Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease
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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.
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mRNA translation is upregulated in the brains of APOE2 carriers relative to those of APOE3 homozygotes and APOE4 carriers, based on examination of previously published transcriptomic and proteomic Alzheimer's datasets.
“Supporting the idea that our findings may have broader disease implications, our examination of previously published transcriptomic and proteomic Alzheimer’s datasets revealed that mRNA translation is a pathway that is upregulated in the brains of APOE2 carriers relative to those of APOE3 homozygotes and APOE4 carriers (41,42).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [42]
~35% of proteins upregulated in E4/4 AD compared to E3/3 AD brains overlapped with proteins enriched on E4 LDs.
“~35 % of proteins upregulated in E4/4 AD compared to E3/3 AD brains (Dai et al., 2018) overlapped with proteins enriched on E4 LDs.”
From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Dai et al., 2018
Nearly a dozen network-based analyses of the AD proteome have been performed in the human brain, including the dorsolateral prefrontal cortex, temporal cortex, and other cortical regions heavily affected in AD.
“Nearly a dozen informative network-based analyses of the AD proteome have been performed in the human brain [62–64, 74, 78, 96, 104–108], including the dorsolateral prefrontal cortex (DLPFC), temporal cortex, and other cortical regions heavily affected in AD.”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [104]
Dai et al. observed the APOEε2 effect on oligodendrocyte and other cell type markers in a separate network proteome of the AD brain.
“Dai et al. also observed this APOEε2 effect on oligodendrocyte and other cell type markers in a separate network proteome of the AD brain [104].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [104]
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WGCNA: an R package for weighted correlation network analysis
Langfelder, P., & Horvath, S. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-559 · Cited by 27,252 · see citing works
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
The Perseus computational platform for comprehensive analysis of (prote)omics data
Tyanova, S., Temu, T., Sinitcyn, P. G., Carlson, A., Hein, M. Y., Geiger, T., Mann, M., & Cox, J. (2016) · Nature Methods · doi:10.1038/nmeth.3901 · Cited by 7,977 · see citing works
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment
Cox, J., Neuhauser, N., Michalski, A., Scheltema, R. A., Olsen, J. V., & Mann, M. (2011) · Journal of Proteome Research · doi:10.1021/pr101065j · Cited by 5,349 · see citing works
Cox, J., Hein, M. Y., Luber, C. A., Paron, I., Nagaraj, N., & Mann, M. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.031591 · Cited by 5,180 · see citing works
Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961 · see citing works
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · see citing works
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268 · see citing works
Neuropathological alterations in Alzheimer disease
Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006189 · Cited by 3,345 · see citing works
Genomic analysis of reactive astrogliosis
Zamanian, J. L., Xu, L., Foo, L. C., Nouri, N., Zhou, L., Giffard, R. G., & Barres, B. A. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.6221-11.2012 · Cited by 2,404 · see citing works
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · see citing works
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
Proteogenomic characterization of human colon and rectal cancer
CPTAC, T. N., Zhang, B., Wang, J., Wang, X., Zhu, J., Liu, Q., Shi, Z., Chambers, M. C., Zimmerman, L. J., Shaddox, K. F., et al. (2014) · Nature · doi:10.1038/nature13438 · Cited by 1,462 · see citing works
Fast R Functions for Robust Correlations and Hierarchical Clustering
Langfelder, P., & Horvath, S. (2012) · Journal of Statistical Software · doi:10.18637/jss.v046.i11 · Cited by 1,297 · see citing works
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · cited 2× · see citing works
“, 2014b) to examine endothelial cell type enrichment, given the known effects of ApoE polymorphism on vascular biology and cerebrovascular disease (Bell et al., 2012; Schilling et al., 2013; Tai et al., 2016; Bouchareychas and Raffai, 2018).”
BackgroundHuman ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · cited 1× · see citing works
“ApoE has been found to regulate clearance of Aβ in an isoform-dependent fashion (E2>E3>E4) in animal models of AD and in humans without cognitive impairment (Castellano et al., 2011; Grothe et al., 2017).”
BackgroundApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220 · see citing works
Cell type- and brain region-resolved mouse brain proteome
Sharma, K., Schmitt, S., Bergner, C. G., Tyanova, S., Kannaiyan, N., Manrique-Hoyos, N., Kongi, K., Cantuti, L., Hanisch, U.-K., Philips, M.-A., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4160 · Cited by 871 · see citing works
Apolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857 · cited 1× · see citing works
“A number of hypotheses have been proposed to explain how the ApoE protein influences risk for AD, including effects on lipid metabolism, amyloid-β metabolism, mitochondrial function, cerebrovascular integrity, and inflammation (Huang, 2010; Verghese et al., 2011; Tai et al., 2016; Zhao et al., 2018).”
BackgroundBoyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W., & Taylor, J. M. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112130 · Cited by 829 · see citing works
Functional organization of the transcriptome in human brain
Oldham, M. C., Konopka, G., Iwamoto, K., Langfelder, P., Kato, T., Horvath, S., & Geschwind, D. H. (2008) · Nature Neuroscience · doi:10.1038/nn.2207 · Cited by 752 · see citing works
(1985) · PubMed · Cited by 706 · see citing works
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
Gene network interconnectedness and the generalized topological overlap measure
Yip, A. M., & Horvath, S. (2007) · BMC Bioinformatics · doi:10.1186/1471-2105-8-22 · Cited by 633 · see citing works
Tau Kinetics in Neurons and the Human Central Nervous System
Sato, C., Barthélemy, N. R., Mawuenyega, K. G., Patterson, B. W., Gordon, B. A., Jockel-Balsarotti, J., Sullivan, M., Crisp, M. J., Kasten, T., Kirmess, K. M., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.015 · Cited by 586 · see citing works
Quantitative proteomics reveals subset-specific viral recognition in dendritic cells
Luber, C. A., Cox, J., Lauterbach, H., Fancke, B., Selbach, M., Tschopp, J., Akira, S., Wiegand, M., Hochrein, H., O'Keeffe, M., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.01.013 · Cited by 576 · see citing works
Inflammation and Atherosclerosis
Stoll, G., & Bendszus, M. (2006) · Stroke · doi:10.1161/01.str.0000226901.34927.10 · Cited by 501 · see citing works
A transcriptomic atlas of aged human microglia
Olah, M., Patrick, E., Villani, A.-C., Xu, J., White, C. C., Ryan, K. J., Piehowski, P., Kapasi, A., Nejad, P., Cimpean, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-02926-5 · Cited by 482 · see citing works
Seyfried, N. T., Dammer, E. B., Swarup, V., Nandakumar, D., Duong, D. M., Yin, L., Deng, Q., Nguyen, T., Hales, C. M., Wingo, T., et al. (2017) · Cell Systems · doi:10.1016/j.cels.2016.11.006 · Cited by 477 · see citing works
Self-citationBeach, T. G., Adler, C. H., Sue, L. I., Serrano, G., Shill, H. A., Walker, D. G., Lue, L., Roher, A. E., Dugger, B. N., Maarouf, C., et al. (2015) · Neuropathology · doi:10.1111/neup.12189 · Cited by 460 · see citing works
Rangaraju, S., Dammer, E. B., Raza, S. A., Rathakrishnan, P., Xiao, H., Gao, T., Duong, D. M., Pennington, M. W., Lah, J. J., Seyfried, N. T., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0254-8 · Cited by 430 · see citing works
Self-citationWang, C., Najm, R., Xu, Q., Jeong, D.-E., Walker, D., Balestra, M. E., Yoon, S. Y., Yuan, H., Li, G., Miller, Z. A., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0004-z · Cited by 428 · see citing works
Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease
Zhao, N., Liu, C.-C., Qiao, W., & Bu, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.03.003 · Cited by 370 · see citing works
Normalization and missing value imputation for label-free LC-MS analysis
Karpievitch, Y. V., Dabney, A. R., & Smith, R. D. (2012) · BMC Bioinformatics · doi:10.1186/1471-2105-13-s16-s5 · Cited by 345 · see citing works
Chang, S., Ma, T. R., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508254102 · Cited by 319 · see citing works
