{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:04:34Z","timestamp":1792177474481,"version":"4.4.0"},"reference-count":102,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia\/Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior","award":["2023.06380.CEECIND"],"award-info":[{"award-number":["2023.06380.CEECIND"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a debilitating neurodegenerative disorder marked by progressive cognitive decline and memory loss, impacting millions of people around the world. The apolipoprotein E4 (ApoE4) allele is the most prominent genetic risk factor for late-onset AD, dramatically increasing disease susceptibility and accelerating onset compared to its isoforms ApoE2 and ApoE3. ApoE4\u2019s unique structure, which arises from single-amino-acid changes, profoundly alters its function. This review examines the critical interplay between ApoE4 and microglia\u2014the brain\u2019s resident immune cells\u2014and how this relationship contributes to AD pathology. We explore the molecular mechanisms by which ApoE4 modulates microglial activity, promoting a pro-inflammatory state, impairing phagocytic function, and disrupting lipid metabolism. These changes diminish microglia\u2019s ability to clear amyloid-beta peptides, exacerbating neuroinflammation and leading to neuronal damage and synaptic dysfunction. Additionally, ApoE4 adversely affects other glial cells, such as astrocytes and oligodendrocytes, further compromising neuronal support and myelination. Understanding the ApoE4\u2013microglia axis provides valuable insights into AD progression and reveals potential therapeutic targets. We discuss current strategies to modulate ApoE4 function using small molecules, antisense oligonucleotides, and gene editing technologies. Immunotherapies targeting amyloid-beta and ApoE4, along with neuroprotective approaches to enhance neuronal survival, are also examined. Future directions highlight the importance of personalized medicine based on individual ApoE genotypes, early biomarker identification for risk assessment, and investigating ApoE4\u2019s role in other neurodegenerative diseases. This review emphasizes the intricate connection between ApoE4 and microglial dysfunction, highlighting the necessity of targeting this pathway to develop effective interventions. Advancing our understanding in this area holds promise for mitigating AD progression and improving outcomes for those affected by this relentless disease.<\/jats:p>","DOI":"10.3390\/cells14040243","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T11:03:51Z","timestamp":1738926231000},"page":"243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["From Genetics to Neuroinflammation: The Impact of ApoE4 on Microglial Function in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Daniela","family":"Dias","sequence":"first","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1093-6545","authenticated-orcid":false,"given":"Camila Cabral","family":"Portugal","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o","family":"Relvas","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Socodato","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1093\/brain\/awy103","article-title":"Longitudinal brain imaging in preclinical Alzheimer disease: Impact of APOE \u03b54 genotype","volume":"141","author":"Mishra","year":"2018","journal-title":"Brain"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yamakawa, M., and Rexach, J.E. (2024). Cell States and Interactions of CD8 T Cells and Disease-Enriched Microglia in Human Brains with Alzheimer\u2019s Disease. Biomedicines, 12.","DOI":"10.3390\/biomedicines12020308"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.celrep.2019.03.099","article-title":"The Major Risk Factors for Alzheimer\u2019s Disease: Age, Sex, and Genes Modulate the Microglia Response to A\u03b2 Plaques","volume":"27","author":"Frigerio","year":"2019","journal-title":"Cell Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Caberlotto, L., Marchetti, L., Lauria, M., Scotti, M., and Parolo, S. (2016). Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer\u2019s disease. Sci. Rep., 6.","DOI":"10.1038\/srep32583"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.stemcr.2019.08.004","article-title":"PSEN1\u0394E9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia","volume":"13","author":"Konttinen","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nature24016","article-title":"ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy","volume":"549","author":"Shi","year":"2017","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41392-022-01006-x","article-title":"Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer\u2019s tau pathology","volume":"7","author":"Huang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3416","DOI":"10.1038\/s41467-021-23762-0","article-title":"Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer\u2019s disease","volume":"12","author":"Fitz","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Staurenghi, E., Leoni, V., Iacono, M.L., Sottero, B., Testa, G., Giannelli, S., Leonarduzzi, G., and Gamba, P. (2022). ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis. Antioxidants, 11.","DOI":"10.3390\/antiox11112168"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S183","DOI":"10.1194\/jlr.R800069-JLR200","article-title":"Apolipoprotein E: Structure determines function, from atherosclerosis to Alzheimer\u2019s disease to AIDS","volume":"50","author":"Mahley","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5540","DOI":"10.1038\/s41467-020-19264-0","article-title":"APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer\u2019s disease patient iPSC-derived cerebral organoids","volume":"11","author":"Zhao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"215","DOI":"10.3390\/cimb43010018","article-title":"Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro","volume":"43","author":"Iannucci","year":"2021","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s00109-016-1427-y","article-title":"Apolipoprotein E: From cardiovascular disease to neurodegenerative disorders","volume":"94","author":"Mahley","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.neuron.2008.04.010","article-title":"ApoE promotes the proteolytic degradation of A\u03b2","volume":"58","author":"Jiang","year":"2008","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/mp.2017.246","article-title":"Markers of microglia in post-mortem brain samples from patients with Alzheimer\u2019s disease: A systematic review","volume":"23","author":"Hopperton","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Friedberg, J.S., Aytan, N., Cherry, J.D., Xia, W., Standring, O.J., Alvarez, V.E., Nicks, R., Svirsky, S., Meng, G., and Jun, G. (2020). Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E \u03b54 genotype. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-59869-5"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10186","DOI":"10.1073\/pnas.1609896113","article-title":"Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes","volume":"113","author":"Chung","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.nbd.2014.08.025","article-title":"Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer\u2019s diseases","volume":"72 Pt A","author":"Huang","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s43587-021-00123-6","article-title":"Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer\u2019s disease","volume":"1","author":"Li","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9611","DOI":"10.1523\/JNEUROSCI.1400-19.2019","article-title":"ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes","volume":"39","author":"Rawat","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1074\/jbc.M111.295451","article-title":"Apolipoprotein E Promotes \u03b2-amyloid trafficking and degradation by modulating microglial cholesterol levels","volume":"287","author":"Lee","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1807","DOI":"10.1073\/pnas.1220484110","article-title":"ApoE influences amyloid-\u03b2 (A\u03b2) clearance despite minimal apoE\/A\u03b2 association in physiological conditions","volume":"110","author":"Verghese","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"48529","DOI":"10.1074\/jbc.M306923200","article-title":"APOE genotype and an apoe-mimetic peptide modify the systemic and central nervous system inflammatory response","volume":"278","author":"Lynch","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1172\/JCI36663","article-title":"apoE isoform\u2013specific disruption of amyloid \u03b2 peptide clearance from mouse brain","volume":"118","author":"Deane","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107962","DOI":"10.1016\/j.celrep.2020.107962","article-title":"In Vivo Chimeric Alzheimer\u2019s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons","volume":"32","author":"Najm","year":"2020","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"112196","DOI":"10.1016\/j.celrep.2023.112196","article-title":"APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge","volume":"42","author":"Lee","year":"2023","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Machlovi, S.I., Neuner, S.M., Hemmer, B.M., Khan, R., Liu, Y., Huang, M., Zhu, J.D., Castellano, J.M., Cai, D., and Marcora, E. (2022). APOE4 confers transcriptomic and functional alterations to primary mouse microglia. Neurobiol. Dis., 164.","DOI":"10.1016\/j.nbd.2022.105615"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Area-Gomez, E., Larrea, D., Pera, M., Agrawal, R.R., Guilfoyle, D.N., Pirhaji, L., Shannon, K., Arain, H.A., Ashok, A., and Chen, Q. (2020). APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-61142-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.neuron.2019.01.056","article-title":"A Quarter Century of APOE and Alzheimer\u2019s Disease: Progress to Date and the Path Forward","volume":"101","author":"Belloy","year":"2019","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1016\/j.cell.2022.05.017","article-title":"Cholesterol and matrisome pathways dysregulated in astrocytes and microglia","volume":"185","author":"Tcw","year":"2022","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1001\/jama.279.10.751","article-title":"The APOE-\u220a4 Allele and the Risk of Alzheimer Disease Among African Americans, Whites, and Hispanics","volume":"279","author":"Tang","year":"1998","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1046\/j.1469-1809.1999.6340301.x","article-title":"Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a \u2018thrifty\u2019 allele?","volume":"63","author":"Corbo","year":"1999","journal-title":"Ann. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s43856-023-00333-6","article-title":"Quantification of race\/ethnicity representation in Alzheimer\u2019s disease neuroimaging research in the USA: A systematic review","volume":"3","author":"Lim","year":"2023","journal-title":"Commun. