Human Central Nervous System (CNS) ApoE Isoforms Are Increased by Age, Differentially Altered by Amyloidosis, and Relative Amounts Reversed in the CNS Compared with Plasma
Open accessAbstract
The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF β-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden.
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Both mass-spectrometry-based and immunoassay-based approaches have shown that plasma ApoE isoform quantification can discriminate ε4 carriers from non-carriers with high accuracy.
“Both mass-spectrometry-based and immunoassay-based approaches have shown that plasma ApoE isoform quantification can discriminate ε4 carriers from non-carriers with high accuracy [16–18].”
From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [16]
The ‘Accuracy of Total and Isoform-specific ApoE Measures’ section (page unavailable) reports plasma measurements by both MS and ELISA, with total ApoE tending to decrease as ε4 copy number increases. But the Discussion says ELISA cannot measure isoforms independently, and Figure 2 reports that the MS measure did not distinguish ε3/ε3 from ε3/ε4 plasma samples. The paper does not establish high-accuracy discrimination of carriers from non-carriers by both approaches. (LLM, conf=0.88)
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Cites
Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., et al. (2012) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.10.007 · Cited by 3,092 · see citing works
Self-citationProtective 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
DeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J.-C., Paul, S. M., & Holtzman, D. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151261398 · Cited by 1,298 · see citing works
Self-citationHuman 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 2× · see citing works
“Similarly, 56% apoE4 was observed in frontal cortex samples from heterozygotes t(16) 6.”
BackgroundSelf-citationMiddeldorp, J., & Hol, E. M. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.01.005 · Cited by 1,080 · see citing works
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
Self-citation<i>APOE</i> predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., & Mintun, M. A. (2010) · Annals of Neurology · doi:10.1002/ana.21843 · Cited by 830 · see citing works
Self-citationAstrocytes 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
Blalock, E. M., Chen, K.-C., Sharrow, K., Herman, J. P., Porter, N. M., Foster, T. C., & Landfield, P. W. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-09-03807.2003 · Cited by 570 · see citing works
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation.
Linton, M. F., Gish, R., Hubl, S. T., Bütler, E., Esquivel, C., Bry, W. I., Boyles, J. K., Wardell, M. R., & Young, S. G. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115288 · Cited by 367 · see citing works
Kang, D. E., Pietrzik, C. U., Baum, L., Chevallier, N., Merriam, D. E., Kounnas, M. Z., Wagner, S. L., Troncoso, J. C., Kawas, C. H., Katzman, R., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11013 · Cited by 354 · see citing works
Abnormal in vivo metabolism of apolipoprotein E4 in humans.
Gregg, R. E., Zech, L. A., Schaefer, E. J., Stark, D., Wilson, D., & Brewer, H. B. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112645 · Cited by 345 · see citing works
Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
Riddell, D. R., Zhou, H., Atchison, K., Warwick, H. K., Atkinson, P. J., Jefferson, J., Xu, L., Aschmies, S., Kirksey, Y., Hu, Y., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1972-08.2008 · Cited by 342 · see citing works
Weisgraber, K. H. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42621-5 · Cited by 304 · see citing works
TOKUDA, T., CALERO, M., MATSUBARA, E., VIDAL, R., KUMAR, A., PERMANNE, B., ZLOKOVIC, B., SMITH, J. D., LADU, M. J., ROSTAGNO, A., et al. (2000) · Biochemical Journal · doi:10.1042/bj3480359 · Cited by 272 · see citing works
Zerbinatti, C. V., Wahrle, S. E., Kim, H., Cam, J. A., Bales, K., Paul, S. M., Holtzman, D. M., & Bu, G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604436200 · Cited by 129 · see citing works
Self-citationHuman APOE genotype affects intraneuronal A 1-42 accumulation in a lentiviral gene transfer model
Zhao, W., Dumanis, S. B., Tamboli, I. Y., Rodriguez, G. A., Jo LaDu, M., Moussa, C. E. H., & William Rebeck, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddt525 · Cited by 32 · see citing works
Method for the simultaneous quantitation of apolipoprotein E isoforms using tandem mass spectrometry
Wildsmith, K. R., Han, B., & Bateman, R. J. (2009) · Analytical Biochemistry · doi:10.1016/j.ab.2009.07.049 · Cited by 31 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
- Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., and Roses, A. D. (1993) Binding of human apolipoprotein E to synthetic amyloid  peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 90, 8098 -8102
- Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D., and Roses, A. D. (1993) Increased amyloid -peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer dis- ease. Proc. Natl. Acad. Sci. U.S.A. 90, 9649 -9653
- Verghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., and Holtzman, D. M. (2013) ApoE influences amy- loid- (A) clearance despite minimal apoE/A association in physiolog- ical conditions. Proc. Natl. Acad. Sci. U.S.A. 110, E1807-E1816
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Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
ApoE 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
A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
Belloy, M. E., Napolioni, V., & Greicius, M. D. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.056 · Cited by 570 · see citing works
Huynh, T.-P. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0337-1 · Cited by 139 · see citing works
Self-citationInsulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites
Rhea, E. M., Banks, W. A., & Raber, J. (2022) · Biomedicines · doi:10.3390/biomedicines10071582 · Cited by 76 · see citing works
Giannisis, A., Al-Grety, A., Carlsson, H., Howell, J. C., Hu, W. T., Kultima, K., & Nielsen, H. M. (2023) · Alzheimer's Research & Therapy · doi:10.1186/s13195-023-01262-1 · Cited by 11 · see citing works
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Coraglia, F., Cecchetti, G., Rugarli, G., Spinelli, E. G., Ghirelli, A., Pisano, S., Canu, E., Filippi, M., & Agosta, F. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-02089-2 · Cited by 1 · see citing works
- Authors
- Baker-Nigh, A. T., Mawuenyega, K. G., Bollinger, J. G., Ovod, V., Kasten, T., Franklin, E. E., Liao, F., Jiang, H., Holtzman, D., Cairns, N. J., Morris, J. C., & Bateman, R. J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Bateman, Randall J.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 291
- Issue
- 53
- Pages
- 27204-27218
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5207148
- OpenAlex
- W2541239761
- Cited by
- 54
- References
- 19
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 10 · 2021: 7 · 2020: 4 · 2019: 8 · 2018: 2 · 2017: 3 · 2016: 1
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institutes of Health (5P50AG005681-31, R01NS065667, P01AG003991, P01AG026276)
- Alzheimer's Drug Discovery Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E isoforms, APOE ε4, APOE3, Alzheimer's disease, amyloidosis, cerebrospinal fluid, amyloid-beta
- MeSH terms
- Adult, Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Amino Acid Sequence, Amyloidosis, Astrocytes, Brain, Cells, Cultured, Dementia, Female, Humans, Male, Middle Aged, Biomarkers, Case-Control Studies, Apolipoprotein E3, Apolipoprotein E4, Young Adult
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