ApoE4 Accelerates Early Seeding of Amyloid Pathology
Open accessAbstract
Accumulation and aggregation of amyloid-β (Aβ) in the brain is an initiating step in the pathogenesis of Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (apoE) gene is the strongest genetic risk factor for late-onset AD. Although there is strong evidence showing that apoE4 enhances amyloid pathology, it is not clear what the critical stage(s) is during amyloid development in which apoE4 has the strongest impact. Using apoE inducible mouse models, we show that increased expression of astrocytic apoE4, but not apoE3, during the seeding stage of amyloid development enhanced amyloid deposition and neuritic dystrophy in amyloid model mice. ApoE4, but not apoE3, significantly increased brain Aβ half-life measured by in vivo microdialysis. Furthermore, apoE4 expression increased whereas apoE3 reduced amyloid-related gliosis in the mouse brains. Together, our results demonstrate that apoE4 has the greatest impact on amyloid during the seeding stage, likely by perturbing Aβ clearance and enhancing Aβ aggregation.
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APOE4 is associated with increased amyloid-β deposition, hyperphosphorylation and aggregation of tau, and accelerated cognitive decline.
“APOE4 is associated with increased amyloid-β deposition, hyperphosphorylation and aggregation of tau, and accelerated cognitive decline4–7.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [4]
The Introduction states that Aβ plaques are more abundant in APOE4 carriers, and the Discussion describes apoE4’s role in early amyloid plaque formation (page numbers unavailable). The passages do not link APOE4 to tau hyperphosphorylation or aggregation, or to accelerated cognitive decline; the Discussion mentions cognitive decline only as a later clinical event relative to Aβ deposition. (LLM, conf=0.88)
Experimental — accuracy not yet measuredUsing homozygous human APOE knock-in mice, previous work demonstrated that APOE4 promotes Aβ aggregation and impairs its clearance relative to APOE3.
“Using homozygous human APOE knock-in mice, previous work demonstrated that APOE4 promotes A β aggregation and impairs its clearance relative to APOE3 34,38,39 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [38]
The Results section reports that astrocytic apoE4 increased Aβ half-life while apoE3 did not affect clearance; the Discussion says apoE4 may enhance early amyloid seeding and aggregation. But this study used inducible, astrocyte-specific human apoE expression in mice retaining murine apoE, not homozygous human APOE targeted-replacement mice (Results, “Novel mouse models”; Discussion). The aggregation mechanism is presented as a likely explanation rather than directly demonstrated. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLiu et al. showed that astrocyte-specific expression of E4 suppressed amyloid clearance, with particularly strong effects during the amyloid seeding phase.
“Using an inverse approach, Liu et al.46 showed that astrocyte-specific expression of E4 suppressed amyloid clearance, with particularly strong effects during the amyloid seeding phase.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as Liu et al.46
The Results section, “Expression of apoE4 in astrocytes suppresses Aβ clearance” (page unavailable), reports impaired Aβ clearance with astrocytic apoE4. A separate Results section finds stronger effects on Aβ levels and amyloid deposition when apoE4 was expressed during seeding than during rapid plaque growth. It does not establish that the suppression of clearance itself was particularly strong during seeding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAssessments of apoE-Aβ aggregates at the end stage of amyloid development may not fully recapitulate the apoE effects on Aβ seeding at the initial stage.
“The assessments of apoE-Aβ aggregates at the end stage of amyloid development may not fully recapitulate the apoE effects on Aβ seeding at the initial stage (47).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [47]
The Results and Discussion (page not available in our copy) show that astrocytic apoE4 has a strong effect during initial Aβ seeding but little effect when expressed after that stage, supporting the concern that timing matters. The paper does not directly assess whether measurements of apoE-Aβ aggregates at the end stage recapitulate those early effects. (LLM, conf=0.82)
Experimental — accuracy not yet measuredApoE is enriched in amyloid plaques as a major constituent and promotes Aβ aggregation.
“apoE is enriched in amyloid plaques as a major constituent and promotes Aβ aggregation”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liu et al 2017
The Discussion (page unavailable) calls apoE a component of cerebral amyloid deposits, but does not establish that it is enriched in plaques or a major constituent. It reports that apoE4 can enhance Aβ fibrillogenesis and may promote amyloid seeding; the claim extends that finding to apoE generally and states it without the paper’s qualification. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Restoration of APOE expression in astrocytes alone is sufficient to induce formation of fibrillar plaques and microglia reactivity.
