The Gut - PRO Study

Probiotic Supplementation Safety and Feasibility Study in Preclinical Alzheimer's Disease

The purpose of this study is to assess the safety and feasibility of an oral probiotic supplement (PS) intervention in individuals with dementia or mild-cognitive impairment (MCI) due to Alzheimer's disease or at risk of dementia due to Alzheimer's disease (AD). 40 participants will be enrolled and can expect to be on study for up to 1 year.

Study Overview

• Status: Not yet recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Probiotic; Other: Placebo

Detailed Description

40 participants will be enrolled. 20 with dementia or mild cognitive impairment (MCI) due to Alzheimer's disease (biomarker confirmed amyloid positivity), and 20 unimpaired cognition, enriched for elevated amyloid (approximately 75-80% amyloid positive). Dementia/mild cognitive impairment will be determined according to 2024 NIA-AA criteria.

Primary Objective

• To assess the safety and feasibility (recruitment, eligibility, enrollment, completion, and follow-up) of an oral probiotic supplementation (PS) intervention in humans with or at risk for dementia due to AD.

Exploratory Objectives

• To demonstrate the effects of PS on the composition and function of the gut microbiota in humans with or at risk for dementia due to AD.
• To collect preliminary data in order to estimate sample size and other critical parameters for a larger study.
• To examine potential mechanisms by which the gut impacts brain, including leading candidate mechanisms such as intestinal permeability and change to bile acid milieu.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alfred Braceros, BA; Phone Number: 608-263-9485; Email: braceros@medicine.wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospitals and Clinics
      • Principal Investigator: Barbara Bendlin, PhD
      • Principal Investigator: Federico Rey, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• MCI/AD or cognitively unimpaired, referred from a Wisconsin clinic that is part of the Wisconsin Alzheimer's Institute's (WAI) network, or recruited from the community. May have participated in:

  • Alzheimer's Disease Research Center (ADRC) clinical core study (2011-0030)
  • ADCP (26695, MCW IRB)
  • Synapse study (2018-1283)
  • ADRC Recruitment Registry (2016-0735)
• At least 60 years of age or older
• Good general health (other than cognitive impairment/dementia) with no conditions/medications affecting the gut microbiome (see exclusion criteria below)
• Willing and able to comply with all study procedures for the duration of the study
• Able to provide signed and dated informed consent form
• Participant is not pregnant, lactating or of childbearing potential (i.e., women must be two years post-menopausal or surgically sterile)
• Able to take oral medications
• An informant to answer questionnaires about the participant

Additional inclusion criteria for unimpaired participants:

• Has MOCA score that falls within the range defined for cognitively healthy individuals

Additional inclusion criteria for participants with MCI/AD

• Abnormal cognitive function documented by neuropsychological testing
• ADRC (2015-0030) Consensus Diagnosis Conference indicates dementia or MCI due to AD (for ADRC, ADCP, and Synapse participants only)
• Meets NIA-AA criteria for MCI or AD.

Exclusion Criteria:

• Active or previous (within 6 months) participation in an Alzheimer's clinical intervention/trial (can be included if previously enrolled in placebo or control group)
• Standard clinical care for dementia and medications used to treat MCI and Alzheimer's disease are acceptable, including monoclonal antibody therapy
• Significant neurologic disease: Any significant neurologic disease, such as Parkinson's disease, stroke, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, subdural hematoma, multiple sclerosis, seizure disorder, or other significant deficits other than Alzheimer's or Mild Cognitive Impairment
• Alcohol/substance: history of alcohol/substance dependence in the past year.
• Significant medical illness: any significant systemic illness or unstable medical condition occurring during ADRC participation that could affect cognition (other than MCI/AD). Examples include malignant cancer, chemotherapy, HIV, untreated thyroid disease, heart failure, or renal insufficiency
• Current diagnosis with diabetes
• Illiterate, blind, or non-English speaking
• Known periodic antibiotic use (i.e., prior to dental appointments)

• Oral PS-specific exclusion criteria:

