Microbiota Mediated Flavonoid Metabolites for Cognitive Health (MAEVE)

MAEVE: Microbiota Mediated Flavonoid Metabolites for Cognitive Health

Globally, populations are ageing increasing the prevalence of Alzheimer's disease (AD), due to lack of effective treatments. The traditional Mediterranean diet, rich in fibre and polyphenols (PPs) can help prevent or delay cognitive dysfunction and preserve healthy brain structure and function. Cognitive decline is inversely associated with higher PP intakes (>421mg/day) i.e., total flavonoids, flavan-3-ols and flavonoid oligomers. The positive brain effects of flavonoid intake are likely mediated in part by gut microbial PP metabolites, consistent with the emerging role of the brain-gut microbiome (BGM) system in neurodegeneration. Our preliminary data indicate that circulating phenyl-γ-valerolactones (PVL), neuroprotective compounds exclusively produced by gut microbiota from flavan-3-ol rich foods18 are associated with delaying cognitive dysfunction. Intake of PPs change gut microbial composition and function, altering the physiology of the host's secondary bile acid (BA) pool through modulation of bacterial 7α-dehydroxylation of de-conjugated primary BAs into secondary BAs. This is noteworthy as 7α-dehydroxylation of BAs does not happen in the brain and because gut microbial BA metabolites have regulatory and signalling functions in the brain. The ratio between certain primary and secondary BAs is also dysregulated in AD with significantly lower serum concentrations of cholic acid (a primary BA) and increased levels of deoxycholic acid (a bacterially produced secondary BA). The increased ratio of cholic acid to deoxycholic acid is correlated with cognitive decline. Increased levels of tyrosine, tryptophan, purine, and tocopherol have also been identified in postmortem AD brains. However, specific pathways and mechanisms underlying these associations are unclear. In this multi-PI application by leaders in the field of BGM interactions, we leverage the collectively (NIH, HSC, SFI) funded Tripartite US-Ireland R&D Partnership Program to determine the mechanisms involved in PP intake on maintaining healthier cognitive and brain function, as mediated by gut microbiota metabolites of PP and BAs in 50+ year old elderly with enhanced AD risk.

Study Overview

• Status: Recruiting
• Conditions: Cognitive Dysfunction; Cognitive Decline
• Intervention / Treatment: Dietary supplement: Polyphenol Supplement; Dietary supplement: Placebo Supplement

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chris Gill, PhD; Phone Number: +44 28 7012 3181; Email: c.gill@ulster.ac.uk
• Study Contact Backup: Name: Aoife Caffrey, PhD; Phone Number: +44 (0) 28 701 23401; Email: a.caffrey@ulster.ac.uk

Study Locations

• United Kingdom
  • Coleraine, United Kingdom, BT52 1SA
    • Recruiting
    • Ulster University, Human Intervention Studies Unit
    • Contact: Aoife Caffrey, PhD; Phone Number: +44 (0) 28 701 23401; Email: a.caffrey@ulster.ac.uk
    • Contact: Email: c.gill@ulster.ac.uk
    • Principal Investigator: Chris Gill, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 50+ years
• BMI ≥ 25 kg/m2
• Enhanced risk of AD - defined as family history of AD, 1st degree family member
• Habitually consume suboptimal diets such as typical Western diet (i.e., high in animal products, refined carbohydrates and processed food).
• Subjects capable of and willing to comply with the protocol and to give their written informed consent.

Exclusion Criteria:

