Brain lipid profiles and oligodendrocyte gene expression show discordant responses to high-fat diet in Alzheimer’s disease mice.

The brain is a lipid-rich organ, with myelin sheaths containing exceptionally high levels of lipids. Oligodendrocyte dysfunction and myelin lipid deregulation have been implicated in Alzheimer’s disease (AD), yet their precise roles remain unclear. In this study, we examined lipid metabolic alterations, with focus on primary myelin lipids, in AppNL-G-F/NL-G-F (App) AD model mice fed either a normal control diet (NCD) or a high-fat diet (HFD). Brain lipid profiles were altered in App mice, with differential effects depending on diet. Notably, oligodendrocyte gene expression patterns, including those involved in myelin lipid metabolic pathways, were similar between NCD- and HFD-fed App mice and did not correspond with the observed changes in brain lipid composition. This discrepancy indicates that myelin lipid homeostasis in the AD brain is regulated by mechanisms beyond transcriptional control, likely involving post-translational regulation, inter-glial metabolic interactions, and brain-periphery lipid exchange. Importantly, HFD intake did not exacerbate cognitive impairment or neuroinflammation in App mice; rather, HFD-fed App mice showed improved learning during behavioral testing and reduced astrocytic activation. These findings suggest that dietary fat intake does not worsen—and may partially ameliorate—certain aspect of AD pathology, highlighting the complex and context-dependent relationship between metabolic interventions and neurodegenerative disease.