Alzheimer’s disease (AD) is the most common form of dementia. The brain is highly enriched in lipids, and the disruption of lipid homeostasis has been reported for decades to be associated with AD pathogenesis. Recent studies have suggested that small extracellular vesicles (EV’s), namely exosomes, that are released from brain tissue into the periphery (e.g., CSF or blood), have biomarker potential for AD diagnosis and as targets for therapeutic treatment. Exosomes are comprised of constitutive molecules and cargo, including proteins, RNA and lipids, which act as key players in cell-to-cell communication and that can be characterised to provide a snapshot of parental cell homeostasis. Here, we have employed a quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) based lipidome analysis workflow to characterize, for the first time, the lipidome compositions of exosomes released by post-mortem frontal cortex brain tissue from a series of AD patients versus healthy controls. The results from this study reveal selective enrichment and remodelling of multiple exosome lipid classes and subclasses including phosphatidylethanoamine, sphingomyelin, lactosylceramide and ganglioside lipid species, that are known to play key roles in the regulation of physiological processes relevant to AD pathogenesis. These results therefore establish a foundation for future investigations of brain-derived exosome lipids as potential biomarkers for AD diagnosis and for the development of novel therapeutic agents acting through relevant lipid pathways for the treatment of this disorder.