“Restoration of APOE expression in astrocytes alone is sufficient to induce formation of fibrillar plaques and microglia reactivity, extending findings from previous studies (Holtzman et al, 2000a; Liu et al, 2017b; Mahan et al, 2022).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Liu et al, 2017b
The Results sections on fibrillar plaques and Aβ-associated gliosis report that astrocytic apoE4 expression increased fibrillar plaque formation and Iba1-positive microglia in APP mice. The claim is broader than those findings: apoE3 did not increase either measure, and the study shows enhanced plaque formation in an amyloid-prone model, not that astrocytic APOE expression alone initiates plaques. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 significantly alters signaling pathways associated with cholesterol homeostasis and transport.
“Consistent with APOE’s biological function2–6, APOE4 significantly altered signaling pathways associated with cholesterol homeostasis and transport.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [4]
ApoE markedly accelerates amyloid deposition and tau-mediated neurodegeneration in mouse models.
“ApoE also markedly accelerates amyloid deposition (23,24) as well as taumediated neurodegeneration in mouse models (25).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [24]
APOE affects the seeding and aggregation of Aβ in an isoform-dependent manner.
“Indeed, APOE affects the seeding and aggregation of Aβ in an isoform-dependent manner112, and the increased propensity of Aβ to oligomerize in the presence of APOE4 is considered a major mechanism by which APOE4 increases AD risk113–116 (Fig. 2c).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [112]
The Aβ changes suggest distinct biochemical interactions influencing Aβ deposition or clearance.
“suggesting the distinct biochemical interactions influencing Aβ deposition or clearance [2, 3, 22, 23].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [23]
ApoE4 can drive amyloid pathology during the seeding stage.
“apoE4 can drive amyloid pathology during the seeding stage”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liu et al 2017
In APP transgenic mouse models, genetic expression of human APOE4 promotes Aβ seeding, accelerates Aβ oligomerization and deposition in the brain.
“In APP transgenic mouse models, genetic expression of human APOE4 was found to promote Aβ seeding, accelerate Aβ oligomerization and deposition in the brain [455, 456].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [456]
ApoE plays a significant role in the initiation of amyloid-β pathology; after amyloid-β pathology has been initiated, lowering apoE modulates plaque size and toxicity.
“Taken together, these results indicate that apoE plays a significant role in the initiation of Aβ pathology; however, after Aβ pathology has been initiated, lowering apoE modulates plaque size and toxicity.”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [54]
ApoE is essential for plaque formation during the initial seeding stage.
“ApoE was found to be essential for plaque formation during the initial seeding stage121,122.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [121]
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Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · 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
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226 · see citing works
Clinical and biomarker changes in dominantly inherited Alzheimer's disease
Bateman, R. J., Xiong, C., Benzinger, T. L. S., Fagan, A. M., Goate, A., Fox, N. C., Marcus, D. S., Cairns, N. J., Xie, X., Blazey, T. M., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1202753 · Cited by 3,814 · see citing works
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · see citing works
Self-citationVillemagne, V. L., Burnham, S., Bourgeat, P., Brown, B., Ellis, K. A., Salvado, O., Szoeke, C., Macaulay, S. L., Martins, R., Maruff, P., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70044-9 · Cited by 2,279 · see citing works
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078 · see citing works
The Amyloid State of Proteins in Human Diseases
Eisenberg, D. S., & Jucker, M. (2012) · Cell · doi:10.1016/j.cell.2012.02.022 · Cited by 1,732 · see citing works
Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia: A Meta-analysis
Jansen, W. J., Ossenkoppele, R., Knol, D. L., Tijms, B. M., Scheltens, P., Verhey, F. R. J., Visser, P. J., Aalten, P., Aarsland, D., Alcolea, D., et al. (2015) · JAMA · doi:10.1001/jama.2015.4668 · Cited by 1,610 · see citing works
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · see citing works
Human 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 · see citing works
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168 · see citing works
Self-citationBiomarker Modeling of Alzheimer’s Disease
Jack, C. R., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.12.003 · Cited by 1,002 · see citing works
Exogenous Induction of Cerebral ß-Amyloidogenesis Is Governed by Agent and Host
Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A. L., et al. (2006) · Science · doi:10.1126/science.1131864 · Cited by 971 · see citing works
Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830 · see citing works
<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
Reiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900345106 · Cited by 785 · see citing works
apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36663 · Cited by 771 · see citing works
Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease
Garcia-Alloza, M., Robbins, E. M., Zhang-Nunes, S. X., Purcell, S. M., Betensky, R. A., Raju, S., Prada, C., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.08.017 · Cited by 744 · see citing works
Multimodal techniques for diagnosis and prognosis of Alzheimer's disease
Perrin, R. J., Fagan, A. M., & Holtzman, D. M. (2009) · Nature · doi:10.1038/nature08538 · Cited by 702 · see citing works
Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders
Jucker, M., & Walker, L. C. (2011) · Annals of Neurology · doi:10.1002/ana.22615 · Cited by 622 · see citing works
Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo
Bateman, R. J., Munsell, L. Y., Morris, J. C., Swarm, R., Yarasheski, K. E., & Holtzman, D. M. (2006) · Nature Medicine · doi:10.1038/nm1438 · Cited by 599 · see citing works
Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.
