{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:49:58Z","timestamp":1787698198630,"version":"build-2784847793"},"reference-count":122,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Apolipoprotein E (APOE = gene, ApoE = protein) is a glycoprotein involved in the biological process of lipid transportation and metabolism, contributing to lipid homeostasis. APOE has been extensively studied for its correlation with neurodegenerative diseases, in particular Alzheimer\u2019s disease (AD), where the possession of the epsilon 4 (E4) allele is established as a risk factor for developing AD in non-familiar sporadic forms. Recently, evidence suggests a broad involvement of E4 also in other neurological conditions, where it has been shown to be a predictive marker for worse clinical outcomes in Parkinson\u2019s disease (PD), brain trauma, and disturbances of consciousness. The mechanisms underlying these associations are complex and involve amyloid-\u03b2 (A\u03b2) peptide accumulation and neuroinflammation, although many others have yet to be identified. Objectives: The aim of this review is to overview the current knowledge on ApoE as a non-protagonist actor in processes underlying neurodegenerative diseases and its clinical significance in AD, PD, acquired brain trauma, and Disorders of Consciousness (DoC). Ethical implications of genetic testing for APOE variants and information disclosure will also be briefly discussed.<\/jats:p>","DOI":"10.3390\/genes15111397","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T12:25:39Z","timestamp":1730291139000},"page":"1397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["ApoE: The Non-Protagonist Actor in Neurological Diseases"],"prefix":"10.3390","volume":"15","author":[{"given":"Lorenzo","family":"Grimaldi","sequence":"first","affiliation":[{"name":"Clinical Neurochemistry Unit and Biobank, IRCCS Santa Lucia Foundation, Via Ardeatina, 306\/354, 00179 Rome, Italy"},{"name":"European Center for Brain Research, Via del Fosso del Fiorano, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Bovi","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Unit and Biobank, IRCCS Santa Lucia Foundation, Via Ardeatina, 306\/354, 00179 Rome, Italy"},{"name":"Parkinson\u2019s Disease Unit, University Hospital of Rome \u201cTor Vergata\u201d, Viale Oxford 81, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2516-0540","authenticated-orcid":false,"given":"Rita","family":"Formisano","sequence":"additional","affiliation":[{"name":"Post-Coma Unit and Neurorehabilitation, IRCCS Santa Lucia Foundation, Via Ardeatina, 306\/354, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Sancesario","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Unit and Biobank, IRCCS Santa Lucia Foundation, Via Ardeatina, 306\/354, 00179 Rome, Italy"},{"name":"European Center for Brain Research, Via del Fosso del Fiorano, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1073\/pnas.90.5.1977","article-title":"Apolipoprotein E: High-avidity binding to \u03b2-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease","volume":"90","author":"Strittmatter","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13024-020-00413-4","article-title":"APOE2: Protective mechanism and therapeutic implications for Alzheimer\u2019s disease","volume":"15","author":"Li","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"314","DOI":"10.2174\/1567202620666230721122957","article-title":"The Metabolic Basis for Nervous System Dysfunction in Alzheimer\u2019s Disease, Parkinson\u2019s Disease, and Huntington\u2019s Disease","volume":"20","author":"Maiese","year":"2023","journal-title":"Curr. Neurovascular Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41582-024-00988-2","article-title":"Multifaceted roles of APOE in Alzheimer disease","volume":"20","author":"Jackson","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.4103\/1673-5374.335824","article-title":"Status of precision medicine approaches to traumatic brain injury","volume":"17","author":"Reddi","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1089\/neu.2017.5583","article-title":"Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms","volume":"38","author":"Zeiler","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6240","DOI":"10.1016\/S0021-9258(18)88963-3","article-title":"Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene","volume":"260","author":"Das","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.stem.2020.12.018","article-title":"ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response","volume":"28","author":"Wang","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1089\/rej.2011.1169","article-title":"The genetics of the human APOE polymorphism","volume":"14","author":"Seripa","year":"2011","journal-title":"Rejuvenation Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41582-019-0228-7","article-title":"Apolipoprotein E and Alzheimer disease: Pathobiology and targeting strategies","volume":"15","author":"Yamazaki","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s13024-022-00566-4","article-title":"APOE in the bullseye of neurodegenerative diseases: Impact of the APOE genotype in Alzheimer\u2019s disease pathology and brain diseases","volume":"17","author":"Konings","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1086\/381662","article-title":"Meat-adaptive genes and the evolution of slower aging in humans","volume":"79","author":"Finch","year":"2004","journal-title":"Q. Rev. Biol."