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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Zhao, N; Ren, Y; Yamazaki, Y; Qiao, W; Li, F; Felton, LM; Mahmoudiandehkordi, S; Kueider-Paisley, A; Sonoustoun, B; Arnold, M; Shue, F; Zheng, J; Attrebi, ON; Martens, YA; Li, Z; Bastea, L; Meneses, AD; Chen, K; Thompson, JW; St John-Williams, L; Tachibana, M; Aikawa, T; Oue, H; Job, L; Yamazaki, A; Liu, C-C; Storz, P; Asmann, YW; Ertekin-Taner, N; Kanekiyo, T; Kaddurah-Daouk, R; Bu, G

Published Date

  • June 3, 2020

Published In

Volume / Issue

  • 106 / 5

Start / End Page

  • 727 - 742.e6

PubMed ID

  • 32199103

Pubmed Central ID

  • PMC7388065

Electronic International Standard Serial Number (EISSN)

  • 1097-4199

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2020.02.034


  • eng

Conference Location

  • United States