• Cognitive impairment at time of recruitment into the study, as measured by the Mini Mental Status Exam (MMSE, score 25-30), and Clinical Dementia Rating (CDR, score=0) or Everyday Cognition Scale-12 (ECog-12, score<1.36 included).
• Pre-existing psychosis or psychiatric conditions.
• Currently receiving treatment for dementia.
• History of substance abuse or cerebrovascular events.
• Heavy use of tobacco (>1/2 pack per day)
• Any intolerance or allergy documented or suspected to one of the components of the study products.
• Have taken probiotics or antibiotic therapy within the last 1 month
• Change in medication use in the last 3 months.
• Frailty, malnutrition, or food allergy/intolerance requiring special diets will also be excluded.
• Following any specific diet (vegetarian, vegan, etc.)
• Body weight at enrolment greater than 400lbs due to weight restrictions on the MRI table.
• Pregnant, breastfeeding, postpartum for less than 6 months, or unwilling to practice birth control during participation in the study.
• Unable to safely participate in the MRI (claustrophobia, presence of devices affected by MRI such as pacemakers, neurostimulators, or metallic foreign body, etc.)
• Chronic pain.
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
• Having a psychological or linguistic inability to sign the informed consent;
• Under legal protection (guardianship, wardship) or deprived from his rights following administrative or judicial decision;
• Subject participating in another biomedical study or participation in another study within the 3 months before entry into this study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Supplement	Dietary supplement: Placebo Supplement; Micronutrient matched placebo
Experimental: Polyphenol Supplement; Juice Plus Essentials, Berry Blend Capsules	Dietary supplement: Polyphenol Supplement; Juice Plus Essentials, Berry Blend Capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in Polyphenol-derived metabolite concentrations pre, mid, & post intervention - blood	Measurement of metabolomics via blood specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in microbiome levels pre & post intervention - Blood	16S RNA sequencing to measure microbiome levels via blood specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in Cognitive Measures pre, mid, & post intervention - Executive Function	Administration of a standardized Trails A & B; participants ability to connect dots, in order, as quickly as possible.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in Cognitive Measures pre, mid, & post intervention	The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in Polyphenol-derived metabolite concentrations pre, mid, & post intervention - stool	Measurement of metabolomics via stool specimen.	Collected three times by the participant at home, once at baseline (week 0), once at mid-study (month 6), and once at the final 12month appointment (month 12)
Differences in microbiome levels pre, mid, & post intervention - Stool	16S RNA sequencing to measure microbiome levels via stool specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in microbiome levels pre, mid, & post intervention - Stool	Shotgun metagenomics, sequencing to measure microbiome levels via stool specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in microbiome levels pre, mid, & post intervention - Blood	Shotgun metagenomics, sequencing to measure microbiome levels via stool specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in Cognitive Measures pre, mid, & post intervention - Executive Function	Administration of a standardized Stroop Neuro-psychological test; participants ability to correctly identify colours when words are printed in conflicting ink colours.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in Cognitive Measures pre, mid, & post intervention	Administration of a standardized arithmetic task; participants ability to complete quick mental math.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in tryptophan-associated metabolite profiles pre, mid, and post intervention - Stool	Measurement of tryptophan-associate metabolite profiles via stool specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in Bile Acid's (BA's) pre, mid, & post intervention - Stool	Measurement of BA's via stool specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Differences in Inflammatory markers pre, mid, & post intervention - Blood	Measurement of inflammatory markers via blood specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Anthropometrics - BMI	Measurement of height(in) and weight(lbs), used to calculate body mass index (BMI)	Measured three times, once at each in-clinic appointment (week 0, month 6, month 12)
Anthropometrics - waist and hip circumference	Measurement of waist and hip circumference (cm)	Measured three times, once at each in-clinic appointment (week 0, month 6, & month 12)
Systolic and Diastolic Blood Pressure	Measurement of the pressure of circulating blood at rest	Measured three times, once at each in-clinic appointment (week 0, month 6, month 12).
Differences in Alzheimer's Disease (AD) markers pre, mid, & post intervention - Blood [Time	Measurement of AD markers via blood specimen.	Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).
Questionnaire Data	Use of validated surveys to assess ingestive behaviours, social isolation, stress, health, physical activity, etc., self-reported by the participant at home.	Collected 3 times (1) before beginning the dietary supplement, (2) mid-study month 6, (3) end of study month 12.
Monthly Questionnaire Data	Collected once a month for the duration of the study (12months).	Collected 3 times (1) before beginning the dietary supplement, (2) mid-study month 6, (3) end of study month 12.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in Multimodal Brain Signatures pre, mid, & post intervention	Neuroimaging of participants brain via magnetic resonance imaging (MRI) procedure.	Measured thrice, once at baseline (week 0), mid-study (month 6), and final 12month appointment (month 12) visit.

Collaborators and Investigators

• Sponsor: University of Ulster
• Collaborators: University of California, Los Angeles; National Institute on Aging (NIA); University College Cork; University of Parma
• Investigators: Principal Investigator: Chris Gill, PhD, Ulster University, Human Intervention Studies Unit, Coleraine, Co. Londonderry, BT52 1SA, United Kingdom.

Study record dates

Study Major Dates

• Study Start (Estimated): November 25, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: November 7, 2025
• First Submitted That Met QC Criteria: November 7, 2025
• First Posted (Estimated): November 10, 2025

Study Record Updates

• Last Update Posted (Actual): November 24, 2025
• Last Update Submitted That Met QC Criteria: November 21, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Alzheimer Disease; Mediterranean Diet; Polyphenols; Gut Microbiome
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease
• Other Study ID Numbers: REC/25/0046; 1R01AG081768-01 (U.S. NIH Grant/Contract); 5R01AG081768-02 (U.S. NIH Grant/Contract)

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