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Basic Science and Pathogenesis.

Yunguang Qiu1,2, Feixiong Cheng1,2,3

  • 1Cleveland Clinic, Cleveland, OH, USA.

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|December 24, 2025
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Summary
This summary is machine-generated.

This study reveals how metabolic signaling changes in Alzheimer's disease (AD) brain cells. It identifies specific metabolite-sensor pairs linked to AD risk and protection, offering new therapeutic targets.

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Area of Science:

  • Neuroscience
  • Metabolomics
  • Systems Biology

Background:

  • Metabolic reprogramming is linked to Alzheimer's disease (AD) pathogenesis and progression.
  • Understanding single-cell metabolic signaling dynamics in AD is crucial for deciphering disease heterogeneity and developing targeted therapies.

Purpose of the Study:

  • To characterize the genetics-supported metabolite signaling network in the AD brain at the single-cell level.
  • To identify cell-type-specific metabolic alterations and metabolite-sensor communications underlying AD.
  • To explore how these metabolic changes relate to AD severity, sex differences, and APOE4 genotype.

Main Methods:

  • Developed a multi-layered omics framework integrating single-cell RNA sequencing, genetics, and metabolomics.
  • Applied a novel algorithm (scFUMES) to predict metabolic sensing profiles at single-cell resolution.
  • Utilized Mendelian Randomization analysis to identify cell-type-specific AD-associated metabolite-sensor pairs.

Main Results:

  • Observed reduced metabolic signaling in neuronal cells and increased activity in non-neuronal cells in AD brain regions (MTG, DLPFC).
  • Identified 410 disease-specific metabolite-sensor pairs, including AD-risk FABP3-palmitic acid and AD-protective FFAR3-butyric acid.
  • Discovered cell-type specific signaling pairs, such as KYAT1-Indole-3-propionic acid in neurons and VDR-arachidonic acid in immune cells, with distinct patterns based on sex and APOE4 status.

Conclusions:

  • The study systematically reveals a metabolite-mediated signaling rewiring network in the AD brain.
  • These findings provide insights into cellular metabolic heterogeneity in AD and potential metabolism-based therapeutic strategies.
  • The identified metabolite-sensor pairs may serve as novel targets for AD and related dementia treatments.