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<p>Apolipoprotein E (<i>APOE</i>) genetic variation is the strongest genetic risk factor for Alzheimer’s Disease (AD). Prior studies on <i>APOE</i> genotype-dependent changes have largely focused on amyloid beta (Aβ) aggregation and lipid metabolism. There is an increased interest in the relationship between metabolic function and <i>APOE</i> genetic variation. We examined how <i>APOE</i> genotype affects brain metabolism in young <i>APOE3</i> and <i>APOE4</i> targeted replacement (TR) mice. In addition, we examined cell type-specific differences using induced pluripotent stem cell (iPSC)-derived astrocytes and neurons. We found sex and <i>APOE</i> genotype dependent changes to brain metabolism where <i>APOE4</i> mice show signs of metabolic stress. Using proteomics and stable isotope tracing, we found that <i>APOE4</i> iAstrocytes and iNeurons exhibit mitochondrial dysfunction, altered citric acid cycle (TCA) cycle, and a metabolic shift from oxidative metabolism towards glycolysis. Taken together, this data indicates <i>APOE4</i> causes early changes to metabolism within the central nervous system, and this has implications for early intervention to prevent AD. These metabolic alterations may contribute to the inflammatory changes observed in <i>APOE4</i> cells, linking disrupted energy metabolism with immune activation in the brain. While this study establishes a relationship between <i>APOE</i> genotype and dysregulated bioenergetics, additional studies are needed to investigate underlying mechanisms.</p>

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APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月1日

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  • Colton R. Lysaker,
  • Chelsea N. Johnson,
  • Vivien Csikos,
  • Edziu Franczak,
  • Maggie Benson,
  • Caleb A. Gilmore,
  • Cole J. Birky,
  • Xin Davis,
  • Colin S. McCoin,
  • Keith P. Smith,
  • Chad Slawson,
  • Peter A. Crawford,
  • Patrycja Puchalska,
  • John P. Thyfault,
  • Paige C. Geiger,
  • Jill K. Morris,
  • Heather M Wilkins

摘要

Apolipoprotein E (APOE) genetic variation is the strongest genetic risk factor for Alzheimer’s Disease (AD). Prior studies on APOE genotype-dependent changes have largely focused on amyloid beta (Aβ) aggregation and lipid metabolism. There is an increased interest in the relationship between metabolic function and APOE genetic variation. We examined how APOE genotype affects brain metabolism in young APOE3 and APOE4 targeted replacement (TR) mice. In addition, we examined cell type-specific differences using induced pluripotent stem cell (iPSC)-derived astrocytes and neurons. We found sex and APOE genotype dependent changes to brain metabolism where APOE4 mice show signs of metabolic stress. Using proteomics and stable isotope tracing, we found that APOE4 iAstrocytes and iNeurons exhibit mitochondrial dysfunction, altered citric acid cycle (TCA) cycle, and a metabolic shift from oxidative metabolism towards glycolysis. Taken together, this data indicates APOE4 causes early changes to metabolism within the central nervous system, and this has implications for early intervention to prevent AD. These metabolic alterations may contribute to the inflammatory changes observed in APOE4 cells, linking disrupted energy metabolism with immune activation in the brain. While this study establishes a relationship between APOE genotype and dysregulated bioenergetics, additional studies are needed to investigate underlying mechanisms.