  • Inability (e.g., dysphagia) or unwilling to swallow capsules
  • Active gastrointestinal infection at time of enrollment
  • Known or suspected toxic megacolon and/or known small bowel ileus
  • History of total colectomy or bariatric surgery
  • Concurrent intensive induction chemotherapy, radiation therapy, or biological treatment for active malignancy
  • Unable or unwilling to comply with protocol requirements
  • Expected life expectancy less than 6 months
  • Previous use of probiotic supplementation (PS) or microbiome-based products within 2 months, large doses of commercial probiotics consumed (greater than or equal to 10^8 cfu or organisms per day). Includes tablets, capsules, lozenges, chewing gum or powders in which probiotic is a primary component (ordinary dietary components such as fermented beverages/milks, yogurts, foods do not apply). Enrollment after 2 months without probiotic use can be considered for eligibility
  • Patients with severe anaphylactic or anaphylactoid food allergy
  • Solid organ transplant recipients less than or equal to 90 days post-transplant or on active treatment for rejection
  • A condition that would jeopardize the safety or rights of the participant, would make it unlikely for the participant to complete the study, or would confound the results of the study

• Exclusionary factors affecting the microbiome:

  • Previous use of systemic antibiotics (intravenous, intramuscular, or oral) within 3 months (depends on the duration of antibiotic use, i.e., less than 3 months is considered exclusion, however, enrollment after 3 months without antibiotic use can be considered for eligibility)
  • Immune stimulating and/or suppressing medications
  • Immunosuppressed as evaluated by complete blood count (CBC) with differential, which includes white blood cell count, total neutrophil count, and total lymphocyte count
  • Unstable dietary history during the previous month, which is defined as major changes in diet by eliminating or significantly increasing a major food group
  • Major surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the past five years
  • Major bowel resection at any time
  • Active uncontrolled gastrointestinal disorders or disease including inflammatory bowel disease, ulcerative colitis (mild-moderate-severe), Crohn's disease (mild-moderate-severe), or indeterminate colitis; irritable bowel syndrome (moderate-severe); persistent, infectious gastroenteritis, colitis, or gastritis; persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated), or chronic constipation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cognitively Impaired due to AD: Probiotic; Diagnosis of mild cognitive impairment (MCI) or dementia	Drug: Probiotic; A single dose of oral PS will be administered once daily for 6 months; Other Names: Encapsulated probiotic preparation
Placebo Comparator: Cognitively Impaired due to AD: Placebo; Diagnosis of mild cognitive impairment (MCI) or dementia	Other: Placebo; A placebo will be given once daily for 6 months.
Experimental: Cognitively Unimpaired Amyloid Positive: Probiotic	Drug: Probiotic; A single dose of oral PS will be administered once daily for 6 months; Other Names: Encapsulated probiotic preparation
Placebo Comparator: Cognitively Unimpaired Amyloid Positive: Placebo	Other: Placebo; A placebo will be given once daily for 6 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety: Proportion of participants with an adverse event (AE) occurring during any point of the study	up to 36 weeks
Safety: Proportion of participants with a severe adverse event (SAE) occurring during any point of the study	up to 36 weeks
Feasibility: Number of weeks or months needed to meet study group numbers	up to 36 weeks
Feasibility: Proportion of individuals expressing interest in study who are Eligible	baseline
Feasibility: Proportion of Participants Who Complete Intervention	up to 36 weeks
Feasibility: Proportion of Participants Who Complete 80 percent of Oral PS	week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin A1C		baseline, week 12, week 24, and week 36
Fasting Glucose		baseline, week 12, week 24, week 36
Fasting Insulin		baseline, week 12, week 24, week 36
C-reactive protein		baseline, week 12, week 24, week 36
Blood lipid profile		baseline, week 12, week 24, week 36
Systolic Blood Pressure		baseline, week 12, week 24, week 36
Diastolic Blood Pressure		baseline, week 12, week 24, week 36
Body Weight		baseline, week 12, week 24, week 36
Body Fat Percentage		baseline, week 12, week 24, week 36
Insulin Resistance indexed by the homeostatic model assessment-insulin resistance (HOMA-IR) method		baseline, week 12, week 24, week 36
Change in Quality of Sleep	General sleep quality will be rated using a 10 item questionnaire, which uses a 6-point Likert scale. Scores range from 10-60, with higher scores indicating better sleep quality.	baseline, week 12, week 24, week 36
Metabolites	Measured from serum, plasma, stool	baseline, week 12, week 24, week 36
