APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease (AD), influencing amyloid-β (Aβ) aggregation, clearance, and glial function. While APOE4 promotes Aβ pathology and APOE2 is protective, how these opposing alleles interact in the heterozygous APOE2/4 state remains unknown. Here, using littermate-controlled heterozygous APOE mice (APOE2/3, APOE3/4, and APOE2/4) alongside APOE3/3 controls crossed with 5xFAD mice, we show that APOE3/4 mice exhibit increased Aβ deposition, maladaptive microglial activation, and reduced microglial interactions with plaques.

These changes were attenuated in APOE2/4 mice, accompanied by a brain proteomic profile more similar to those of APOE3/3 and APOE2/3 mice. Increased myelin basic protein (MBP) abundance was observed in APOE2/3 but not APOE2/4 mice. Plasma lipidomics revealed shared alterations in APOE3/4 and APOE2/4 mice, with distinct signatures in APOE2/3 mice.

These findings define allele interaction-dependent effects of APOE on brain and systemic phenotypes and provide a framework for understanding the biological consequences of the APOE2/4 genotype. Phillips for assistance in preparing the mouse brain slides for this study. This work was supported by the Cure Alzheimer’s Fund (to N.Z. and Y.R.), the Mayo Clinic Kogod Center on Aging (to N.Z.), and NIH grant U19AG069701 (to N.Z., J.P., X.H., D.W.D., and D.M.H.).

Present address: Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA Kai Chen, Yixing Chen, Zonghua Li, Monica Castanedes Casey, Wenhui Qiao, Gisela Xhafkollari, Hannah Santhakumar, Allison M. Dickson, Guojun Bu & Na Zhao Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA Departments of Structural Biology and Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in St.

Louis, MO, USA D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory boards of Denali, Genentech, Cajal Neuroscience, and Switch and consults for Pfizer, Novartis, and Roche. G.B. is a consultant for SciNeuro Pharmaceuticals.

All the other authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.