Alzheimer Disease Related Dementia
Conditions
Keywords
caregivers, Probiotic fermented milk, Gut microbiome, Gut-brain axis, Microbiome diversity, Nutrient absorption, Randomized controlled trial
Brief summary
This double-blind, randomized, placebo-controlled clinical trial will evaluate the effects of a probiotic fermented milk (PFM) drink on gut and brain health in individuals with Alzheimer's disease and related dementias (ADRD) and their caregivers. Up to 40 participants will be enrolled. Participants will be randomly assigned to consume either the PFM drink or a matched placebo daily for 30 days. The primary objective is to determine whether PFM consumption improves gut microbiome abnormalities. Secondary objectives include evaluating effects on nutrient absorption, gut microbiome diversity and composition, and systemic inflammation. The study will also explore relationships between changes in nutrient absorption, microbiome profiles, inflammation, and behavioral outcomes in participants with ADRD and their caregivers. Each participant will participate in the study for approximately 30 days. This pilot study is intended to generate preliminary clinical and biological data regarding the potential role of probiotic nutrition in supporting gut and brain health and to inform the design of future larger clinical trials.
Detailed description
This pilot clinical trial will investigate the effects of a human-origin probiotic fermented milk (PFM) beverage on biological pathways related to gut and brain health in individuals with Alzheimer's disease and related dementias (ADRD) and their caregivers. The study is based on evidence suggesting that alterations in the gut microbiome, nutrient metabolism, and systemic inflammation may be associated with cognitive and behavioral health and may represent modifiable targets in ADRD. Participants with ADRD and their caregivers will be enrolled as patient-caregiver dyads and independently randomized to receive either the PFM intervention or a matched placebo for 30 days. The PFM contains four human-origin probiotic strains: Limosilactobacillus reuteri HL278, Lactiplantibacillus plantarum HL279, Lacticaseibacillus paracasei HL260, and Lactiplantibacillus plantarum HL82. Biological assessments will be performed before and after the intervention to characterize changes in the gut microbiome, nutrient-related measures, and systemic inflammation. Fecal microbiome composition will be evaluated using metagenomic sequencing and bioinformatics approaches to examine microbial diversity and taxonomic composition. Blood- and stool-based laboratory analyses will be used to assess selected nutrient and inflammatory biomarkers. Clinical and behavioral measures will also be evaluated to explore whether biological changes associated with the intervention are related to measures of health, quality of life, agitation, stress, or anxiety in participants with ADRD and their caregivers. Analyses will compare changes between the PFM and placebo groups and explore relationships among microbiome characteristics, nutrient-related measures, inflammatory markers, and behavioral outcomes. The study is intended to generate preliminary information regarding the biological effects and feasibility of the PFM intervention and to provide data that may inform the design of larger future clinical trials.
Interventions
DIETARY_SUPPLEMENTProbiotic Fermented Milk (PFM) Drink
A human-origin probiotic fermented milk (PFM) drink has been developed for this clinical study. Over 1,000 human-derived probiotic strains were screened for gut and brain health effects using C. elegans, identifying 36 promising strains. These were further evaluated for growth in milk, fermentation capacity (pH reduction and coagulation), and effects on healthspan. Four strains with strong performance were selected: Limosilactobacillus reuteri HL278, Lactiplantibacillus plantarum HL279, Lacticaseibacillus paracasei HL260, and Lactiplantibacillus plantarum HL82. A multi-strain formulation was produced in a dedicated facility. The final PFM contains GRAS-designated probiotic strains and is manufactured for research use only in this study.
DIETARY_SUPPLEMENTPlacebo
Participants will receive two 4-ounce servings of a placebo drink daily for 30 days. The placebo drink is matched in taste, appearance, and volume but does not contain active probiotic components.
Sponsors
University of South Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double-blind, randomized, placebo-controlled clinical trial.
