# Novel Imaging Biomarkers of Lipid and Ketone Metabolism in Alzheimer's Disease

> **NIH NIH RF1** · UNIVERSITY OF PENNSYLVANIA · 2024 · $2,105,574

## Abstract

Alzheimer’s disease (AD) is the most common form of dementia accounting for 60% to 80% of total
dementia cases and the sixth leading cause of death in the US. Over 25 million people are affected by the
disease and as the aging population increases, this number is expected to double by 2050. Although disease
modifying treatments for AD are now becoming available, they are not curative, and there remains a pressing
need for additional therapeutic strategies. Disruption of brain glycolytic metabolism is recognized as a hallmark
feature of AD that has deleterious consequences given the brain’s high metabolic rate. Ketone bodies are
alternative substrates that can be used by the brain to support mitochondrial oxidate metabolism. Mounting
evidence suggests that the AD brain may metabolize endogenous ketones derived from myelin lipids, leading to
derangements in lipid homeostasis and demyelination. Ketogenic diets or ketone drinks are now being
investigated as promising therapeutic strategies in the AD continuum to meet brain energy requirements and to
maintain lipid homeostasis. However, a major challenge in the development, validation, and optimization of
ketone therapies in AD is the lack of robust non-invasive tool to probe the metabolic fate of lipids and ketone
bodies in the human brain. Our preliminary data demonstrate the feasibility of using deuterium magnetic
resonance spectroscopy (DMRS) with deuterium labeled precursors to directly characterize and quantify ketone
metabolism in the brain. In addition, nuclear Overhauser effect (NOE) based MRI offers the potential of
measuring changes in myelin/lipid integrity with high sensitivity.
 We propose to further develop and optimize DMRS for tracking glucose and ketone metabolism and NOE
MRI for studying brain lipids with a goal to probe initiating mechanisms underlying brain metabolic derangements
in AD. Specifically, we will first establish the precision of the methods in measuring glucose and ketone
metabolism and brain lipids in AD pathology. Then, we will perform longitudinal DMRS and NOE MRI in AD
mouse models (APP-KI, AD-APP-KI) that closely recapitulate human AD to determine the onset and progression
of changes in ketone and lipid metabolism and their association with the changes in immunohistochemical
measures of myelin, lipids and other hallmark features of AD. Successful completion of the proposed project will
lead to: (i) new mechanistic insights about the critical role of lipid catabolism and ketone metabolism in the
initiating stages of AD onset and progression (ii) validated imaging biomarkers that can measure changes in
ketone metabolism and lipid integrity in AD disease progression and its treatment with ketone supplementation,
and (iii) noninvasive and clinically translatable biomarkers that can be used to identify and longitudinally evaluate
disease targets and disease modifying ketone therapies, thereby contributing to enhanced patient care.

## Key facts

- **NIH application ID:** 10884020
- **Project number:** 1RF1AG087306-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ravinder Reddy
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,105,574
- **Award type:** 1
- **Project period:** 2024-05-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884020

## Citation

> US National Institutes of Health, RePORTER application 10884020, Novel Imaging Biomarkers of Lipid and Ketone Metabolism in Alzheimer's Disease (1RF1AG087306-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10884020. Licensed CC0.

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