# Imaging and Reversibility of Cellular and Network Metabolic Dysfunction in Alzheimer's Disease

> **NIH NIH RF1** · WASHINGTON UNIVERSITY · 2022 · $2,244,795

## Abstract

PROJECT SUMMARY
In Alzheimer’s disease (AD), Aβ accumulation and plaque formation precedes dementia by decades, suggesting
that other downstream pathophysiological processes are responsible for precipitating symptomatic disease. Prior
studies in humans reveal that brain metabolism is impaired in early AD, including an initial regional energy deficit
with a superimposed, marked metabolic shift away from whole-brain and regional glycolysis. However, it is not
yet clear how amyloid-induced metabolic dysfunction manifests at the cellular level and affects different cell
types, how cellular metabolic dysfunction relates to tissue energy deficit and disruption of functional brain
organization, and if and when this might be reversible. These questions have been difficult to answer due to
technical challenges in spatiotemporally assessing cell type-specific mitochondrial function and energy
metabolism, along with plaque deposition, at the microscopic and mesoscopic levels in vivo. Our central
hypothesis is that plaque deposition induces metabolic dysfunction localized to specific cell types and/or cellular
components. We further hypothesize that specific cellular changes in metabolic dysfunction differentially affect
metabolism at the tissue level and functional brain organization at the regional and global levels. To test these
hypotheses, our team has developed several technologies in mice including two-photon fluorescence lifetime
imaging microscopy (TP-FLIM), multi-parametric photoacoustic microscopy (PAM), and wide-field optical
imaging (WFOI). We will use these methods to measure concentrations of nicotinamide adenine dinucleotide
(NADH), flavin adenine dinucleotide (FAD), cerebral metabolic rate of oxygen (CMRO2), and neural and
hemodynamic activity. In addition to indicating overall mitochondrial activity, the ratio of NADH to FAD (N/F ratio)
provides an optically-accessible index of metabolic shifts towards or away from glycolysis in vivo, a key early
aspect of AD-related metabolic dysfunction. Since brain amyloid clearance is now readily achievable in both
mice and humans, our approach will further allow us to determine whether the metabolic dysfunctions discovered
from the efforts above are reduced following amyloid clearance. In the project, we aim to (Aim 1) determine the
in vivo relationship between amyloid plaque deposition and cellular N/F ratio in AD mice at the microscopic level
using TP-FLIM; (Aim 2) determine how amyloid plaque deposition and cellular metabolic dysfunction affect
regional and global measures of tissue metabolism and functional brain organization using PAM and WFOI; and
(Aim 3) determine whether amyloid plaque clearance reverses the metabolic abnormalities identified in Aims 1
and 2. Understanding the spatiotemporal relationship between Aβ accumulation, metabolic dysfunction, and
functional brain organization from the cellular to systems level will be critical to revealing the mechanisms by
which amyloid deposition aff...

## Key facts

- **NIH application ID:** 10536491
- **Project number:** 1RF1AG079503-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** ADAM Q BAUER
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,244,795
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536491

## Citation

> US National Institutes of Health, RePORTER application 10536491, Imaging and Reversibility of Cellular and Network Metabolic Dysfunction in Alzheimer's Disease (1RF1AG079503-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10536491. Licensed CC0.

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