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Author Notes:

Correspondence: Erik C. B. Johnson erik.c.b.johnson@emory.edu; Nicholas T. Seyfried nseyfri@emory.edu

JD, ECBJ, and EBD contributed equally to this work

JD, ED, EJ, TW, NS, AL, and JL: conceptualization; DD, ED, JD, EJ, TW, and NS: methodology; JD and DD: investigation; ED, JD, EJ, and NS: formal analysis; EJ, JD, and ED: writing – original draft; EJ, JD, ED, DD, MG, TW, NS, JL, and AL: writing – review and editing; AL and NS: funding acquisition; MG: resources.

We are grateful to those who donated their brains to the Emory and Banner Sun Health Research Institute Brain Banks.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Research Funding:

Support for this research was provided by funding from the National Institute on Aging (5R01AG053960, R01AG057911, R01AG061800), the Accelerating Medicine Partnership for AD (U01AG046161), the Emory Alzheimer's Disease Research Center (P50 AG025688), and the NINDS Emory Neuroscience Core (P30NS055077).

NS was also supported in part by grants from the Alzheimer's Association (ALZ), Alzheimer's Research UK (ARUK), The Michael J. Fox Foundation for Parkinson's Research (MJFF), and the Weston Brain Institute (11060).

TW was also supported by IK2 BX001820 (Veterans Health Administration) and R01 AG056533.

The Banner Institute Brain and Body Donation Program is supported by the NIA (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 001, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson's Research.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Alzheimer's disease
  • proteomics
  • apolipoprotein E
  • inflammation
  • deconvolution
  • TAU
  • GLIA

Journal Title:

Frontiers in Molecular Neuroscience


Volume 11


, Pages 454-454

Type of Work:

Article | Final Publisher PDF


Polymorphic alleles in the apolipoprotein E (APOE) gene are the main genetic determinants of late-onset Alzheimer's disease (AD) risk. Individuals carrying the APOE E4 allele are at increased risk to develop AD compared to those carrying the more common E3 allele, whereas those carrying the E2 allele are at decreased risk for developing AD. How ApoE isoforms influence risk for AD remains unclear. To help fill this gap in knowledge, we performed a comparative unbiased mass spectrometry-based proteomic analysis of post-mortem brain cortical tissues from pathologically-defined AD or control cases of different APOE genotypes. Control cases (n = 10) were homozygous for the common E3 allele, whereas AD cases (n = 24) were equally distributed among E2/3, E3/3, and E4/4 genotypes. We used differential protein expression and co-expression analytical approaches to assess how changes in the brain proteome are related to APOE genotype. We observed similar levels of amyloid-β, but reduced levels of neurofibrillary tau, in E2/3 brains compared to E3/3 and E4/4 AD brains. Weighted co-expression network analysis revealed 33 modules of co-expressed proteins, 12 of which were significantly different by APOE genotype in AD. The modules that were significantly different by APOE genotype were associated with synaptic transmission and inflammation, among other biological processes. Deconvolution and analysis of brain cell type changes revealed that the E2 allele suppressed homeostatic and disease-associated cell type changes in astrocytes, microglia, oligodendroglia, and endothelia. The E2 allele-specific effect on brain cell type changes was validated in a separate cohort of 130 brains. Our systems-level proteomic analyses of AD brain reveal alterations in the brain proteome and brain cell types associated with allelic variants in APOE, and suggest further areas for investigation into the upstream mechanisms that drive ApoE-associated risk for AD.

Copyright information:

© 2018 Dai, Johnson, Dammer, Duong, Gearing, Lah, Levey, Wingo and Seyfried.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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