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0197-4580(99)00053-6","article-title":"The evolution of Alzheimer disease, the reproductive schedule, and apoE isoforms","volume":"20","author":"Finch","year":"1999","journal-title":"Neurobiol. Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e23260","DOI":"10.1002\/ajp.23260","article-title":"Aging-related Alzheimer\u2019s disease-like neuropathology and functional decline in captive vervet monkeys (Chlorocebus aethiops sabaeus)","volume":"83","author":"Frye","year":"2021","journal-title":"Am. J. Primatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S1537-1891(02)00198-2","article-title":"Circulating amyloid-\u03b2 peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer\u2019s disease lesions","volume":"38","author":"Mackic","year":"2002","journal-title":"Vasc. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.arr.2017.06.002","article-title":"Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors","volume":"37","author":"Huebbe","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.neuron.2009.06.026","article-title":"The role of apolipoprotein E in Alzheimer\u2019s disease","volume":"63","author":"Kim","year":"2009","journal-title":"Neuron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1074\/jbc.M007008200","article-title":"Transcription factors Zic1 and Zic2 bind and transactivate the apolipoprotein E gene promoter","volume":"276","author":"Salero","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1042\/bj20021142","article-title":"Identification of a non-canonical E-box motif as a regulatory element in the proximal promoter region of the apolipoprotein E gene","volume":"370","author":"Salero","year":"2003","journal-title":"Biochem. J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lee, E.G., Tulloch, J., Chen, S., Leong, L., Saxton, A.D., Kraemer, B., Darvas, M., Keene, C.D., Shutes-David, A., and Todd, K. (2020). Redefining transcriptional regulation of the APOE gene and its association with Alzheimer\u2019s disease. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0227667"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1523\/JNEUROSCI.3253-07.2008","article-title":"Intron-3 retention\/splicing controls neuronal expression of apolipoprotein E in the CNS","volume":"28","author":"Xu","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1093\/hmg\/ddn091","article-title":"Identification of ZNF313\/RNF114 as a novel psoriasis susceptibility gene","volume":"17","author":"Capon","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5036","DOI":"10.1093\/hmg\/ddt354","article-title":"Epigenetic signature and enhancer activity of the human APOE gene","volume":"22","author":"Yu","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S1050-1738(00)00033-5","article-title":"The cell biology and physiologic relevance of ApoE recycling","volume":"10","author":"Fazio","year":"2000","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1194\/jlr.R082313","article-title":"Is ABCA1 a lipid transfer protein?","volume":"59","author":"Phillips","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/prot.20080","article-title":"Apolipoprotein E-low density lipoprotein receptor binding: Study of protein-protein interaction in rationally selected docked complexes","volume":"55","author":"Raussens","year":"2004","journal-title":"Proteins"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14813","DOI":"10.1073\/pnas.1106420108","article-title":"Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions","volume":"108","author":"Chen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8913","DOI":"10.1073\/pnas.1207022109","article-title":"Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer\u2019s disease","volume":"109","author":"Frieden","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/S0022-2275(20)42621-5","article-title":"Apolipoprotein E distribution among human plasma lipoproteins: Role of the cysteine-arginine interchange at residue 112","volume":"31","author":"Weisgraber","year":"1990","journal-title":"J. Lipid Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1161\/01.ATV.8.1.1","article-title":"Apolipoprotein E polymorphism and atherosclerosis","volume":"8","author":"Davignon","year":"1988","journal-title":"Arteriosclerosis"},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.dadm.2018.10.005","article-title":"Apolipoprotein E particle size is increased in Alzheimer\u2019s disease","volume":"11","author":"Nelson","year":"2019","journal-title":"Alzheimers Dement. (Amst.)"