Alzheimer’s disease (AD) affects 50 million people worldwide. Neuropathologically, AD is characterized by beta-amyloid (Aβ) intracellular accumulation, which forms senile plaques and tangles of hyperphosphorylated tau intraneuronal, resulting in synaptic and neuronal loss. Lipid metabolism, primarily of cholesterol, phospholipids, and sphingolipids, is closely connected to brain health and function. There is strong evidence that disruptions in lipid metabolism are associated with AD risk, pathogenesis, and progression. Alterations in phospholipid levels have been linked to cognitive decline, as well as changes in sphingomyelin and ceramide levels characterizing the early stages of the disease. The ApoE gene is particularly important among genetic factors due to its strong association with AD risk and lipid metabolism. The ε4 allele is associated with an increased risk of AD, while the ε2 allele is protective. This book chapter highlights the latest findings supporting the theory that the ApoE genotype influences AD’s lipid metabolism and Aβ processing. It provides an overview of lipid alterations observed in the pre-clinical and clinical phases, emphasizing the role of the ApoE genotype in AD. Together, these studies provide a foundation of knowledge about the functional role of ApoE in AD.