# Investigating Neuroenergetic Changes through Diet in Aging and Alzheimer’s Disease (INC-AD)

> **NIH NIH R61** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $744,628

## Abstract

PROJECT SUMMARY
 Impaired brain energy metabolism is increasingly recognized as an important target mechanism for
Alzheimer’s disease (AD) prevention and treatment. Increasing evidence suggests that manipulating brain
energy substrates improves brain health in aging and may be therapeutic in AD through a metabolic shift of the
brain. Particularly, the ketogenic diet (KD) shows substantial effects on improving clinical outcomes, including
cognitive function, in AD patients, by shifting the major brain energy substrate from glucose to ketones.
However, the underlying mechanisms for such approaches are not well understood mainly due to a lack of
non-invasive methods to directly assess brain bioenergetics in humans, limiting further progress in developing
effective intervention strategies for AD. Thus, we designed a randomized clinical trial to overcome current
limitations through the development of advanced 1H and 31P magnetic resonance spectroscopy (MRS)
techniques to measure neuroenergetic biomarkers with 3T clinical scanners and to use the developed
techniques to test our hypothesis that the KD significantly enhances brain energy metabolism in aging and AD.
 During the R61 developmental phase, we will develop techniques to measure 1) primary circulating ketone
produced in response to a KD, b-hydroxybutyrate (BHB); 2) bioenergetic co-enzymes involved in both cytosolic
and mitochondrial metabolism, NAD, NAD+, NADH; 3) the primary energy-carrying molecules, adenosine
triphosphate (ATP) and phosphocreatine (PCr) in AD-relevant brain regions.
 During the R33 Basic Experiment Study involving Humans (BESH) trial, we will investigate the physiological
effects of the KD on brain energy metabolism in aging and AD by measuring the 1H/31P MRS neuroenergetic
biomarkers that we develop during the R61 phase. Both AD patients and older adults with normal cognition will
be randomized to either the 4-week, experimentally-controlled feeding of the KD or therapeutic lifestyles
changes (TLC) diet. In Aim 1, we will quantify the degree of brain energetic manipulation via the KD in aging
and AD using neuroenergetic imaging. In Aim 2, we will elucidate the association between brain energetic
manipulation and brain antioxidant status in aging and AD using antioxidant (GSH) imaging. In Aim 3, we will
determine the effect of aging and AD on neuroenergetic status by utilizing baseline data from participants in
both R61 and R33 phases (30 healthy adults, 30 older adults with normal cognition, 30 AD patients).
 We anticipate that this project will provide proof-of-concept that the KD truly manipulates and enhances
neuroenergetics in aging and AD for the first time by directly assessing this widely hypothesized mechanism
with in vivo neuroimaging biomarkers in humans. The infrastructure established through the R61 phase will
provide a critical platform for AD intervention trials that can be extended across the NIA’s network of
Alzheimer’s Disease Research Centers (ADRC) for us...

## Key facts

- **NIH application ID:** 10889811
- **Project number:** 1R61AG087449-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Phil Lee
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $744,628
- **Award type:** 1
- **Project period:** 2024-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889811

## Citation

> US National Institutes of Health, RePORTER application 10889811, Investigating Neuroenergetic Changes through Diet in Aging and Alzheimer’s Disease (INC-AD) (1R61AG087449-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10889811. Licensed CC0.

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