Variants at APOE influence risk of deep and lobar intracerebral hemorrhage
Biffi, A., Sonni, A., Anderson, C. D., D, B. M. K. M., Jagiella, J. M., Schmidt, H., Jiménez-Conde, J., Hansen, B. M., Fernández‐Cadenas, I., Cortellini, L., et al. (2010) · Annals of Neurology · doi:10.1002/ana.22134 · Cited by 278 · see citing works
Genes and pathways underlying regional and cell type changes in Alzheimer’s disease
Miller, J. A., Woltjer, R. L., Goodenbour, J. M., Horvath, S., & Geschwind, D. H. (2013) · Genome Medicine · doi:10.1186/gm452 · Cited by 275 · see citing works
The role of APOE in cerebrovascular dysfunction
Tai, L. M., Thomas, R., Marottoli, F. M., Koster, K. P., Kanekiyo, T., Morris, A. W. J., & Bu, G. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1547-z · Cited by 231 · see citing works
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Yin, L., Thambisetty, M., Troncoso, J. C., Lah, J. J., Levey, A. I., & Seyfried, N. T. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0282-4 · Cited by 225 · cited 3× · see citing works
“Digital Sorting Algorithm for Cell Type Proportion Analysis of Tissue Proteomes Digital sorting of cell types was performed using the samplewise unregressed abundances of proteins collapsed to a single measurement of maximum variance for each gene symbol in the abundance matrix overlapping with the above gene symbol l…”
BackgroundMethodSelf-citationGlobal quantitative analysis of the human brain proteome in Alzheimer’s and Parkinson’s Disease
Ping, L., Duong, D. M., Yin, L., Gearing, M., Lah, J. J., Levey, A. I., & Seyfried, N. T. (2018) · Scientific Data · doi:10.1038/sdata.2018.36 · Cited by 221 · see citing works
Self-citationDigital sorting of complex tissues for cell type-specific gene expression profiles
田中, 義., Wan, Y., Pang, K., Chow, L. M. L., & Liu, Z. (2013) · BMC Bioinformatics · doi:10.1186/1471-2105-14-89 · Cited by 207 · see citing works
Biffi, A., Anderson, C. D., Jagiella, J. M., Schmidt, H., D, B. M. K. M., Hansen, B. M., Jiménez-Conde, J., Pires, C. R., Ayres, A. M., Schwab, K. M., et al. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70148-x · Cited by 194 · see citing works
APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old
Berlau, D. J., Corrada, M. M., Head, E., & Kawas, C. H. (2009) · Neurology · doi:10.1212/01.wnl.0000343853.00346.a4 · Cited by 185 · see citing works
Serrano‐Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A., & Hyman, B. T. (2015) · Annals of Neurology · doi:10.1002/ana.24369 · Cited by 176 · see citing works
APOE genotype and MRI markers of cerebrovascular disease
Schilling, S., DeStefano, A. L., Sachdev, P. S., Choi, S. H., Mather, K. A., DeCarli, C. S., Wen, W. X., Høgh, P., Raz, N., Au, R., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e31829bfda4 · Cited by 171 · see citing works
Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease
Huang, Y. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.04.004 · Cited by 170 · see citing works
Lee, G. S., & Leugers, C. J. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00004-7 · Cited by 166 · see citing works
Raz, N., Yang, Y., Dahle, C. L., & Land, S. J. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.007 · Cited by 163 · see citing works
Umoh, M. E., Dammer, E. B., Dai, J., Duong, D. M., Lah, J. J., Levey, A. I., Gearing, M., Glass, J. D., & Seyfried, N. T. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201708202 · Cited by 154 · see citing works
Self-citationRangaraju, S., Dammer, E. B., Raza, S. A., Gao, T., Xiao, H., Betarbet, R. S., Duong, D. M., Webster, J. A., Hales, C. M., Lah, J. J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0266-4 · Cited by 133 · see citing works
Self-citationFarrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · cited 1× · see citing works
“The presence of an E2 allele lowers the odds to develop AD to 0.6 (Corder et al., 1994; Farrer et al., 1997).”