Gut Microbiome Composition	Change in gut microbiome composition will be assessed using 16srRNA seq and metagenomic analysis of stool samples.	baseline, week 12, week 24, week 36
Plasma Biomarkers of Alzheimer's Disease Related Dementias (ADRD)	Change in plasma biomarkers of ADRD, including pTau217, neurofilament light chain (NfL), and Glial Fibrillary Acidic Protein (GFAP). Emerging plasma biomarkers may also be assessed.	baseline, week 12, week 24, week 36
Change in Montreal Cognitive Assessment (MoCA) score	The MoCA is a cognitive screening test used for detecting cognitive impairment. MoCA scores range between 0 and 30. Lower scores are indicative of impairment.	screening, week 24, week 36
Change in Repeatable Battery for the Assessment of Neuropsychological Status: Performance	The Repeatable Battery for the Assessment of Neuropsychological Status consists of twelve subtests which give five scores, one for each of the five domains tested (immediate memory, visuospatial/constructional, language, attention, delayed memory). Raw scores on each domain are scaled to account for a person's age. Scaled scores are converted to percentiles which are used to determine a range of performance (impaired, borderline impaired, expected score, high average, superior).	baseline, week 24, week 36
Change in Repeatable Battery for the Assessment of Neuropsychological Status: Cognitive Status	The Repeatable Battery for the Assessment of Neuropsychological Status consists of twelve subtests which give five scores, one for each of the five domains tested (immediate memory, visuospatial/constructional, language, attention, delayed memory). Raw scores on each domain are scaled to account for a person's age. Scaled scores are converted to percentiles which are used to determine overall cognitive status (impaired/not impaired).	baseline, week 24, week 36
Change in the results of Trail Making Test (TMT)	The TMT is a neuropsychological test of visual attention and task switching. It consists of two parts, A and B. Participant is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. Results for both TMT A and B are reported as the number of seconds required to complete the task; therefore, higher scores reveal greater impairment.	baseline, week 24, week 36
Total score on the Bristol Activities of Daily Living Scale	This is a tool used to measure functional ability (ability to independently carry out activities of daily living), and was developed for use with people with dementia. The minimum score is "0". The maximum score is "60". A lower score (better) indicates that a person is independent in their activities of daily living, and a higher score (worse) indicates that the individual is dependent on others.	baseline, week 12, week 24, week 36
Intestinal Permeability	Investigators may measure proteins or other markers related to intestinal permeability (in blood).	baseline, week 12, week 24, week 36
Change in Epworth Sleepiness Scale (ESS)	ESS is an 8 item questionnaire, using a 4-point Likert scale. Scores range from 0-24, with higher scores indicating greater levels of sleepiness throughout the day.	baseline, week 12, week 24, week 36
Change in Insomnia Severity Index (ISI)	ISI is an 7 item questionnaire, using a 5-point Likert scale. Scores range from 35-24, with higher scores indicating greater levels of insomnia.	baseline, week 12, week 24, week 36
Change in Pittsburgh Sleep Quality Index (PSQI)	PSQI scoring involves summing scores from 7 components, each ranging from 0 (no difficulty) to 3 (severe difficulty), to get a global score from 0 to 21, with higher scores indicating worse sleep quality. A global score over 5 suggests significant sleep difficulties.	baseline, week 12, week 24, week 36

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Institute on Aging (NIA); International Flavors & Fragrances Inc.
• Investigators: Principal Investigator: Barbara Bendlin, PhD, UW School of Medicine and Public Health; Principal Investigator: Federico Rey, PhD, Department of Bacteriology

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: January 7, 2026
• First Submitted That Met QC Criteria: February 9, 2026
• First Posted (Actual): February 17, 2026

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: probiotics
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Dietary Supplements; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Probiotics
• Other Study ID Numbers: 2024-0622; A534255 (Other Identifier: UW- Madison); 1R61AG088913-01A1 (U.S. NIH Grant/Contract); Protocol Version 4/13/26 (Other Identifier: UW- Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Collected specimens (including stool, blood, and CSF) will be stored and may be used for future research. Participants will be asked to consent to the use of the samples for future research.
• IPD Sharing Time Frame: The samples will be kept until all analyses for this project are complete or until the samples are exhausted.
• IPD Sharing Access Criteria: Drs. Bendlin and Rey will review all requests to utilize the data, tissue, and results of specimen analysis.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No