Dementia is a clinical syndrome characterized by a progressive decline in two or more cognitive domains. Alzheimer’s disease (AD) is the most common type of dementia and is described as a progressive neurodegenerative condition. Among the identified genetic risk factors, the Apolipoprotein E gene (APOE) is considered the most significant single genetic risk in AD. The APOEε4 allele notably increases the risk of AD, while the APOEε2 allele provides some protection compared to the common APOEε3 allele. Different isoforms of Apolipoprotein E (APOE) regulate lipid transport in both the brain and periphery. Additionally, APOEε4 is associated with the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, with the isoform APOE4 leading to a late onset of AD. This chapter explores the biological pathways of APOE and its associated targeting proteins. Furthermore, the impact of APOE genetics on AD biomarkers is discussed, as well as the evidence supporting APOE as a key factor in the clinical and biological progression of AD. The importance of APOE testing and the potential for future therapies targeted to AD are also emphasized.