BackgroundInfluentialApolipoprotein E Expression by Neurons Surviving Excitotoxic Stress
Boschert, U., Merlo‐Pich, E., Higgins, G. A., Roses, A. D., & Catsicas, S. (1999) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0251 · Cited by 110 · see citing works
Apolipoprotein E Polymorphism and Silent Microangiopathy-Related Cerebral Damage
Schmidt, R., Schmidt, H., Fazekas, F., Schumacher, M., Niederkorn, K., Kapeller, P., Weinrauch, V., & Kostner, G. M. (1997) · Stroke · doi:10.1161/01.str.28.5.951 · Cited by 101 · see citing works
The Dominantly Inherited Alzheimer Network (DIAN), Li, Z., Del-Aguila, J. L., Dube, U., Budde, J., Martinez, R., Black, K., Xiao, Q., Cairns, N. J., Dougherty, J. D., et al. (2018) · Genome Medicine · doi:10.1186/s13073-018-0551-4 · Cited by 56 · see citing works
Bouchareychas, L., & Raffaı̈, R. L. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5020030 · Cited by 48 · see citing works
Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load
Grothe, M. J., Villeneuve, S., Dyrba, M., David Bartrés-faz, A., Wirth, M., Initiative, A. D. N., Initiative, A. D. N., Weiner, M. W., Aisen, P., Weiner, M. W., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000003585 · Cited by 47 · see citing works
Association of Apolipoprotein E ε2 With White Matter Disease but Not With Microbleeds
Lemmens, R., Görner, A., Schrooten, M., & Thijs, V. (2007) · Stroke · doi:10.1161/01.str.0000259816.31370.44 · Cited by 37 · see citing works
Flagged first, then by citations
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Sorted by citations
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0815-6 · Cited by 1,001 · see citing works
Self-citationApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
Johnson, E. C. B., Carter, E. K., Dammer, E. B., Duong, D. M., Gerasimov, E. S., Liu, Y., Liu, J., Betarbet, R., Ping, L., Yin, L., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-00999-y · Cited by 561 · see citing works
Self-citationHigginbotham, L., Ping, L., Dammer, E. B., Duong, D. M., Zhou, M., Gearing, M., Hurst, C., Glass, J. D., Factor, S. A., Johnson, E. C. B., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz9360 · Cited by 367 · see citing works
Self-citationApolipoprotein E in lipid metabolism and neurodegenerative disease
Yang, L. G., March, Z. M., Stephenson, R. A., & Narayan, P. S. (2023) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2023.05.002 · Cited by 286 · see citing works
Lee, S., Devanney, N. A., Golden, L. R., Smith, C. T., Schwartz, J. L., Walsh, A. E., Clarke, H. A., Goulding, D. S., Allenger, E. J., Morillo-Segovia, G., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112196 · Cited by 203 · see citing works
Compilation of reported protein changes in the brain in Alzheimer's disease
Askenazi, M., Kavanagh, T., Pires, G., Ueberheide, B., Wisniewski, T., & Drummond, E. (2023) · Nature Communications · doi:10.1038/s41467-023-40208-x · Cited by 174 · see citing works
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
The amyloid plaque proteome in early onset Alzheimer’s disease and Down syndrome
Drummond, E., Kavanagh, T., Pires, G., Marta-Ariza, M., Kanshin, E., Nayak, S., Faustin, A., Berdah, V., Ueberheide, B., & Wisniewski, T. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01356-1 · Cited by 137 · see citing works
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Hampel, H. J., Nisticò, R., Seyfried, N. T., Levey, A. I., Modeste, E. S., Lemercier, P., Baldacci, F., Toschi, N., Garaci, F., Perry, G. L., et al. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101346 · Cited by 142 · see citing works
Self-citationGlobal quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer’s disease
Ping, L., Kundinger, S. R., Duong, D. M., Yin, L., Gearing, M., Lah, J. J., Levey, A. I., & Seyfried, N. T. (2020) · Scientific Data · doi:10.1038/s41597-020-00650-8 · Cited by 127 · see citing works