(1994) · PubMed Central · Cited by 441 · see citing works
Chen, Y., Durakoglugil, M. S., Xian, X., & Herz, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914984107 · Cited by 368 · see citing works
Bajenaru, M. L., Zhu, Y., Hedrick, N. M., Donahoe, J. S., Parada, L. F., & Gutmann, D. H. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.14.5100-5113.2002 · Cited by 322 · see citing works
Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age
Kok, E., Haikonen, S., Luoto, T., Huhtala, H., Goebeler, S., Haapasalo, H., & Karhunen, P. J. (2009) · Annals of Neurology · doi:10.1002/ana.21696 · Cited by 299 · see citing works
Human<i>APOE</i>Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
Bales, K. R., Liu, F., Wu, S., Lin, S., Koger, D., DeLong, C., Hansen, J. C., Sullivan, P. M., & Paul, S. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0887-09.2009 · Cited by 274 · see citing works
Liu, C.-C., Tsai, C.-W., Deak, F., Rogers, J., Penuliar, M., Sung, Y. M., Maher, J. N., Fu, Y., Li, X., Xu, H., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.048 · Cited by 222 · see citing works
Gong, J.-S., Kobayashi, M., Hayashi, H., Zou, K., Sawamura, N., Fujita, S. C., Yanagisawa, K., & Michikawa, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203934200 · Cited by 214 · see citing works
Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis
Huynh, T.-P. V., Liao, F., Francis, C. M., Robinson, G. O., Serrano, J. R., Jiang, H., Roh, J., Finn, M. B., Sullivan, P. M., Esparza, T. J., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.014 · Cited by 209 · see citing works
Liu, C.-C., Zhao, N., Yamaguchi, Y., Cirrito, J. R., Kanekiyo, T., Holtzman, D. M., & Bu, G. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad3650 · Cited by 180 · see citing works
Self-citationNeuronal LRP1 Regulates Glucose Metabolism and Insulin Signaling in the Brain
Liu, C., Hu, J., Tsai, C., Yue, M., Melrose, H. L., Kanekiyo, T., & Bu, G. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.5180-14.2015 · Cited by 140 · see citing works
Self-citationLaDu, M. J., Shah, J. A., Reardon, C. A., Getz, G. S., Bu, G., Hu, J., Guo, L., & Van Eldik, L. J. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00050-x · Cited by 118 · see citing works
Self-citationGrace, E. A., & Busciglio, J. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-02-00493.2003 · Cited by 113 · see citing works
Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils
Hatters, D. M., Zhong, N., Rutenber, E., & Weisgraber, K. H. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.06.080 · Cited by 105 · see citing works
Liu, D.-S., Pan, X.-D., Zhang, J., Shen, H., Collins, N. C., Cole, A. M., Koster, K. P., Ben Aissa, M., Dai, X.-M., Zhou, M., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0002-2 · Cited by 99 · see citing works
Zhao, J., Fu, Y., Liu, C., Shinohara, M., Nielsen, H. M., Dong, Q., Kanekiyo, T., & Bu, G. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.526095 · Cited by 70 · see citing works
Self-citationIn vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques
Burgold, S., Filser, S., Dorostkar, M. M., Schmidt, B., & Herms, J. (2014) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-2-30 · Cited by 59 · see citing works
Plasma Signaling Proteins in Persons at Genetic Risk for Alzheimer Disease
Ringman, J. M., Elashoff, D. A., Geschwind, D. H., Welsh, B. T., Gylys, K. H., Lee, C., Cummings, J. L., & Cole, G. M. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.277 · Cited by 55 · see citing works
Thal, D. R., Capetillo-Zarate, E., Schultz, C., Rüb, U., Saido, T. C., Yamaguchi, H., Haass, C., Griffin, W. S. T., Del Tredici, K., Braak, H., et al. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1053-1 · Cited by 50 · see citing works
LaDu, M. J., Stine, Narita, M., Getz, G. S., Reardon, C. A., & Bu, G. (2006) · Biochemistry · doi:10.1021/bi051765s · Cited by 36 · see citing works
Self-citationDevelopment of a single-cassette system for spatiotemporal gene regulation in mice
Miyazaki, S., Miyazaki, T., Tashiro, F., Yamato, E., & Miyazaki, J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.10.054 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952 · see citing works