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13024-022-00577-1","article-title":"Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination","volume":"17","author":"Wang","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s41586-022-05439-w","article-title":"APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes","volume":"611","author":"Blanchard","year":"2022","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/s43587-021-00073-z","article-title":"APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer\u2019s mice via cyclophilin A independently of amyloid-\u03b2","volume":"1","author":"Montagne","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.immuni.2023.12.001","article-title":"An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer\u2019s brains","volume":"57","author":"Millet","year":"2023","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s13311-022-01193-z","article-title":"Culture, Ethnicity, and Level of Education in Alzheimer\u2019s Disease","volume":"19","author":"Rosselli","year":"2022","journal-title":"Neurother.: J. Am. Soc. Exp. NeuroTherapeutics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/gerona\/glab231","article-title":"Racial\/Ethnic Disparities in Alzheimer\u2019s Disease Risk: Role of Exposure to Ambient Fine Particles","volume":"77","author":"Younan","year":"2021","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1084\/jem.20171265","article-title":"ApoE facilitates the microglial response to amyloid plaque pathology","volume":"215","author":"Ulrich","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.cell.2016.12.044","article-title":"ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and A\u03b2 Secretion","volume":"168","author":"Huang","year":"2017","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.1038\/s41467-018-06783-0","article-title":"APOE \u03b52 is associated with increased tau pathology in primary tauopathy","volume":"9","author":"Zhao","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/ana.25455","article-title":"Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease","volume":"85","author":"Wadhwani","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13024-024-00712-0","article-title":"Updates on mouse models of Alzheimer\u2019s disease","volume":"19","author":"Zhong","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1038\/s41590-023-01627-6","article-title":"APOE4 impairs the microglial response in Alzheimer\u2019s disease by inducing TGF\u03b2-mediated checkpoints","volume":"24","author":"Yin","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_46","first-page":"1311","article-title":"Apolipoprotein \u03b5 in Brain and Retinal Neurodegenerative Diseases","volume":"14","author":"Abyadeh","year":"2024","journal-title":"Aging Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6002","DOI":"10.1038\/s41380-020-00956-4","article-title":"C\/EBP\u03b2 is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer\u2019s disease","volume":"26","author":"Xia","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"158980","DOI":"10.1016\/j.bbalip.2021.158980","article-title":"Apolipoprotein E isoform-dependent effects on the processing of Alzheimer\u2019s amyloid-\u03b2. Biochimica et biophysica acta","volume":"1866","author":"Chai","year":"2021","journal-title":"Mol. Cell Biol. Lipids"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"755","DOI":"10.3233\/JAD-231163","article-title":"Alzheimer\u2019s Disease Immunotherapy: Current Strategies and Future Prospects","volume":"98","author":"Aljassabi","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/s41593-021-00851-3","article-title":"Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer\u2019s disease","volume":"24","author":"Zalocusky","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13024-024-00714-y","article-title":"APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward A\u03b2, through P2RY12","volume":"19","author":"Sepulveda","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e467","DOI":"10.15252\/embr.202256467","article-title":"Reduced binding of apoE4 to complement factor H promotes amyloid-\u03b2 oligomerization and neuroinflammation","volume":"24","author":"Chernyaeva","year":"2023","journal-title":"EMBO Rep."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Andronie-Cioara, F.L., Ardelean, A.I., Nistor-Cseppento, C.D., Jurcau, A., Jurcau, M.C., Pascalau, N., and Marcu, F. (2023). Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer\u2019s Disease Progression. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24031869"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s12035-014-9070-5","article-title":"Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases","volume":"53","author":"Tang","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5135","DOI":"10.1007\/s12035-022-02873-9","article-title":"Cyanidin-3-O-Glucoside Regulates the M1\/M2 Polarization of Microglia via PPAR\u03b3 and A\u03b242 Phagocytosis Through TREM2 in an Alzheimer\u2019s Disease Model","volume":"59","author":"Sanjay","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Xie, L., Liu, Y., Zhang, N., Li, C., Sandhu, A.F., Williams, G., Shen, Y., Li, H., Wu, Q., and Yu, S. (2021). Electroacupuncture Improves M2 Microglia Polarization and Glia Anti-inflammation of Hippocampus in Alzheimer\u2019s Disease. