Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that profoundly impacts cognitive function and overall quality of life. AD is associated with a series of specific behavioral changes as the disease progresses known as neuropsychiatric symptoms (NPSs). The multifaceted role of apolipoprotein E (APOE) isoforms on sporadic AD extends to modulate key pathophysiological processes implicated in AD pathogenesis from lipid metabolism to neurodegeneration. APOE isoforms have not only profound influences on disease risk, progression, and clinical manifestation but also in determining NPS. Evidence from clinical, genetic, brain imaging, and neuropathology studies has now emerged to provide an initial understanding of the neurobiology of NPS and mild behavioral impairment. Contrasting associations between APOE isoforms with a range of NPS have been identified using psychometric, neuroimaging, and brain structure measures. In the present chapter, we summarize studies on the relationship between APOE isoforms, NPS, and sporadic AD.