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
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
Self-citationMolecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037 · 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
Self-citationImaging the evolution and pathophysiology of Alzheimer disease
Jagust, W. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0067-3 · Cited by 604 · see citing works
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0296-9 · Cited by 555 · see citing works
Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
Shi, Y., & Holtzman, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0051-1 · Cited by 595 · see citing works
APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes
Blanchard, J. W., Akay, L. A., Davila-Velderrain, J., von Maydell, D., Mathys, H., Davidson, S. M., Effenberger, A., Chen, C.-Y., Maner-Smith, K., Hajjar, I., et al. (2022) · Nature · doi:10.1038/s41586-022-05439-w · Cited by 493 · see citing works
“5g,h and Supplementary Tables 9 and 10) genes.”
InfluentialWang, 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
ApoE facilitates the microglial response to amyloid plaque pathology
Ulrich, J. D., Ulland, T. K., Mahan, T. E., Nyström, S., Nilsson, K. P., Song, W. M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171265 · Cited by 297 · see citing works
Wang, C., Xiong, M., Gratuze, M., Bao, X., Shi, Y., Andhey, P. S., Manis, M., Schroeder, C., Yin, Z., Madore, C., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.03.024 · Cited by 334 · see citing works
ApoE attenuates unresolvable inflammation by complex formation with activated C1q
Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0336-8 · Cited by 305 · see citing works
Jeremic, D., Jiménez-Díaz, L., & Navarro-López, J. D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101496 · Cited by 306 · see citing works
Emerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297 · see citing works
Apolipoprotein E and Alzheimer’s disease: Findings, hypotheses, and potential mechanisms
Koutsodendris, N., Nelson, M. R., Rao, A., & Huang, Y. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-030421-112756 · Cited by 231 · see citing works
Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime?
Liddelow, S. A., Marsh, S. E., & Stevens, B. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.07.006 · Cited by 226 · see citing works
Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors
Van Acker, Z. P., Bretou, M., & Annaert, W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0323-7 · Cited by 222 · see citing works
Morris, G. P., Clark, I. A., & Vissel, B. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1918-8 · Cited by 212 · see citing works
Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis
Huynh, T.-P. V., Liao, F., Francis, C. M., Robinson, G. O., Serrano, J. R., Jiang, H., Roh, J., Finn, M. B., Sullivan, P. M., Esparza, T. J., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.014 · Cited by 209 · see citing works
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96429 · Cited by 178 · see citing works
APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1
Tachibana, M., Holm, M.-L., Liu, C.-C., Shinohara, M., Aikawa, T., Oue, H., Yamazaki, Y., Martens, Y. A., Murray, M. E., Sullivan, P. M., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124853 · Cited by 156 · see citing works
Self-citationTzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147 · see citing works
Liu, C.-C., Wang, N., Chen, Y., Inoue, Y., Shue, F., Ren, Y., Wang, M., Qiao, W., Ikezu, T. C., Li, Z., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01640-9 · Cited by 146 · see citing works
Self-citationMahan, T. E., Wang, C., Bao, X., Choudhury, A., Ulrich, J. D., & Holtzman, D. M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00516-0 · Cited by 134 · see citing works
<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108 · see citing works
Self-citationLi, H., Liu, C.-C., Zheng, H., & Huang, T. Y. (2018) · Translational Neurodegeneration · doi:10.1186/s40035-018-0139-3 · Cited by 103 · see citing works
