# Dietary Modulation of Neuroinflammation in Age-Related Memory Disorders

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $764,114

## Abstract

Within 25 years, the US population aged 65 and over will double in size to 80 million bringing, with it an
epidemic of aging-related cognitive decline, from normal cognitive aging to neurodegenerative disorders
including Alzheimer’s Disease (AD). These conditions impair quality of life and functional status, impose an
enormous burden on individuals, their families, the healthcare system, and require elucidation of mechanisms
and development of new treatments to prevent or at least slow their progression.
 The use of plant-based food and drink for health purposes has a long and well-documented history. Cocoa
beans contain the flavanol epicatechin, an anti-oxidant with beneficial effects on blood pressure, endothelium-
dependent vasomotor function, platelet reactivity, insulin sensitivity, vascular inflammation, and circulating
progenitor cells. Importantly, flavanols have neuroprotective effects, suppressing oxidative stress and
inflammation and promoting neurogenesis, neuronal survival and synaptic plasticity, all of which are relevant to
the pathophysiology of neurodegenerative disorders like AD, amyotrophic lateral sclerosis (ALS), and
Parkinson’s Disease (PD).
 Evidence from humans, non-human primates, and rodents points to a role for the hippocampus and its
subregions in aging-related neurodegenerative disorders including AD. We recently reported that dietary
intake of cocoa flavanols increased hippocampal function, measured as fMRI cerebral blood volume (CBV) and
a pilot mediation analysis showed that cocoa flavanols led to a decrease in the sentinel pro-inflammatory
mediator HMGB1, an activator of the innate immune system. In turn, this decrease in HMGB1 was linked to
improved hippocampal function. Recent evidence implicates HMGB1 in cognitive decline and impairment.
HMGB1 binds to Toll-like receptor 4 (TLR4), triggering the production of pro-inflammatory cytokines including
TNFa via NFkB-dependent pathways. In rodent models of endotoxemia and surgical trauma, HMGB1
mediated hippocampal-dependent memory impairment similar to that seen in septic patients, an effect
eliminated by neutralizing HMGB1.
 These data mechanistically link HMGB1 to neurodegenerative impairment, suggesting its potential as a
therapeutic target, consistent with evidence that amplified systemic inflammation is associated with a variety of
age-related pathologies including Alzheimer’s Disease. They strongly support our major hypothesis that cocoa
flavanols improve hippocampal function by their effects on neuroinflammation, specifically HMGB1, via a
TLR4-NFkB-TNFa signaling pathway. We propose to test this model in a randomized controlled trial of 146
participants, age 50-69, receiving high or low daily cocoa flavanol for 12 weeks. Such a trial has potential for
significant clinical impact.

## Key facts

- **NIH application ID:** 9975668
- **Project number:** 5R01AG058417-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Richard P SLOAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $764,114
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975668

## Citation

> US National Institutes of Health, RePORTER application 9975668, Dietary Modulation of Neuroinflammation in Age-Related Memory Disorders (5R01AG058417-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9975668. Licensed CC0.

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