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1007\/s00018-003-3018-7","article-title":"Cholesterol homeostasis and function in neurons of the central nervous system","volume":"60","author":"Pfrieger","year":"2003","journal-title":"Cell Mol. Life Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1126\/science.294.5545.1354","article-title":"CNS synaptogenesis promoted by glia-derived cholesterol","volume":"294","author":"Mauch","year":"2001","journal-title":"Science"},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.biopsych.2017.03.003","article-title":"Apolipoprotein E, Receptors, and Modulation of Alzheimer\u2019s Disease","volume":"83","author":"Zhao","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"7410","DOI":"10.1074\/jbc.275.10.7410","article-title":"Modulation of \u03b2-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer\u2019s disease","volume":"275","author":"Ulery","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1172\/JCI11013","article-title":"Modulation of amyloid \u03b2-protein clearance and Alzheimer\u2019s disease susceptibility by the LDL receptor-related protein pathway","volume":"106","author":"Kang","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Stuckey, S.M., Ong, L.K., Collins-Praino, L.E., and Turner, R.J. (2021). Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313101"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1177\/10738584211036693","article-title":"Biobanking for Neurodegenerative Diseases: Challenge for Translational Research and Data Privacy","volume":"29","author":"Giannella","year":"2023","journal-title":"Neuroscientist"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000354764","article-title":"Increased levels of serum IL-18 are associated with the long-term outcome of severe traumatic brain injury","volume":"21","author":"Ciaramella","year":"2014","journal-title":"Neuroimmunomodulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A Unique Microglia Type Associated with Restricting Development of Alzheimer\u2019s Disease","volume":"169","author":"Spinrad","year":"2017","journal-title":"Cell"},{"key":"ref_46","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_47","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":"2024","journal-title":"Immunity"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/jnc.13607","article-title":"Neuroinflammation: The devil is in the details","volume":"139","author":"DiSabato","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_49","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_50","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.neuron.2016.06.015","article-title":"TREM2 Binds to Apolipoproteins, Including APOE and CLU\/APOJ, and Thereby Facilitates Uptake of Amyloid-\u03b2 by Microglia","volume":"91","author":"Yeh","year":"2016","journal-title":"Neuron"},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/s41582-018-0072-1","article-title":"TREM2\u2014A key player in microglial biology and Alzheimer disease","volume":"14","author":"Ulland","year":"2018","journal-title":"Nat Rev Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","article-title":"The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases","volume":"47","author":"Krasemann","year":"2017","journal-title":"Immunity"},{"key":"ref_54","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_55","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2009). 2009 Alzheimer\u2019s disease facts and figures. Alzheimers Dement., 5, 234\u2013270.","DOI":"10.1016\/j.jalz.2009.03.001"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"(2022). 2022 Alzheimer\u2019s disease facts and figures. Alzheimers Dement., 18, 700\u2013789.","DOI":"10.1002\/alz.12638"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.clinbiochem.2018.06.011","article-title":"Alzheimer\u2019s disease in the omics era","volume":"59","author":"Sancesario","year":"2018","journal-title":"Clin. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Wisniewski, T., and Drummond, E. (2020). APOE-amyloid interaction: Therapeutic targets. Neurobiol. Dis., 138.","DOI":"10.1016\/j.nbd.2020.104784"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Broekema, R.V., Bakker, O.B., and Jonkers, I.H. (2020). A practical view of fine-mapping and gene prioritization in the post-genome-wide association era. Open Biol., 10.","DOI":"10.1098\/rsob.190221"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"101594","DOI":"10.1016\/j.smim.2022.101594","article-title":"APOE mediated neuroinflammation and neurodegeneration in Alzheimer\u2019s disease","volume":"59","author":"Parhizkar","year":"2022","journal-title":"Semin. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Papaliagkas, V., Kalinderi, K., Vareltzis, P., Moraitou, D., Papamitsou, T., and Chatzidimitriou, M. (2023). CSF Biomarkers in the Early Diagnosis of Mild Cognitive Impairment and Alzheimer\u2019s Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108976"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1006\/exnr.2000.7613","article-title":"Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E epsilon4 frequency, but no tau gene mutations","volume":"168","author":"Fabre","year":"2001","journal-title":"Exp. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00401-015-1386-3","article-title":"Amyloid \u03b2 oligomers in Alzheimer\u2019s disease pathogenesis, treatment, and diagnosis","volume":"129","author":"Viola","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ebiom.2016.03.035","article-title":"The Role of Amyloid-\u03b2 Oligomers in Toxicity, Propagation, and Immunotherapy","volume":"6","author":"Sengupta","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s disease","volume":"25","author":"Lane","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"865","DOI":"10.3233\/JAD-2012-120211","article-title":"The load of amyloid-\u03b2 oligomers is decreased in the cerebrospinal fluid of Alzheimer\u2019s disease patients","volume":"31","author":"Sancesario","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0002-9440(10)64538-5","article-title":"Endocytic pathway abnormalities precede amyloid \u03b2 deposition in sporadic Alzheimer\u2019s disease and Down syndrome: Differential effects of APOE genotype and presenilin mutations","volume":"157","author":"Cataldo","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.biopsych.2004.07.021","article-title":"Cerebrospinal fluid \u03b2-amyloid1-42 and tau in control subjects at risk for Alzheimer\u2019s disease: The effect of APOE epsilon4 allele","volume":"56","author":"Sunderland","year":"2004","journal-title":"Biol. Psychiatry"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Toniolo, S., Di Lorenzo, F., Bernardini, S., Mercuri, N.B., and Sancesario, G.M. (2023). Blood-Brain Barrier Dysfunction and A\u03b242\/40 Ratio Dose-Dependent Modulation with the ApoE Genotype within the ATN Framework. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512151"},{"key":"ref_72","first-page":"9497147","article-title":"Meta-Analysis of the Relationship between the","volume":"2018","author":"Pang","year":"2018","journal-title":"Park. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0140-6736(23)01478-2","article-title":"The pathogenesis of Parkinson\u2019s disease","volume":"403","author":"Morris","year":"2024","journal-title":"Lancet"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1016\/j.ajpath.2011.07.021","article-title":"Apolipoprotein E and LRP1 Increase Early in Parkinson\u2019s Disease Pathogenesis","volume":"179","author":"Wilhelmus","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40035-023-00378-6","article-title":"Role of dopamine in the pathophysiology of Parkinson\u2019s disease","volume":"12","author":"Zhou","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1007\/s00018-008-7589-1","article-title":"Mitochondrial association of \u03b1-synuclein causes oxidative stress","volume":"65","author":"Parihar","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_77","first-page":"4709322","article-title":"Mercury and Parkinson\u2019s Disease: Promising Leads, but Research Is Needed","volume":"2023","author":"Torrey","year":"2023","journal-title":"Parkinsons Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12031-007-9001-2","article-title":"ApoE distribution and family history in genetic prion diseases in Germany","volume":"34","author":"Krasnianski","year":"2008","journal-title":"J. Mol. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1212\/01.WNL.0000130159.28215.6A","article-title":"APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease","volume":"62","author":"Huang","year":"2004","journal-title":"Neurology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.neurobiolaging.2023.07.011","article-title":"Clinical and neurochemical correlates of the APOE genotype in early-stage Parkinson\u2019s disease","volume":"131","author":"Zenuni","year":"2023","journal-title":"Neurobiol. Aging"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/mds.24946","article-title":"Genetic influences on cognitive decline in Parkinson\u2019s disease","volume":"27","author":"Morley","year":"2012","journal-title":"Mov. Disord."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1177\/0891988709332945","article-title":"APOE alleles in Parkinson disease and their relationship to cognitive decline: A population-based, longitudinal study","volume":"22","author":"Kurz","year":"2009","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1007\/s00403-023-02597-3","article-title":"Downregulation of circ_0024028 inhibits IL-22-induced keratinocyte proliferation and migration by miR-486-3p\/AKT3 axis","volume":"315","author":"Zhang","year":"2023","journal-title":"Arch. Dermatol. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1196\/annals.1377.005","article-title":"LRP in amyloid-\u03b2 production and metabolism","volume":"1086","author":"Bu","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41586-020-2156-5","article-title":"LRP1 is a master regulator of tau uptake and spread","volume":"580","author":"Rauch","year":"2020","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Liuzzi, P., Magliacano, A., De Bellis, F., Mannini, A., and Estraneo, A. (2022). Predicting outcome of patients with prolonged disorders of consciousness using machine learning models based on medical complexity. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-17561-w"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Formisano, R., D\u2019ippolito, M., Giustini, M., Catani, S., Mondello, S., Piccolino, I., Iannuzzi, F., Wang, K.K., and Hayes, R.L. (2024). The Prognostic Role of Candidate Serum Biomarkers in the Post-Acute and Chronic Phases of Disorder of Consciousness: A Preliminary Study. Brain Sci., 14.","DOI":"10.3390\/brainsci14030239"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Magliacano, A., Liuzzi, P., Formisano, R., Grippo, A., Angelakis, E., Thibaut, A., Gosseries, O., Lamberti, G., No\u00e9, E., and Bagnato, S. (2022). Predicting Long-Term Recovery of Consciousness in Prolonged Disorders of Consciousness Based on Coma Recovery Scale-Revised Subscores: Validation of a Machine Learning-Based Prognostic Index. Brain Sci., 13.","DOI":"10.3390\/brainsci13010051"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nm0295-135","article-title":"Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid \u03b2-protein following head injury","volume":"1","author":"Nicoll","year":"1995","journal-title":"Nat. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/S0140-6736(97)04318-3","article-title":"Association of apolipoprotein E polymorphism with outcome after head injury","volume":"350","author":"Teasdale","year":"1997","journal-title":"Lancet"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/nm0995-852","article-title":"ApoE as a prognostic factor for post-traumatic coma","volume":"1","author":"Sorbi","year":"1995","journal-title":"Nat. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S0140-6736(95)91411-0","article-title":"ApoE genotype and survival from intracerebral haemorrhage","volume":"346","author":"Alberts","year":"1995","journal-title":"Lancet"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1212\/WNL.52.2.244","article-title":"Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury","volume":"52","author":"Friedman","year":"1999","journal-title":"Neurology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1212\/WNL.55.10.1536","article-title":"Apolipoprotein E and functional recovery from brain injury following postacute rehabilitation","volume":"55","author":"Lichtman","year":"2000","journal-title":"Neurology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1212\/WNL.58.7.1115","article-title":"APOE genotype influences acquisition and recall following traumatic brain injury","volume":"58","author":"Crawford","year":"2002","journal-title":"Neurology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1212\/WNL.58.7.1038","article-title":"Apolipoprotein E epsilon 4 and short-term recovery from predominantly mild brain injury","volume":"58","author":"Liberman","year":"2002","journal-title":"Neurology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1212\/01.WNL.0000129268.83927.A8","article-title":"APOE influences on neuropsychological function after mild head injury: Within-person comparisons","volume":"62","author":"Sundstrom","year":"2004","journal-title":"Neurology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1093\/brain\/awh296","article-title":"Six-month recovery from mild to moderate Traumatic Brain Injury: The role of APOE-epsilon4 allele","volume":"127","author":"Chamelian","year":"2004","journal-title":"Brain."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1089\/neu.2010.1623","article-title":"The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample","volume":"28","author":"Ponsford","year":"2011","journal-title":"J. Neurotrauma"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1089\/neu.2007.0489","article-title":"Meta-analysis of APOE4 allele and outcome after traumatic brain injury","volume":"25","author":"Zhou","year":"2008","journal-title":"J. Neurotrauma"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1093\/brain\/awh595","article-title":"The association between APOE epsilon4, age and outcome after head injury: A prospective cohort study","volume":"128","author":"Teasdale","year":"2005","journal-title":"Brain"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.ymthe.2024.03.024","article-title":"APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease","volume":"32","author":"Jackson","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1002\/alz.13703","article-title":"Silencing