Intervention model description
ADRD and caregivers
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Diagnosed with ADRD and accompanied with their caregiver * Age ≥ 18 years old * Willing to consume PFM and/or willing to consume placebo drink, follow instructions of study team and sign consent form
Exclusion criteria
* Lactose intolerance or another intolerance that prevents the safe consumption of dairy products * Allergy to any ingredients in the PFM formulations, including almonds/nuts, lactose/dairy, dextrose, artificial sweeteners, or dyes used in flavoring * Known allergy or hypersensitivity to peanuts or soy, as indicated on the pectin product label. * Known allergy, intolerance, or hypersensitivity to Ensure® or any of its components. * Cancer patients receiving chemotherapy, due to potential increased risk of infection from GI tract damage * Participants who require systemic antibiotics after randomization will have the antibiotic use documented and will be withdrawn due to potential effects on the gut microbiome. Data collected prior to antibiotic use may be retained, and withdrawn participants will be replaced to maintain the target sample size. * Major surgery(ies) of the gut or brain within the past five years * Diagnosis of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, acid reflux, gastroesophageal reflux disease (GERD), Clostridium difficile infection (CDI), or any other gastrointestinal disease that could significantly change the microbiome History of fecal microbiota transplantation * Small intestinal bacterial overgrowth * History of anticipatory nausea, vomiting, constipation, or diarrhea * Antibiotic or probiotic or heavy yogurt (3 servings per day) use within the past 30 days o Probiotic use is defined as consumption of ≥108 CFU/day, in the form of tablets, capsules, lozenges, powders, or dairy products in which probiotics are a major ingredient * Critical or terminal illnesses including diabetes * Pregnant women will be excluded from the study based on self-report during the screening process. No pregnancy testing kits will be provided, and pregnancy testing will not be performed as part of this study. Therefore, individuals who are currently pregnant are excluded from participation. * Significant mental health conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gut Microbiome Shannon Diversity Index | Baseline and Day 30 | Change in gut microbiome alpha diversity from baseline to Day 30, quantified using the Shannon diversity index derived from whole-genome shotgun metagenomic sequencing of stool samples. A single change value will be calculated for each participant as the Day 30 Shannon diversity index minus the baseline Shannon diversity index. Unit of Measure: Shannon diversity index |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Stool Lipocalin-2 Concentration | Baseline and Day 30 | Change in stool lipocalin-2 concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: ng/g stool |
| Change in Stool Calprotectin Concentration | Baseline and Day 30 | Change in stool calprotectin concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: µg/g stool |
| Change in Serum Monocyte Chemoattractant Protein-1 Concentration | Baseline and Day 30 | Change in serum monocyte chemoattractant protein-1 (MCP-1) concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: pg/mL |
| Change in Serum Interleukin-1 Beta Concentration | Baseline and Day 30 | Change in serum interleukin-1 beta (IL-1β) concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: pg/mL |
| Change in Serum Tumor Necrosis Factor-Alpha Concentration | Baseline and Day 30 | Change in serum tumor necrosis factor-alpha (TNF-α) concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: pg/mL |
| Change in Serum Interleukin-6 Concentration | Baseline and Day 30 | Change in serum interleukin-6 (IL-6) concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: pg/mL |
| Change in Serum C-Reactive Protein Concentration | Baseline and Day 30 | Change in serum C-reactive protein (CRP) concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: µg/mL |
| Change in Serum Zinc Concentration | Baseline and Day 30 | Change in serum zinc concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: µg/dL |
| Change in Serum Iodine Concentration | Baseline and Day 30 | Change in serum iodine concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: µg/dL |
| Change in Serum Magnesium Concentration | Baseline and Day 30 | Change in serum magnesium concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: mg/dL |
| Change in Serum Folate Concentration | Baseline and Day 30 | Change in serum folate concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: ng/mL |
| Change in Serum Vitamin D3 Concentration | Baseline and Day 30 | Change in serum vitamin D3 concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: ng/mL |
| Change in Serum Vitamin B12 Concentration | Baseline and Day 30 | Change in serum vitamin B12 concentration from baseline to Day 30, calculated as the Day 30 value minus the baseline value. Unit: pg/mL |
| Gut Microbiome Beta Diversity Assessed by Bray-Curtis Dissimilarity | Baseline and Day 30 | Gut microbial community composition will be assessed at baseline and Day 30 using Bray-Curtis dissimilarity calculated from stool metagenomic sequencing data. Bray-Curtis dissimilarity will be used to evaluate differences in microbial community composition between intervention groups and study time points. Unit of Measure: Bray-Curtis dissimilarity |
| Change in EQ-5D Index Score in ADRD Participants | Baseline and Day 30 | Change in EuroQoL-5D (EQ-5D) health utility index score from baseline to Day 30 in participants with ADRD. Responses across the EQ-5D health dimensions will be converted to a single health utility index score according to the instrument scoring procedure. The outcome will be the Day 30 index score minus the baseline index score. Unit: EQ-5D index score |
| Change in Cohen-Mansfield Agitation Inventory Total Score | Baseline and Day 30 | Change in Cohen-Mansfield Agitation Inventory (CMAI) total score from baseline to Day 30 in participants with ADRD. Responses to individual CMAI items will be combined according to the instrument scoring procedure to generate one total agitation score at each time point. The outcome will be the Day 30 total score minus the baseline total score. Unit: CMAI total score |
| Change in Perceived Stress Scale Total Score in Caregivers | Baseline and Day 30 | Description: Change in Perceived Stress Scale (PSS) total score from baseline to Day 30 in caregivers. Individual PSS item responses will be combined according to the instrument scoring procedure to generate one total perceived stress score at each time point. The outcome will be the Day 30 total score minus the baseline total score. Unit: PSS total score |
| Change in State-Trait Anxiety Inventory State Anxiety Score | Baseline and Day 30 | Description: Change in the State-Trait Anxiety Inventory (STAI) State Anxiety score from baseline to Day 30 in caregivers. Responses to the State Anxiety items will be combined according to the instrument scoring procedure to generate one State Anxiety score at each time point. The outcome will be the Day 30 score minus the baseline score. Unit: STAI State Anxiety score |
| Change in State-Trait Anxiety Inventory Trait Anxiety Score | Baseline and Day 30 | Description: Change in the State-Trait Anxiety Inventory (STAI) Trait Anxiety score from baseline to Day 30 in caregivers. Responses to the Trait Anxiety items will be combined according to the instrument scoring procedure to generate one Trait Anxiety score at each time point. The outcome will be the Day 30 score minus the baseline score. Unit: STAI Trait Anxiety score |
Countries
United States
Contacts
CONTACTShalini Jain, PhD
CONTACTHariom Yadav, PhD
Outcome results
None listed