APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease
Abstract
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.
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BibTeX
@article{chen2026apoe2,
title = {{APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease}},
author = {Kai Chen and Yixing Chen and Yingxue Ren and Zhen Wang and Ya Huang and Meixia Pan and Zonghua Li and Monica Castanedes Casey and Wenhui Qiao and Ji Shi and Dehui Kong and Gisela Xhafkollari and Hannah Santhakumar and Allison M. Wetmore and E. Aubrey Thompson and Xusheng Wang and Dennis W. Dickson and David M. Holtzman and Guojun Bu and Xianlin Han and Junmin Peng and Na Zhao},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78407-x},
url = {https://www.nature.com/articles/s41467-026-78407-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease
AU - Kai Chen
AU - Yixing Chen
AU - Yingxue Ren
AU - Zhen Wang
AU - Ya Huang
AU - Meixia Pan
AU - Zonghua Li
AU - Monica Castanedes Casey
AU - Wenhui Qiao
AU - Ji Shi
AU - Dehui Kong
AU - Gisela Xhafkollari
AU - Hannah Santhakumar
AU - Allison M. Wetmore
AU - E. Aubrey Thompson
AU - Xusheng Wang
AU - Dennis W. Dickson
AU - David M. Holtzman
AU - Guojun Bu
AU - Xianlin Han
AU - Junmin Peng
AU - Na Zhao
PY - 2026
DA - 2026/10/08
JO - Nature Communications
DO - 10.1038/s41467-026-78407-x
UR - https://www.nature.com/articles/s41467-026-78407-x
AB - 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.
SN - 2041-1723
ER -