<p>Alzheimer’s disease, the leading cause of dementia worldwide, is profoundly influenced by the apolipoprotein E4 allele, the primary genetic risk factor for sporadic Alzheimer’s disease. This allele exacerbates amyloid-beta pathology, tau phosphorylation, mitochondrial dysfunction, neuroinflammation, synaptic impairment, vascular dysfunction, and gut-brain axis alterations, contributing to disease progression. Recent advances elucidate apolipoprotein E4’s molecular mechanisms, including its role in lipid metabolism and receptor interactions, which drive these pathological processes. This review synthesizes current understanding of apolipoprotein E4’s contributions to Alzheimer’s disease pathogenesis, evaluates emerging therapeutic strategies such as gene editing, immunotherapy, and non-pharmacological interventions, and addresses ethical considerations in gene therapy. By integrating insights from molecular biology, clinical research, and therapeutic development, the review highlights apolipoprotein E4’s potential as a therapeutic target. It emphasizes the importance of personalized medicine and combination therapies to mitigate disease progression and improve patient outcomes, while underscoring the need for ethical frameworks to guide novel interventions.</p>