Brain lipid homeostasis plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis.