# Dissecting connections between diet, the microbiome and Alzheimers disease

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $209,375

## Abstract

Project Summary/Abstract
Our population is aging. As our population ages, the incidence of Alzheimer’s Disease (AD), an
age-associated illness, grows, resulting in elevated health care costs. A second factor contributing
to the current rise in age-associated aliments is the American diet with its ever-increasing amount
of added sugar. The negative effects of added dietary sugar is in part due to advanced glycation
end products (AGEs) which form from the process of glycation where a sugar molecule attaches
to a protein or lipid without enzymatic regulation thereby altering its structure and/or function.
AGEs form in normal metabolism but when AGEs rise to high levels in tissues and circulation, as
in diabetes or high dietary sugar, they can become pathogenic since AGEs promote oxidative
stress and inflammation. A third contributor to the increases in AD is the microbiome; recent
studies have linked age-associated illness with changes in the microbiome. The central unifying
hypothesis of this proposal is that consumption of a sugar-loaded diet alters the microbiome and
contributes to the onset and severity of AD. We will address this hypothesis with two specific aims
using a Caenorhabditis elegans–Escherichia coli system.
 Our experimental C. elegans–E. coli paradigm is an excellent system for these studies
because: (1) C. elegans are bacterivores and have an obligatory symbiotic relationship with
microbes as their food source, which becomes the intestinal microbiota; (2) C. elegans possess
stress and immune signaling pathways that are evolutionarily conserved; (3) Genetic tools are
available including transgenic strains for AD whereby human β-Amyloid precursor protein (Aβ
peptide) is driven by a tissue specific promoter. (4) We can modify the environment (added sugar)
resulting in changes in the levels of dietary AGEs(dAGEs); and (5) Our preliminary data show
when C. elegans consume live (microbiota) or heat killed (no microbiota) sugar-loaded high-
dAGE E. coli, C. elegans have a shortened lifespan and reduced healthspan. Our results also
demonstrate the importance of the microbiota as a buffer for stress. In Specific Aim 1, we will
address the effects of a sugar-loaded high-dAGEs diet on AD transgenic animals with heat killed
or live bacteria. In Specific Aim 2, we use a series of genetic tools, (including mutants,
transgenics)to provide mechanistic insight. This proposal exploits a symbiotic relationship to
define how a sugar loaded/high dAGEs diet promotes Aβ accumulation. Our results in the two-
year period could be paradigm shifting in our understanding of the impact of added dietary glucose
on AD. The long-term goal is to modify diet to delay or even eliminate the onset of AD.

## Key facts

- **NIH application ID:** 10925366
- **Project number:** 5R21AG084042-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** HEIDI A TISSENBAUM
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2023-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10925366

## Citation

> US National Institutes of Health, RePORTER application 10925366, Dissecting connections between diet, the microbiome and Alzheimers disease (5R21AG084042-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10925366. Licensed CC0.

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