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.689629"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.neuron.2018.05.008","article-title":"APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer\u2019s Disease Phenotypes in Human iPSC-Derived Brain Cell Types","volume":"98","author":"Lin","year":"2018","journal-title":"Neuron"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Muth, C., Hartmann, A., Sepulveda-Falla, D., Glatzel, M., and Krasemann, S. (2019). Phagocytosis of Apoptotic Cells Is Specifically Upregulated in ApoE4 Expressing Microglia in vitro. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00181"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.stem.2024.10.005","article-title":"Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer\u2019s disease model","volume":"32","author":"Rao","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13024-023-00610-x","article-title":"Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy","volume":"18","author":"Xiong","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Mhatre-Winters, I., Eid, A., Han, Y., Tieu, K., and Richardson, J.R. (2022). Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Microglia from APOE Targeted Replacement Mice. Int. J. Mol. Sci., 23.","DOI":"10.21203\/rs.3.rs-1281462\/v1"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13024-020-00407-2","article-title":"Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration","volume":"15","author":"Franzmeier","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.stem.2022.07.005","article-title":"Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity","volume":"29","author":"Victor","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13024-020-00394-4","article-title":"Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice","volume":"15","author":"Fitz","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.neuron.2017.11.013","article-title":"ApoE4 Accelerates Early Seeding of Amyloid Pathology","volume":"96","author":"Liu","year":"2017","journal-title":"Neuron"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13024-020-0358-9","article-title":"Therapeutic approaches targeting Apolipoprotein E function in Alzheimer\u2019s disease","volume":"15","author":"Williams","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1038\/s41591-023-02380-x","article-title":"Astrocyte reactivity influences amyloid-\u03b2 effects on tau pathology in preclinical Alzheimer\u2019s disease","volume":"29","author":"Bellaver","year":"2023","journal-title":"Nat. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1007\/s10571-023-01365-1","article-title":"Roles of ApoE4 on the Pathogenesis in Alzheimer\u2019s Disease and the Potential Therapeutic Approaches","volume":"43","author":"Sun","year":"2023","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1016\/j.neurobiolaging.2007.04.013","article-title":"Neocortical glial cell numbers in human brains","volume":"29","author":"Pelvig","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s40035-023-00385-7","article-title":"Oligodendrocyte progenitor cells in Alzheimer\u2019s disease: From physiology to pathology","volume":"12","author":"Zou","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rajani, R.M., Ellingford, R., Hellmuth, M., Harris, S.S., Taso, O.S., Graykowski, D., Lam, F.K.W., Arber, C., Fertan, E., and Danial, J.S.H. (2024). Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer\u2019s disease. PLoS Biol., 22.","DOI":"10.1101\/2024.06.21.600003"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"111200","DOI":"10.1016\/j.celrep.2022.111200","article-title":"APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-\u03baB activation","volume":"40","author":"Arnaud","year":"2022","journal-title":"Cell Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent advances in Alzheimer\u2019s disease: Mechanisms, clinical trials and new drug development strategies","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s12276-023-00935-z","article-title":"TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia","volume":"55","author":"Wang","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.neuron.2020.02.034","article-title":"Alzheimer\u2019s Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways","volume":"106","author":"Zhao","year":"2020","journal-title":"Neuron"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.neuron.2012.11.020","article-title":"Apolipoprotein e sets the stage: Response to injury triggers neuropathology","volume":"76","author":"Mahley","year":"2012","journal-title":"Neuron"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1084\/jem.20190980","article-title":"Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model","volume":"216","author":"Shi","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/j.neuron.2021.03.024","article-title":"Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia","volume":"109","author":"Wang","year":"2021","journal-title":"Neuron"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy","volume":"9","author":"Liu","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1111\/j.1582-4934.2007.00130.x","article-title":"Apolipoprotein E and Alzheimer\u2019s disease: Molecular mechanisms and therapeutic opportunities","volume":"11","year":"2007","journal-title":"J. Cell. Mol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.neuron.2017.11.014","article-title":"Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of \u03b2-amyloidosis","volume":"96","author":"Huynh","year":"2017","journal-title":"Neuron"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1002\/ana.26043","article-title":"Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model","volume":"89","author":"Litvinchuk","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_83","first-page":"439","article-title":"The Potential of CRISPR\/Cas9 Gene Editing as a Treatment Strategy for Alzheimer\u2019s Disease","volume":"8","author":"Rohn","year":"2018","journal-title":"J. Alzheimer\u2019s Dis. Park."