Polyphenols and Cognitive Decline
NCT Number: NCT06507254
Acronym: MAEVE
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Cognitive Decline|Cognitive Dysfunction
Interventions: DIETARY_SUPPLEMENT: Polyphenol Supplement|DIETARY_SUPPLEMENT: Placebo Supplement
Sponsor: University of California, Los Angeles
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 300
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: TRIPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR)|Primary Purpose: PREVENTION
Start Date: 2024-08-01
Completion Date: 2029-12-31

Summary:
Globally, populations are aging thereby increasing healthcare burden, overall cognitive impairment, and dementia including Alzheimer's 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 PP's can also change gut microbial composition and function, altering the physiology of the host's 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 PP's and BA's.

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 stress testing appointments, collect 3 stool samples with corresponding diet diaries, and provide 3 blood samples over the course of 12months.

Primary Outcome Measures: 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 - Episodic Memory, Administration of a standardized list of words that participants will be asked to remember and recall after a set amount of time., 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 - Semantic Memory, Administration of a standardized verbal fluency task; participants ability to name items belonging to a certain category., 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 - Perceptual Speed, Administration of a standardized number comparison task; participants ability to identify if pairs of multi-digit numbers are the same or different., 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).
Secondary Outcome Measures: 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).|Differences in Alzheimer's Disease (AD) markers pre, mid, & post intervention - Blood, 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).|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)|Questionnaire Data, Use of validated surveys to assess ingestive behaviors, 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, Use of validated surveys to assess anxiety, depression, stress, and diet, self-reported by the participant at home,, Collected once a month for the duration of the study (12months).|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).
Other Outcome Measures: 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.