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Rayaprolu, S., Higginbotham, L., Bagchi, P., Watson, C. M., Zhang, T., Levey, A. I., Rangaraju, S., & Seyfried, N. T. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00840-3 · Cited by 118 · see citing works
Self-citationVitek, M. P., Araujo, J. A., Fossel, M., Greenberg, B. D., Howell, G. R., Rizzo, S. J. S., Seyfried, N. T., Tenner, A. J., Territo, P. R., Windisch, M., et al. (2020) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12114 · Cited by 103 · see citing works
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Self-citationCellular senescence in brain aging and cognitive decline
Shafqat, A., Khan, S., Omer, M. H., Niaz, M., Albalkhi, I., AlKattan, K. M., Yaqinuddin, A., Tchkonia, T., Kirkland, J. L., & Hashmi, S. K. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1281581 · Cited by 75 · see citing works
Rayaprolu, S., Gao, T., Xiao, H., Ramesha, S., Weinstock, L. D., Shah, J., Duong, D. M., Dammer, E. B., Webster, J. A., Lah, J. J., et al. (2019) · doi:10.1101/802694 · Cited by 71 · see citing works
Self-citationTan, M. S., Cheah, P., Chin, A., Looi, L., & Chang, S. (2021) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2021.104947 · Cited by 64 · see citing works
Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction
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Fernandez, H. R., Varma, A., Flowers, S. A., & Rebeck, G. W. (2020) · Cancers · doi:10.3390/cancers12123842 · Cited by 62 · see citing works
Iannucci, J., Sen, A., & Grammas, P. (2021) · Current Issues in Molecular Biology · doi:10.3390/cimb43010018 · Cited by 55 · see citing works
Batch correction and harmonization of –Omics datasets with a tunable median polish of ratio
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Self-citationPhysiological and Pathological Ageing of Astrocytes in the Human Brain
Verkerke, M., Hol, E. M., & Middeldorp, J. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03256-7 · Cited by 49 · see citing works
Kumar, P., Goettemoeller, A. M., Espinosa‐García, C., Tobin, B. R., Tfaily, A., Nelson, R. S., Natu, A., Dammer, E. B., Santiago, J. V., Malepati, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47028-7 · Cited by 48 · see citing works
Self-citationHigginbotham, L. A., Carter, E. K., Dammer, E. B., Haque, R. U., Johnson, E. C. B., Duong, D. M., Yin, L., Jager, P. L. D., Bennett, D. A., Felsky, D., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106286 · Cited by 44 · see citing works
Self-citationYang, M., Lian, N., Yu, Y., Wang, Y., Xie, K., & Yu, Y. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11131 · Cited by 37 · see citing works
APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses
Friday, C. M., Stephens, I. O., Smith, C. T., Lee, S., Satish, D., Devanney, N. A., Cohen, S., Morganti, J. M., Gordon, S. M., & Johnson, L. A. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106983 · Cited by 33 · see citing works
Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease
Higginbotham, L., Dammer, E., Duong, D., Modeste, E., Montine, T., Lah, J., Levey, A., & Seyfried, N. (2019) · Proteomes · doi:10.3390/proteomes7030030 · Cited by 32 · see citing works
Self-citationSMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Aβ aggregation
Balcomb, K., Johnston, C., Kavanagh, T., Leitner, D., Schneider, J. A., Halliday, G. M., Wısnıewskı, T., Sunde, M., & Drummond, E. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02819-6 · Cited by 32 · see citing works
Ojo, J. O., Reed, J. M., Crynen, G. C., Vallabhaneni, P., Evans, J., Shackleton, B., Eisenbaum, M., Ringland, C., Edsell, A., MULLAN, M. J., et al. (2021) · Molecular Brain · doi:10.1186/s13041-021-00803-9 · Cited by 29 · see citing works
Kong, Y., Huang, L., Li, W., Liu, X., Zhou, Y., Liu, C., Zhang, S., Xie, F., Zhang, Z., Jiang, D., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.609908 · Cited by 29 · see citing works
