Dynamic Response to Probiotics in Context of Alzheimer Disease: a Proof-of-concept Study (HISTEPPA)

HIgh Frequency Sampling to sTudy the Physiological Effect of Probiotics on Peripheral Markers of Alzheimer's Pathology: a Proof-of-concept Study

proof-of-concept study to adequately design a larger trial to investigate the effect of supplementation of a probiotic (SLAB51) on AD biomarker.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Dietary supplement: SLAB51

Detailed Description

BACKGROUND: A growing body of evidence suggests an effect of gut bacteria and their metabolites on brain health, including the development of neurodegenerative conditions and Alzheimer's disease (AD). Probiotic supplementation is commonplace in medicine but targeting the gut microbiome to prevent AD is poorly understood and little is known on the dynamic effects of probiotics on physiology.

AIM: This is a proof-of-concept study to adequately design a larger trial to investigate the effect of supplementation of a probiotic (SLAB51) on AD biomarker. The study will use a high frequency sampling to closely monitor the physiological dynamics as the result of low and high dose consumption of the probiotic.

METHODS: Study subjects will be three patients with prodromal AD between 60 and 80 years old and carrying the apolipoprotein E (APOE) e4 allele. Participants will sequentially receive no supplement (run-in), low and high doses of probiotics for five consecutive days with a washout period in-between. Blood and stools will be collected every day or every second days. The main readout will be the established plasma markers of AD, and more exploratory analysis will be performed on putative mediators of the gut-brain axis.

EXPECTED OUTCOME: Curves of dynamic change of the readouts will be built for each subject, and a model of the response will be estimated. The results of this project will help design a larger trial to identify the most promising analytes showing a dynamic response to probiotic consumption and better understand the link to the pathology.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland, 1205
    • Geneva University hospitals - Memory clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of mild cognitive impairment (MCI) due to AD, obtained from the clinical path of the participant in the memory clinic according to the criteria of Petersen et al. 1999 (46)
• Previous evidence of brain amyloidosis (assessed by positron emission tomographie (PET) or cerebrospinal fluid (CSF))
• Carrier of APOEe4 gene allele
• Defecates at least once a day

Exclusion Criteria:

• Antibiotic consumption 1 month prior the intervention
• Prebiotic consumption 1 month prior the intervention
• Recent change in diet habit (eg: vegetarian, vegan, high protein diet)
• Current alcohol addiction
• Current smoking habit
• Clinical diagnosis of dementia.
• Contraindications to probiotic consumption
• Inability to undergo the procedures of the study, e.g., severe behavioural disturbances.

• severe diseases:

  1. Life threatening diseases,
  2. Severe systemic diseases (e.g., kidney insufficiency, cardiac insufficiency, decompensated diabetes, decompensated metabolic diseases, decompensated hypothyroidism, uncontrolled autoimmune diseases);
  3. Chronic digestive diseases (e.g.: Crohn's disease, Ulcerative colitis, C. difficile infection)
  4. Chronic immune diseases
• The participation to a clinical trial involving potential Alzheimer's disease modifying therapies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: participant procedure; each participant will go through 3 phases of identical protocol. In each phases blood and stools will be collected at specific days, as well as cardiometabolic measures, transit time, cognitive tests and food consumption. Each phase last 2 weeks with a washout period of 1 month in between. In the first phase, no treatment will be provided, in the second phase a low dose of probiotic (once a day for five days) will be given and in the third phase high dose of probiotic (twice a day for five days) will be administered.

Dietary supplement: SLAB51; One dose of probiotic consists of a bag of probiotic powder to dissolve in a glass of water according to the manufacturer instructions. Each bag contains 100 billion bacteria of the following strains: streptococcus thermophilus DSM 32245, 2 Bifidobacteria lactis DSM 32246 and DSM 32247, Lactobacillus acidophilus DSM 32241, Lactobacillus helveticus DSM 32242, Lactobacillus paracasei DSM 32243, Lactobacillus plantarum DSM 32244 and Lactobacillus brevis DSM 27961.; Other Names: Agimixx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of plasma AD biomarker, Amyloid	The dynamic changes of plasma amyloid concentration, namely Ab40 and Ab42 in pg/ml, will be reported in the blood shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study
Concentration of plasma AD biomarker, Tau	The dynamic changes of plasma Tau concentration more specifically p-Tau-181, p-Tau-231 and Tau in pg/ml, will be reported in the blood shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study
Concentration of plasma AD biomarker, Nfl	The dynamic changes of plasma concentration neurofilament light (NfL in pg/ml), will be reported in the blood shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration of GFAP	The dynamic changes in concentration of plasma glial fibrillary acidic protein (GFAP), as a marker of neuroinflammation, will be reported shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study
Plasma concentration of a panel of cytokines	The dynamic changes in concentraion of a large panel of cytokines measured in plasma, as markers of systemic inflammation, will be reported shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study
Plasma concentration of VCAM and NCAM	The dynamic changes in concentration of plasma VCAM and NCAM, as markers of endothelial dysfunction, will be reported shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study
Profiling of gut bacterial population isolated from stools	The dynamic changes in alpha and beta diversity, as well as the functionality of gut bacterial population isolated from stools will be reported shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study
Plasma and stool concentration of bacterial derived metabolites	The dynamic changes of plasma and stool concentration of bacterial derived metabolites or small molecules (eg: short chain fatty acids (SCFAs) or lipopolysaccharide (LPS) will be reported shortly before, during and shortly after the consumption of probiotic (low or high doses) as compared to the baseline without treatment.	within a year of last participant finalising the study

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Investigators: Principal Investigator: Giovanni B Frisoni, MD, HUG

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Actual): February 28, 2024
• Study Completion (Actual): February 28, 2024

Study Registration Dates

• First Submitted: August 23, 2022
• First Submitted That Met QC Criteria: August 25, 2022
• First Posted (Actual): August 30, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 20, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: probiotic; microbiome; alzheimer disease
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: 2022-01052

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No