Apoe with divalent-siRNAs improves amyloid burden and activates immune response pathways in Alzheimer\u2019s disease","volume":"20","author":"Ferguson","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"9416","DOI":"10.1007\/s12035-024-04143-2","article-title":"Application of CRISPR\/Cas9 System in the Treatment of Alzheimer\u2019s Disease and Neurodegenerative Diseases","volume":"61","author":"Rahimi","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_105","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_106","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s40259-023-00633-2","article-title":"Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer\u2019s Disease","volume":"38","author":"Cummings","year":"2024","journal-title":"BioDrugs"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3233\/ADR-230025","article-title":"Antibody-Mediated Clearance of Brain Amyloid-\u03b2: Mechanisms of Action, Effects of Natural and Monoclonal Anti-A\u03b2 Antibodies, and Downstream Effects","volume":"7","author":"Loeffler","year":"2023","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_108","first-page":"197","article-title":"Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer\u2019s Disease","volume":"9","author":"Haeberlein","year":"2022","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Foley, K.E., and Wilcock, D.M. (2024). Three major effects of APOE. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1412006"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.3233\/JAD-160467","article-title":"ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies","volume":"54","author":"Bar","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5812","DOI":"10.1038\/s41380-020-0764-y","article-title":"Prediction of clinical diagnosis of Alzheimer\u2019s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years","volume":"26","author":"Stocker","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Statement on use of apolipoprotein E testing for Alzheimer disease (1995). American College of Medical Genetics\/American Society of Human Genetics Working Group on ApoE and Alzheimer disease. JAMA, 274, 1627\u20131629.","DOI":"10.1001\/jama.274.20.1627"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"292.e7","DOI":"10.1016\/j.neurobiolaging.2018.04.015","article-title":"Genetic screening in early-onset dementia patients with unclear phenotype: Relevance for clinical diagnosis","volume":"69","author":"Perrone","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1159\/000487079","article-title":"An Estimate of Attributable Cases of Alzheimer Disease and Vascular Dementia due to Modifiable Risk Factors: The Impact of Primary Prevention in Europe and in Italy","volume":"8","author":"Mayer","year":"2018","journal-title":"Dement. Geriatr. Cogn. Dis. Extra"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3109\/10408363.2015.1051658","article-title":"How many biomarkers to discriminate neurodegenerative dementia?","volume":"52","author":"Sancesario","year":"2015","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Giannella Emilia Bau\u00e7a Josep Miquel (2024). Digital Health, Data Science and Privacy: The choices of 1410 Volunteers and Neurological Patients Regarding Limitations on Use of Data and Biological Samples, Return of Results and Transfer, Elsevier.","DOI":"10.2139\/ssrn.4830487"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"04160","DOI":"10.7189\/jogh.13.04160","article-title":"Global, regional, and national burden of neurological disorders in 204 countries and territories worldwide","volume":"13","author":"Huang","year":"2023","journal-title":"J. Glob. Health"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1007\/s12264-019-00360-1","article-title":"Effect of Apolipoprotein E Genotypes on Huntington\u2019s Disease Phenotypes in a Han Chinese Population","volume":"35","author":"Li","year":"2019","journal-title":"Neurosci. Bull."},{"key":"ref_119","first-page":"108","article-title":"Age of onset in Huntington disease: Sex specific influence of apolipoprotein E genotype and normal CAG repeat length","volume":"36","author":"Kehoe","year":"1999","journal-title":"J. Med. Genet."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1136\/jnnp.2003.022756","article-title":"Apolipoprotein E genotypes do not influence the age of onset in Huntington\u2019s disease","volume":"75","author":"Saft","year":"2004","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_122","unstructured":"(2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res., 51, D523\u2013D531."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:23:47Z","timestamp":1760113427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,30]]},"references-count":122,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["genes15111397"],"URL":"https:\/\/doi.org\/10.3390\/genes15111397","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,30]]}}}