Qin, Q., & Li, Y. (2019) · Journal of Medical Virology · doi:10.1002/jmv.25481 · Cited by 26 · see citing works
Guo, Q., Dammer, E. B., Zhou, M., Kundinger, S. R., Gearing, M., Lah, J. J., Levey, A. I., Shulman, J. M., & Seyfried, N. T. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.623659 · Cited by 23 · see citing works
Self-citationMhatre‐Winters, I., Eid, A., Han, Y., Tieu, K., & Richardson, J. R. (2023) · ASN NEURO · doi:10.1177/17590914221144549 · Cited by 20 · see citing works
Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction
Krogsaeter, E., McKetney, J., Valiente‐Banuet, L., Marquez, A., Willis, A., Cakir, Z., Stevenson, E. J., Jang, G. Μ., Rao, A. T., Li, E., et al. (2025) · Autophagy · doi:10.1080/15548627.2025.2576613 · Cited by 22 · see citing works
Proteins linking APOE ɛ4 with Alzheimer's disease
Oveisgharan, S., Yu, L., Lopes, K. D. P., Tasaki, S., Wang, Y., Menon, V., Schneider, J. A., Seyfried, N. T., & Bennett, D. A. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13867 · Cited by 19 · see citing works
Self-citationApolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis
Adaku, N., Ostendorf, B. N., Mei, W., & Tavazoie, S. F. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1252 · Cited by 15 · see citing works
Yang, M., Tan, H. L. E., Zhang, K., Lian, N., Yu, Y., & Yu, Y. (2020) · International Journal of Developmental Neuroscience · doi:10.1002/jdn.10041 · Cited by 14 · see citing works
İş, Ö., Min, Y., Wang, X., Oatman, S. R., Daniel, A. A., & Ertekin‐Taner, N. (2024) · Glia · doi:10.1002/glia.24652 · Cited by 13 · see citing works
Proteomic Insight Into Alzheimer's Disease Pathogenesis Pathways
Ryu, T., Kim, K., Asiimwe, N., & Na, C. H. (2025) · PROTEOMICS · doi:10.1002/pmic.202400298 · Cited by 12 · see citing works
Using Proteomics to Understand Alzheimer’s Disease Pathogenesis
Drummond, E., & Wısnıewskı, T. (2019) · Codon Publications eBooks · doi:10.15586/alzheimersdisease.2019.ch3 · Cited by 12 · see citing works
Nguyen, T. T., Dammer, E. B., Owino, S., Giddens, M. M., Madaras, N. S., Duong, D. M., Seyfried, N. T., & Hall, R. A. (2020) · Journal of Proteome Research · doi:10.1021/acs.jproteome.9b00622 · Cited by 12 · see citing works
Self-citationLaffoon, S. B., Doecke, J. D., Roberts, A. M., Vance, J. A., Reeves, B. D., Pertile, K. K., Rumble, R. L., Fowler, C. J., Trounson, B. O., Ames, D. J., et al. (2022) · Proteome Science · doi:10.1186/s12953-021-00185-9 · Cited by 11 · see citing works
Zhang, Z., Lin, W., Gan, Q., Lei, M., Gong, B., Zhang, C., Henrique, J. S., Han, J., Tian, H., Tao, Q., et al. (2024) · Angiogenesis · doi:10.1007/s10456-024-09946-4 · Cited by 10 · see citing works
Shapley, S. M., Shantaraman, A., Gadhavi, J. D., Kearney, M. A., Dammer, E. B., Duong, D. M., Bowen, C. A., Watson, C. M., Bagchi, P., Guo, Q., et al. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101458 · Cited by 9 · see citing works
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Lu, L., Binette, A. P., Hristovska, I., Janelidze, S., Smets, B., Cumplido-Mayoral, I., Vasanthakumar, A., Milkovich, B., An, L., Ossenkoppele, R., et al. (2026) · Nature Aging · doi:10.1038/s43587-026-01123-0 · Cited by 7 · see citing works
Abiose, O., Rutledge, J., Losada, P. M., Belloy, M. E., Wilson, E. N., He, Z., Trelle, A. N., Channappa, D., Romero, A., Park, J., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13576 · Cited by 6 · see citing works
Higginbotham, L. A., Carter, K., Dammer, E. B., Haque, R. U., Johnson, E. C. B., Duong, D. M., Yin, L., Jager, P. L. D., Bennett, D. A., Lah, J. J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.22.501017 · Cited by 4 · see citing works
Self-citationCompilation of all known protein changes in the human Alzheimer’s disease brainPreprint
Askenazi, M., Kavanagh, T., Pires, G., Ueberheide, B. M., Wısnıewskı, T., & Drummond, E. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.13.536828 · Cited by 4 · see citing works
