Polyphenols and Cognitive Decline

NCT06507254 | Recruiting DMC

• 2 other identifiers: IRB 24-0001131R01AG081768
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

Globally, populations are aging thereby increasing healthcare burden, overall cognitive impairment, and dementia including Alzheimers diseases (AD). The lack of effective treatments makes it essential to develop new strategies for healthy cognitive aging, including interventions to slow or prevent cognitive decline. A traditional Mediterranean diet, rich in polyphenols (PPs), may prevent or delay the onset of cognitive dysfunction in older adults, preserving healthy brain structure and function, and lowering the risk of AD. These effects, mediated in part by gut microbiome-derived PP metabolites, highlight the role alterations in the brain-gut microbiome system play in neurodegeneration. Moreover, high levels of circulating phenyl-y-valerolactones, neuroprotective compounds, exclusively produced by gut microbiota from flavan-3-ol-rich foods (e.g., cocoa, tea, berries) are associated with delaying the onset of cognitive dysfunction in older adults. Intake of such PPs can also change gut microbial composition and function, altering the physiology of the hosts secondary bile acid (BA) pool, affecting regulatory and signaling functions in the brain as well as cognitive decline and AD. The investigators hypothesize that, in older adults with enhanced AD risk, dietary intake of PPs maintains healthier brain features and cognitive function, and that this beneficial effect is mediated by gut microbiota metabolites of PPs and BAs. In this multi-PI application by leaders in the field of brain-gut microbiome interactions, the investigators will conduct a year-long, multi-center, randomized double-blind placebo-controlled study in 300 older adults in the United States (validation sample of 100 from Northern Ireland) who are at enhanced risk of developing AD. Ultimately, the investigators will establish the protective effects of regular dietary PP intake on cognitive function and on brain-gut microbiome interactions, ideally allowing the development of effective dietary regimes to prevent of delay the onset of AD in at-risk elderly, thereby reducing cognitive decline and healthcare costs. Participants will be asked to provide information about their diet, mood, and behaviors via food diaries, physical body measures (e.g. height, weight, etc.), and online questionnaires collected before each in-clinic appointment, as well as monthly online questionnaires. MR imaging will be collected on participants to assess neurocognitive changes as a result of the supplement. Participants will be asked to provide both stool and blood samples. Participants will be randomly assigned to either the Juice Plus+ intervention group or the placebo treatment group and then asked to take their respective supplement 4 pills twice a day. All participants will be asked to come in for 4 in-clinic appointments, including 3 brain MRI scans and 3 cognitive testing appointments, collect 3 stool samples with corresponding diet diaries, and provide 3 blood samples over the course of 12 months. Participants will also meet with a nutritionist 3 times over the 12 months to discuss diet to ensure study eligibility and any questions about the supplement.

Conditions

Cognitive Decline; Cognitive Dysfunction

Keywords

Polyphenols; Mediterranean Diet; Gut Microbiome; Alzheimers Disease

Outcome Measures

Primary Outcomes (10)

• 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 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, mid, & post intervention - Stool

  16S RNA sequencing to measure microbiome levels 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 & 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 microbiome levels pre, mid, & post intervention - Stool

  Shotgun metagenomics, sequencing to measure microbiome levels 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 - Blood

  Shotgun metagenomics, 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 Stroop Neuro-psychological test; participants ability to correctly identify colors when words are printed in conflicting ink colors.

  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 Cognitive Measures pre, mid, and post intervention - Executive Functioning

  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 Outcomes (9)

• Differences in tryptophan-associated metabolite profiles pre, mid, and post intervention - Stool

  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

  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

  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 Alzheimer's Disease (AD) markers pre, mid, & post intervention - Blood

  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

  Measured three times, once at each in-clinic appointment (week 0, month 6, month 12)

Other Outcomes (1)

• Differences in Multimodal Brain Signatures pre, mid, & post intervention

  Measured thrice, once at baseline (week 0), mid-study (month 6), and final 12month appointment (month 12) visit.

Study Arms (2)

Polyphenol Supplement

EXPERIMENTAL

Juice Plus Essentials, Berry Blend Capsules

Dietary Supplement: Polyphenol Supplement

Placebo Supplement

PLACEBO COMPARATOR

Dietary Supplement: Placebo Supplement

Interventions

Polyphenol Supplement DIETARY_SUPPLEMENT

Dietary supplement taken twice daily for 12 months.

Also known as: Juice Plus Essentials, Berry Blend Capsules

Polyphenol Supplement

Placebo Supplement DIETARY_SUPPLEMENT

Dietary supplement taken twice daily for 12 months.

Placebo Supplement

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• + Years of age
• Male or Female
• At enhanced risk of Alzheimers Disease (defined as family history of AD, 1st degree family member)
• Overweight or Obese (BMI≥25kg/m\^2)
• Habitually consume suboptimal diets such as typical Western Diet (i.e., high in animal products, refined carbohydrates and processed food)
• Able to communicate well in English

You may not qualify if:

• Vegan or Vegetarian
• Presence of cognitive impairment at the 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).
• Pre-existing psychosis or psychiatric conditions
• Currently receiving treatment for dementia
• History of alcohol and/or substance abuse/dependence as determined by a positive endorsement on the MINI+/ If the MINI+ is positive for alcohol or drug dependence, or abuse, the participants will be excluded.
• Heavy use of tobacco (greater than 1/2 pack per day)
• History of cerebrovascular events
• Existing allergies to berry fruits
• Use of oral/IV antibiotics in the last 3 months. Use of probiotics in the last 1 month.
• Recent Changes (last 3 months) in the use of psychoactive medications or other medications that interfere with the measured outcomes.
• Frailty, malnutrition, or food allergy/intolerance requiring special diets.
• Body weight at enrollment greater than 400lbs due to weight restrictions on the MRI table.
• Women who are pregnant, lactating, or postpartum for less than 6months.
• Women of childbearing age who are not practicing birth control or are planning to get pregnant during the study.
• Unable to safely participate in the MRI (claustrophobia, presence of devices affected by MRI such as pacemakers, neurostimulators, metallic foreign body, etc.)

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (1)

University of California, Los Angeles

Los Angeles, California, 90095, United States

RECRUITING

MeSH Terms

Conditions

Cognitive Dysfunction; Alzheimer Disease

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases

Study Officials

• Arpana Church, PhD

  The Regents of the University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marika Dy, MPH

CONTACT

2670089; ChurchLab@mednet.ucla.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 15, 2024
• First Posted: July 18, 2024
• Study Start: January 9, 2025
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: May 31, 2025

Record last verified: 2025-05

Locations

US (1)