Alzheimer’s disease (AD), is considered a chronic neurodegenerative disease accounting for around 70% of dementia forms. Its commonest early symptom is the difficulty of remembering recent events. Apolipoprotein E (APOE) is the most important genetic risk for sporadic AD. The multifaceted role of APOE isoforms on sporadic AD extends to modulate key pathophysiological processes implicated in brain function such as memory and learning and AD pathogenesis from lipid metabolism to neurodegeneration. It has three major isoforms (ApoE2, ApoE3, and ApoE4) with profound influences on disease risk, progression, and clinical manifestation. Contrasting associations between APOE isoforms with neurobiology of sporadic AD have been identified. Elucidation of the functional domains within this protein and of the structure of the major isoforms of ApoE has contributed significantly to our understanding of its physiological and pathophysiological roles at a molecular level. In the present chapter, we summarize studies on the relationship between APOE isoforms and neurobiology of sporadic AD.