Overview

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.

Eligibility

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.