{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T15:42:33Z","timestamp":1792856553145,"version":"4.5.0"},"reference-count":182,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Rijeka, Croatia","award":["uniri-iskusni-biomed-23-82"],"award-info":[{"award-number":["uniri-iskusni-biomed-23-82"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Apolipoprotein E (APOE) remains the most robust and widely replicated genetic risk factor for late-onset Alzheimer\u2019s disease (AD) susceptibility, with the \u03b54 allele (APOE4) demonstrating profound associations with accelerated symptom manifestation, enhanced disease trajectory, and modified therapeutic responsiveness. This comprehensive review synthesizes contemporary evidence regarding the clinical utility of APOE4 genotyping, emphasizing its integration into personalized therapeutic frameworks and early diagnostic paradigms. The APOE4 variant exerts pathogenic influence through impaired amyloid-\u03b2 clearance, enhanced tau pathology, and compromised neuronal repair mechanisms that alter disease phenotype. We systematically examine available genotyping methodologies, encompassing polymerase chain reaction (PCR) and next-generation sequencing (NGS) platforms, and evaluate their practical implementation within clinical environments. Recent investigations demonstrate that APOE4 status profoundly influences therapeutic efficacy, particularly with anti-amyloid interventions such as lecanemab, where carriers exhibit enhanced treatment response alongside increased adverse event susceptibility. Emerging gene therapeutic approaches show promise in mitigating APOE4-associated risks through targeted molecular interventions. The integration of APOE4 genotyping with fluid biomarkers and neuroimaging techniques enables refined patient stratification and enhanced diagnostic precision, facilitating earlier intervention windows that optimize therapeutic outcomes before irreversible neuronal damage occurs. This review underscores APOE4 testing as a transformative component of precision medicine in AD management, emphasizing its contribution to diagnostic refinement, clinical decision support, and targeted therapeutic interventions.<\/jats:p>","DOI":"10.3390\/jcm14176047","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T08:19:32Z","timestamp":1756282772000},"page":"6047","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Clinical Significance of APOE4 Genotyping: Potential for Personalized Therapy and Early Diagnosis of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Jelena","family":"Raji\u010d Bumber","sequence":"first","affiliation":[{"name":"Department of Basic and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentino","family":"Ra\u010dki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"},{"name":"Department of Neurology, Clinical Hospital Centre Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5107-3670","authenticated-orcid":false,"given":"Silvestar","family":"Me\u017enari\u0107","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3322-1470","authenticated-orcid":false,"given":"Gordana","family":"Pel\u010di\u0107","sequence":"additional","affiliation":[{"name":"Health Care Center of Primorsko-Goranska County, Rijeka, 51000 Rijeka, Croatia"},{"name":"Department of Social Sciences and Medical Humanities, School of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6313-9232","authenticated-orcid":false,"given":"Jasenka","family":"Mr\u0161i\u0107-Pel\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102481","DOI":"10.1016\/j.arr.2024.102481","article-title":"Pathogenesis, Diagnostics, and Therapeutics for Alzheimer\u2019s Disease: Breaking the Memory Barrier","volume":"101","author":"Kamatham","year":"2024","journal-title":"Ageing Res. 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