Lipidomic Analysis of Human Plasma and Hippocampus Across Alzheimer’s Progression and Preclinical 5xFAD Mouse Model

Abstract Alzheimer’s disease (AD) poses a significant global health burden, underscoring the need for early and accessible biomarkers to enable timely diagnosis and intervention. Lipids, which constitute over half of the brain’s mass, play essential roles in numerous cellular processes, and their dysregulation has been increasingly implicated in AD pathophysiology. In this study, we performed lipidomic profiling of hippocampal samples derived from individuals at different Braak stages and plasma samples from patients with mild cognitive impairment (MCI), AD, and healthy controls. Parallel analyses were conducted in 5xFAD transgenic mice and wild-type littermates. Our results revealed lipid alterations across central and peripheral compartments in both human subjects and the 5xFAD mouse model. Notably, specific lipid changes identified in particular lipid species at early/mild Braak stages or in MCI persisted into advanced stages of the disease, highlighting the systemic nature of lipid dysregulation in AD and supporting the potential of these lipid signatures as diagnostic and prognostic biomarkers.