# Neuroenergetic Adaptations in Alzheimer's Disease: Implications on Amyloid Burden and Cognition

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $254,250

## Abstract

Project Summary
Alzheimer's disease (AD) accounts for the majority of dementia cases worldwide. The number of persons with
AD in the US is expected to reach 13.5 million by 2050, and the medical costs associated with AD are
expected to exceed $20 trillion over the next 40 years. Available drugs offer only moderate symptom
alleviation. Most importantly, no therapeutic strategies have demonstrated clinically significant disease-
modifying benefits, with more than 100 failed clinical trials in the last 20 years. Emerging evidence suggests
striking similarities between energetic adaptations observed in central nervous system (CNS) cells in sporadic
AD and those shown by cancer cells. These include a shift from oxidative phosphorylation (OxPhos) to
upregulation of aerobic glycolysis (AG) as an adaptive mechanism against neurotoxic conditions (e.g., the
accumulation of amyloid beta [Aβ] oligomers in the case of AD). This energetic shift could explain the
paradoxical observation that many elderly individuals remain cognitively normal (NL) despite the presence of
high levels of Aβ deposition. While AG upregulation may serve as a stopgap to rescue select neurons and
preserve cognition, its long-term upregulation reduces neuron viability due to improper processing of lactate,
increased levels of which cause oxidative stress and neuronal loss. Subsequently, greater energy demands
are placed on the diminished neuron population, which initiates a new shift to increased OxPhos that is also
consistent with reduced efficiency in ATP synthesis by mitochondrial dysregulation (a hallmark of AD) and
neuronal death. This model predicts: i) increased AG in Aβ+ NL subjects compared to Aβ– NL controls, ii)
decreased OxPhos in Aβ+ NL subjects compared to Aβ– NL controls, and iii) increased OxPhos in neuronal
cells that have survived apoptosis in amnestic mild cognitive impairment (aMCI) or AD patients compared to
Aβ+ NL controls. Combined multinuclear MR/PET is a uniquely suitable tool to directly test such neuroenergetic
models. While our study focuses on the compensatory energy pathways and Aβ in AD, the tools we develop
can provide vital insight on a range of amyloid cascade and/or neuroenergetic hypotheses. We will use our
MR/PET system to measure amyloid deposition with PiB (Pittsburgh compound)-PET, OxPhos with
phosphorus (31P) Magnetic Resonance Spectroscopic Imaging (MRSI), and lactate with proton (1H)-MRSI. This
work has been propelled by our recent instrumentation grant that has enabled multinuclear MRSI/PET on our
clinical scanner. In addition, we engineered and tested a highly sensitive dual/tuned (31P/1H) head coil array
with low PET attenuation, and developed a software pipeline that uses anatomical MR images to create
volumes of interest that selectively include cortical regions with high AG in the presence of adequate oxygen in
healthy subjects. Together, these tools will enable simultaneous co-localized 31P/1H-MRSI and PET imaging for
pioneering AD neuro...

## Key facts

- **NIH application ID:** 9875421
- **Project number:** 5R21AG061579-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Ryan Brown
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,250
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875421

## Citation

> US National Institutes of Health, RePORTER application 9875421, Neuroenergetic Adaptations in Alzheimer's Disease: Implications on Amyloid Burden and Cognition (5R21AG061579-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9875421. Licensed CC0.

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