Kumar, P., Goettemoeller, A. M., Espinosa‐García, C., Tobin, B. R., Tfaily, A., Nelson, R. S., Natu, A., Dammer, E. B., Santiago, J. V., Malepati, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.17.541038 · Cited by 4 · see citing works
Self-citationNeurodegeneration risk variants promote lysosomal TMEM106B fibril accumulationPreprint
Replogle, J. M., Marks, J. D., Fernandez, M. G., Yuan, H., Yu, D., Winters, E., Jawahar, V. M., Deshmukh, R., Sutanto, R., Kowal, I., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.26.714634 · Cited by 6 · see citing works
Self-citationStructural signature of plasma proteins classifies the status of Alzheimer’s disease
Son, A., Kim, H., Diedrich, J. K., Bamberger, C., Wilkins, H. M., Burns, J. M., Morris, J. K., Rissman, R., Swerdlow, R., & Yates, J. (2026) · Nature Aging · doi:10.1038/s43587-026-01078-2 · Cited by 4 · see citing works
APOE4 alters the lipid droplet proteome and modulates droplet dynamicsPreprint
Friday, C. M., Stephens, I. O., Smith, C. T., Lee, S., Satish, D., Devanney, N. A., Cohen, S., Morganti, J. M., Gordon, S. M., & Johnson, L. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.16.628710 · Cited by 1 · see citing works
Qiu, W. Q., Zhang, Z., Lin, W., Gan, Q., Lei, M., Gong, B., Zhang, C., Henrique, J. S., Han, J., Tian, H., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-3491703/v1
Glial Cell Biology and Their Multifaceted Functions in Alzheimer's Disease
Laadraoui, J., Kabdy, H., Azraida, H., Aimrane, A., & Smimih, K. (2023) · Advances in bioinformatics and biomedical engineering book series · doi:10.4018/978-1-6684-9675-6.ch015
Roland, N. J., Zigmond, J. W., Manganaro, J. E., Estrella, L. D., & Stauch, K. L. (2026) · Neurochemistry International · doi:10.1016/j.neuint.2026.106125 · Cited by 1 · see citing works
APOE and Proteomics in Chronic Inflammation
Shvetcov, A., & Finney, C. A. (2026) · Springer eBooks · doi:10.1007/978-3-031-52641-1_82-1
The Use of Localized Proteomics to Understand the Pathogenesis of Alzheimer's Disease
Pires, G. (2021) · theses.fr (ABES) · doi:10.70675/45826fd6zd2c8z4b3dz91e0za5080544cb17
APOE and Proteomics in Chronic Inflammation
Shvetcov, A., & Finney, C. A. (2026) · Springer eBooks · doi:10.1007/978-3-031-96089-5_82
- Authors
- Dai, J., Johnson, E. C. B., Dammer, E. B., Duong, D. M., Gearing, M., Lah, J. J., Levey, A. I., Wingo, T. S., & Seyfried, N. T.
- Affiliations
- Central South University (CN)
- Emory University (US)
- Corresponding author
- Johnson, Erik C. B.
- Seyfried, Nicholas T.
- ORCID
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2018-12-18
- Volume
- 11
- Pages
- 454-454
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC6305300
- OpenAlex
- W2905281204
- Cited by
- 62
- References
- 61
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 13 · 2022: 5 · 2021: 10 · 2020: 13 · 2019: 3
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs (IK2 BX001820)
- Michael J. Fox Foundation for Parkinson's Research (05-901, 211002, 11060, P30 AG19610)
- Alzheimer's Association (P50 AG025688, 11060)
- Emory University (R01AG061800, P50AG025688, AG025688, P30NS055077)
- Arizona Department of Health Services (P30 AG19610, P50 AG025688, 05-901, 211002, Contract 211002)
- Weston Brain Institute (11060)
- Arizona Biomedical Research Commission (P30 AG19610, 05–901, 211002)
- Alzheimer's Disease Research Center, Emory University (P50 AG025688, AG025688)
- National Institute on Aging (211002, P30-AG-19610, R01AG056533, AG 025688, AG-19610, R01AG057911, P30AG019610, U01AG046161, 05-901, AG056533, P50AG025688, R01AG053960, R01AG061800)
- National Institute of Neurological Disorders and Stroke (211002, P30NS055077, 05-901, P30 AG19610)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, APOE genotype, apolipoprotein E, APOE e2 allele, APOE ε4, brain proteome, astrocytes, microglia, oligodendrocytes, amyloid-beta, tau protein, synaptic transmission, neuroinflammation, cortical tissue
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