Self-citationKaji, S., Berghoff, S. A., Spieth, L., Schlaphoff, L., Sasmita, A. O., Vitale, S., Büschgens, L., Kedia, S., Zirngibl, M., Nazarenko, T., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.09.014 · Cited by 104 · see citing works
Enhancing face validity of mouse models of Alzheimer’s disease with natural genetic variation
Onos, K. D., Uyar, A., Keezer, K. J., Jackson, H. M., Preuss, C., Acklin, C. J., O’Rourke, R., Buchanan, R., Cossette, T. L., Sukoff Rizzo, S. J., et al. (2019) · PLOS Genetics · doi:10.1371/journal.pgen.1008155 · Cited by 93 · see citing works
Cashikar, A. G., Toral-Rios, D., Timm, D., Romero, J., Strickland, M., Long, J. M., Han, X., Holtzman, D. M., & Paul, S. M. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100350 · Cited by 72 · see citing works
The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
Lau, S.-F., Wu, W., Wong, H. Y., Ouyang, L., Qiao, Y., Xu, J., Lau, J. H.-Y., Wong, C., Jiang, Y., Holtzman, D. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00491-1 · Cited by 70 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
Self-citationVance, J. M., Farrer, L. A., Huang, Y., Cruchaga, C., Hyman, B. T., Pericak‐Vance, M. A., Goate, A. M., Greicius, M. D., Griswold, A. J., Haines, J. L., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26864 · Cited by 52 · see citing works
Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
Staurenghi, E., Giannelli, S., Testa, G., Sottero, B., Leonarduzzi, G., & Gamba, P. (2021) · Antioxidants · doi:10.3390/antiox10121890 · Cited by 44 · see citing works
Henningfield, C. M., Arreola, M. A., Soni, N., Spangenberg, E. E., & Green, K. N. (2022) · Glia · doi:10.1002/glia.24105 · Cited by 40 · see citing works
Microglial phagocytosis in Alzheimer disease
Brown, G. C., St George-Hyslop, P., Paolicelli, R. C., & Lemke, G. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-025-01162-y · Cited by 36 · see citing works
Preman, P., Moechars, D., Fertan, E., Wolfs, L., Serneels, L., Shah, D., Lamote, J., Poovathingal, S., Snellinx, A., Mancuso, R., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00162-7 · Cited by 32 · see citing works
Current insights into apolipoprotein E and the immune response in Alzheimer's disease
Lin, P. B., & Holtzman, D. M. (2024) · Immunological Reviews · doi:10.1111/imr.13414 · Cited by 19 · see citing works
Golden, L. R., Siano, D. S., Stephens, I. O., MacLean, S. M., Saito, K., Nolt, G. L., Funnell, J. L., Pallerla, A. V., Lee, S., Smith, C., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02094-y · Cited by 18 · see citing works
ApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2 · see citing works
Chen, K., Chen, Y., Ren, Y., Wang, Z., Huang, Y., Pan, M., Li, Z., Casey, M. C., Qiao, W., Shi, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-78407-x
Self-citationAstrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice
Raulin, A.-C., Alnobani, A., Rodriguez-Martinez, P., Lee, E., Linares, C., Yslas, A. R., Li, M., Ren, Y., Doss, S. V., Roy, B., et al. (2026) · Translational Psychiatry · doi:10.1038/s41398-026-04002-9
Self-citation
- Authors
- Liu, C.-C., Zhao, N., Fu, Y., Wang, N., Linares, C., Tsai, C.-W., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Liu, Chia-Chen
- Bu, Guojun
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 96
- Issue
- 5
- Pages
- 1024-1032.e3
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5948105
- OpenAlex
- W2774718202
- Cited by
- 451
- References
- 43
- Citations by year
- 2026: 56 · 2025: 69 · 2024: 57 · 2023: 47 · 2022: 59 · 2021: 53 · 2020: 49 · 2019: 36 · 2018: 22 · 2017: 2 · 2015: 1
- FWCI
- 22.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- NIH (R01AG046205, R37AG027924, R01AG035355, RF1AG051504, P01NS074969, P50AG016574)
- Cure Alzheimer's Fund
- BrightFocus Foundation (A2016346F)
- Alzheimer's Association (AARG-17-500335)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, apolipoprotein E3, amyloid-beta, amyloid seeding, Alzheimer's disease, astrocytes, amyloid deposition, neuritic dystrophy, amyloid clearance, gliosis, inducible mouse model
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Astrocytes, Brain, Gliosis, Humans, Mice, Transgenic, Neurites, Mice, Apolipoprotein E3, Apolipoprotein E4, Gene Knock-In Techniques
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