Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways

Na Zhao, Yingxue Ren, Yu Yamazaki, Wenhui Qiao, Fuyao Li, Lindsey M. Felton, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Berkiye Sonoustoun, Matthias Arnold, Francis Shue, Jiaying Zheng, Olivia N. Attrebi, Yuka A. Martens, Zonghua Li, Ligia Bastea, Axel D. Meneses, Kai Chen, J. Will Thompson, Lisa St John-WilliamsMasaya Tachibana, Tomonori Aikawa, Hiroshi Oue, Lucy Job, Akari Yamazaki, Chia Chen Liu, Peter Storz, Yan W. Asmann, Nilüfer Ertekin-Taner, Takahisa Kanekiyo, Rima Kaddurah-Daouk, Guojun Bu

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.

Original languageEnglish (US)
Pages (from-to)727-742.e6
JournalNeuron
Volume106
Issue number5
DOIs
StatePublished - Jun 3 2020

Keywords

  • APOE
  • Alzheimer's disease
  • Serpina3
  • age
  • extracellular vesicles
  • inflammation
  • lipid metabolism
  • metabolomics
  • sex
  • transcriptomics

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Zhao, N., Ren, Y., Yamazaki, Y., Qiao, W., Li, F., Felton, L. M., Mahmoudiandehkordi, S., Kueider-Paisley, A., Sonoustoun, B., Arnold, M., Shue, F., Zheng, J., Attrebi, O. N., Martens, Y. A., Li, Z., Bastea, L., Meneses, A. D., Chen, K., Thompson, J. W., ... Bu, G. (2020). Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways. Neuron, 106(5), 727-742.e6. https://doi.org/10.1016/j.neuron.2020.02.034