain fatty acids) that have anti-inflammatory properties
• Lactobacillus rhamnosus: Modulates gut barrier function and reduces intestinal permeability
• Lactobacillus helveticus: Associated with improved cognitive function in preclinical studies
• Bifidobacterium breve: Supports gut homeostasis and immune function

Rationale

Preclinical studies in APP/PS1 transgenic mice (a model of AD) have shown that probiotic supplementation:

• Reduces systemic inflammatory markers (IL-6, TNF-α)[@bonfili2020]
• Improves performance on cognitive behavioral tests
• Modulates gut microbiota composition toward a healthier profile
• Reduces amyloid plaque burden in the hippocampus

Study Design

Arms

| Arm | Type | Description |
|-----|------|-------------|
| Probiotics | Experimental | 1 capsule daily of probiotic blend for 16 weeks |
| Placebo | Placebo Comparator | 1 capsule daily of placebo for 16 weeks |

Primary Outcome

• Measure: Level of inflammatory markers
• Description: Peripheral inflammation markers implicated in mild AD pathogenesis
• Pro-inflammatory: IL-6, IL-1β, CXCL2, NLRP3
• Anti-inflammatory: IL-10
• Timepoints: Baseline (week 0), end of study (week 16)
• Sample: Blood plasma

Secondary Outcomes

| Measure | Assessment | Timepoints |
|---------|------------|------------|
| Cognitive function | Mini-Mental State Examination (MMSE) | Week 0, Week 16 |
| Cognitive function | Montreal Cognitive Assessment (MoCA) | Week 0, Week 16 |
| Cognitive function | Rey-Osterrieth Complex Figure Test | Week 0, Week 16 |
| Cognitive function | Wechsler Abbreviated Scale of Intelligence (WASI) | Week 0, Week 16 |
| Neurophysiological activity | Electroencephalogram (EEG) | Week 0, Week 16 |
| Neurophysiological activity | Electrocardiogram (EKG) | Week 0, Week 16 |
| Microbiome profile | 16S rDNA gene sequencing | Week 0 |
| Dietary habits | Food Frequency Questionnaire (confounding) | Week 0 |

Eligibility Criteria

Inclusion Criteria

• Adults ≥65 years of age
• Able to provide informed consent
• MMSE scores 19-23 (mild AD)
• Approximately equal male:female ratio

Exclusion Criteria

• Inability to give consent
• Other neurological disease
• Relevant psychiatric disorders (e.g., major depression)
• Gastrointestinal/metabolic conditions
• History of alcohol/substance dependence
• Use of systemic antibiotics in the previous 6 months
• Corticosteroid use
• Immune stimulating medications
• Immunosuppressive agents
• Probiotics consumption in the previous 6 months
• Immunosuppression
• Structural heart disease
• Neutropenia
• Radiation
• Active intestinal disease

Contact Information

Principal Investigator: Nicoletta Nicolaou

• Email: [nicolaou.nic@unic.ac.cy](mailto:nicolaou.nic@unic.ac.cy)
• Phone: +357 2247 1903

• The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
• Contact: Ioanna Kousiappa
• Email: [ioannak@cing.ac.cy](mailto:ioannak@cing.ac.cy)

Scientific Significance

This trial addresses several key questions in AD therapeutics:

If successful, this approach could provide a simple, safe, and inexpensive adjunct therapy for AD patients.

References