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The exact mechanism by which <jats:italic>APOE<\/jats:italic> gene variants increase\/decrease Alzheimer's disease (AD) risk is not fully understood, but <jats:italic>APOE<\/jats:italic> isoforms differently affect brain homeostasis and neuroinflammation, blood\u2013brain barrier (BBB) permeability, glial function, synaptogenesis, oral\/gut microbiota, neural networks, amyloid beta (A\u03b2) deposition, and tau\u2010mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of <jats:italic>APOE<\/jats:italic>\u2010mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different <jats:italic>APOE<\/jats:italic>\u2010targeting approaches being developed as potential AD therapies. Intracisternal adeno\u2010associated viral\u2010mediated delivery of <jats:italic>APOE<\/jats:italic> \u03b52 is being tested in AD <jats:italic>APOE<\/jats:italic> \u03b54\/\u03b54 carriers, while <jats:italic>APOE<\/jats:italic> mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including <jats:italic>APOE<\/jats:italic> \u03b54 antisense oligonucleotides, anti\u2010<jats:italic>APOE<\/jats:italic> \u03b54 monoclonal antibodies, <jats:italic>APOE<\/jats:italic> \u03b54 structure correctors, and <jats:italic>APOE<\/jats:italic>\u2013A\u03b2 interaction inhibitors produced positive results in transgenic AD mouse models.<\/jats:p>","DOI":"10.1002\/alz.12728","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T09:55:30Z","timestamp":1659002130000},"page":"353-368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1674-9724","authenticated-orcid":false,"given":"Madia","family":"Lozupone","sequence":"first","affiliation":[{"name":"Neurodegenerative Disease Unit Department of Basic Medicine Neuroscience and Sense Organs University of Bari Aldo Moro  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno Pietro","family":"Imbimbo","sequence":"additional","affiliation":[{"name":"Department of Research and Development Chiesi Farmaceutici  Parma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Balducci","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Istituto di Ricerche Farmacologiche \u201cMario Negri\u201d IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"Lo Vecchio","sequence":"additional","affiliation":[{"name":"Research Laboratory Complex Structure of Geriatrics Department of Medical Sciences Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Bisceglia","sequence":"additional","affiliation":[{"name":"Research Laboratory Complex Structure of Geriatrics Department of Medical Sciences Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaela Rita","family":"Latino","sequence":"additional","affiliation":[{"name":"Complex Structure of Neurology Department of Medical Sciences Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Leone","sequence":"additional","affiliation":[{"name":"Complex Structure of Neurology Department of Medical Sciences Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Dibello","sequence":"additional","affiliation":[{"name":"Department of Orofacial Pain and Dysfunction Academic Centre for Dentistry Amsterdam (ACTA) University of Amsterdam and Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Solfrizzi","sequence":"additional","affiliation":[{"name":"\u201cCesare Frugoni\u201d Internal and Geriatric Medicine and Memory Unit University of Bari \u201cAldo Moro  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Greco","sequence":"additional","affiliation":[{"name":"Research Laboratory Complex Structure of Geriatrics Department of Medical Sciences Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo  Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Daniele","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Catholic University of Sacred Heart  Rome Italy"},{"name":"Neurology Unit IRCCS Fondazione Policlinico Universitario A. 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