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.neurobiolaging.2006.03.013","article-title":"NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies","volume":"28","author":"McGeer","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1172\/JCI96429","article-title":"Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation","volume":"128","author":"Liao","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s10787-019-00613-5","article-title":"Microglial polarization: Novel therapeutic mechanism against Alzheimer\u2019s disease","volume":"28","author":"Yao","year":"2019","journal-title":"Inflammopharmacology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1084\/jem.20121274","article-title":"Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of A\u03b2 amyloidosis","volume":"209","author":"Kim","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/s41593-019-0352-0","article-title":"In vivo neuronal gene editing via CRISPR\u2013Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer\u2019s disease","volume":"22","author":"Park","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Yang, W., Tu, Z., Sun, Q., and Li, X.-J. (2016). CRISPR\/Cas9: Implications for Modeling and Therapy of Neurodegenerative Diseases. Front. Mol. Neurosci., 9.","DOI":"10.3389\/fnmol.2016.00030"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.pnpbp.2017.04.003","article-title":"Use of CRISPR\/Cas9 to model brain diseases","volume":"81","author":"Yan","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13024-022-00574-4","article-title":"ApoE in Alzheimer\u2019s disease: Pathophysiology and therapeutic strategies","volume":"17","author":"Raulin","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces A\u03b2 plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"ref_93","first-page":"e12377","article-title":"ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer\u2019s disease","volume":"9","author":"Honig","year":"2023","journal-title":"Alzheimer\u2019s Dementia: Transl. Res. Clin. Interv."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9677","DOI":"10.1523\/JNEUROSCI.4742-11.2012","article-title":"An Effector-reduced anti-\u03b2-amyloid (A\u03b2) antibody with unique A\u03b2 binding properties promotes neuroprotection and glial engulfment of A\u03b2","volume":"32","author":"Adolfsson","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1089\/ars.2020.8134","article-title":"Preventive and Therapeutic Strategies in Alzheimer\u2019s Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis","volume":"34","author":"Perry","year":"2021","journal-title":"Antioxidants Redox Signal."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Monacelli, F., Acquarone, F.M.E., Giannotti, C., Borghi, R., and Nencioni, A. (2017). Vitamin C, Aging and Alzheimer\u2019s Disease. Nutrients, 9.","DOI":"10.3390\/nu9070670"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"877","DOI":"10.3233\/JAD-220700","article-title":"Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer\u2019s Disease","volume":"96","author":"Mani","year":"2023","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1016\/j.neuron.2024.02.009","article-title":"Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer\u2019s disease profile and possible mechanisms of disease protection","volume":"112","author":"Almeida","year":"2024","journal-title":"Neuron"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1038\/s41467-017-01444-0","article-title":"Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer\u2019s disease-like pathology","volume":"8","author":"Nuriel","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1002\/alz.13809","article-title":"2024 Alzheimer\u2019s disease facts and figures","volume":"20","author":"Better","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e20221137","DOI":"10.1084\/jem.20221137","article-title":"A \u201cmulti-omics\u201d analysis of blood\u2013brain barrier and synaptic dysfunction in APOE4 mice","volume":"219","author":"Barisano","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.neurobiolaging.2018.07.007","article-title":"The spectrum of preclinical Alzheimer\u2019s disease pathology and its modulation by ApoE genotype","volume":"71","author":"Pletnikova","year":"2018","journal-title":"Neurobiol. Aging"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/4\/243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:29:02Z","timestamp":1760027342000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/4\/243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,7]]},"references-count":102,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cells14040243"],"URL":"https:\/\/doi.org\/10.3390\/cells14040243","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,7]]}}}