APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
9 affiliations
- 1Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
- 2University of Kansas Alzheimer’s Disease Research Center, Kansas City, KS, USA
- 3Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
- 4Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA
- 5Kansas Center for Metabolism and Obesity Research, University of Kansas Medical Center, Kansas City, KS, USA
- 6Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA
- 7Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA
- 8Division of Molecular Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
- 9Department of Internal Medicine, Division of Endocrinology, University of Kansas Medical Center, Kansas City, KS, USA
Abstract
Apolipoprotein E ( APOE ) genetic variation is the strongest genetic risk factor for late onset Alzheimer’s disease (LOAD). Studies on APOE genotype dependent changes have largely focused on amyloid beta (Aβ) aggregation, disease pathology, and lipid metabolism. Recently, there has been increased interest in the relationship between metabolic function and APOE genetic variation. In this study, we examined how APOE genotype can alter metabolism in the brains of young male and female APOE3 and APOE4 targeted replacement (TR) mice. In combination with this, we also examined cell type-specific differences using induced pluripotent stem cell (iPSC) derived astrocytes and neurons. We found sex and genotype dependent changes to metabolism in the brains of young APOE TR mice. Specifically, APOE4 mice show signs of metabolic stress and compensatory mechanisms in the brain. Using proteomics and stable isotope tracing metabolomics, we found that APOE4 iAstrocytes and iNeurons exhibit signs of inflammation, mitochondrial dysfunction, altered TCA cycle and malate-aspartate shuttle activity, and a metabolic shift toward glycolysis. Taken together, this data indicates APOE4 causes early changes to metabolism within the central nervous system. While this study establishes a relationship between APOE genotype and alterations in bioenergetics, additional studies are needed to investigate underlying mechanisms.
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BibTeX
@article{lysaker2026apoe4drives,
title = {{APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology}},
author = {Colton R Lysaker and Chelsea N. Johnson and Vivien Csikós and Edziu Franczak and Maggie N. Benson and Caleb A. Gilmore and Cole J. Birky and Xin Davis and Colin S. McCoin and Keith P. Smith and Chad M Slawson and Peter A. Crawford and Patrycja Puchalska and John P. Thyfault and Paige C. Geiger and Jill K. Morris and Heather Wilkins},
journal = {npj Dementia},
year = {2026},
month = jul,
doi = {10.1038/s44400-026-00105-8},
url = {https://doi.org/10.1038/s44400-026-00105-8},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
AU - Colton R Lysaker
AU - Chelsea N. Johnson
AU - Vivien Csikós
AU - Edziu Franczak
AU - Maggie N. Benson
AU - Caleb A. Gilmore
AU - Cole J. Birky
AU - Xin Davis
AU - Colin S. McCoin
AU - Keith P. Smith
AU - Chad M Slawson
AU - Peter A. Crawford
AU - Patrycja Puchalska
AU - John P. Thyfault
AU - Paige C. Geiger
AU - Jill K. Morris
AU - Heather Wilkins
PY - 2026
DA - 2026/07/01
JO - npj Dementia
DO - 10.1038/s44400-026-00105-8
UR - https://doi.org/10.1038/s44400-026-00105-8
AB - Apolipoprotein E ( APOE ) genetic variation is the strongest genetic risk factor for late onset Alzheimer’s disease (LOAD). Studies on APOE genotype dependent changes have largely focused on amyloid beta (Aβ) aggregation, disease pathology, and lipid metabolism. Recently, there has been increased interest in the relationship between metabolic function and APOE genetic variation. In this study, we examined how APOE genotype can alter metabolism in the brains of young male and female APOE3 and APOE4 targeted replacement (TR) mice. In combination with this, we also examined cell type-specific differences using induced pluripotent stem cell (iPSC) derived astrocytes and neurons. We found sex and genotype dependent changes to metabolism in the brains of young APOE TR mice. Specifically, APOE4 mice show signs of metabolic stress and compensatory mechanisms in the brain. Using proteomics and stable isotope tracing metabolomics, we found that APOE4 iAstrocytes and iNeurons exhibit signs of inflammation, mitochondrial dysfunction, altered TCA cycle and malate-aspartate shuttle activity, and a metabolic shift toward glycolysis. Taken together, this data indicates APOE4 causes early changes to metabolism within the central nervous system. While this study establishes a relationship between APOE genotype and alterations in bioenergetics, additional studies are needed to investigate underlying mechanisms.
SN - 3005-1940
ER -