Altered lipid raft homeostasis has been considered to contribute to cellular deregulation, leading to neuronal loss in Alzheimer disease. Alterations in these microdomains affect amyloid precursor protein (APP) processing, resulting in neurotoxic conditions, but modifications of the molecular structure of lipid rafts in Alzheimer disease model mice have not been characterized. Using a lipidomic approach, we investigated frontal cortex lipid rafts inwild-type mice and in double-transgenic APP/presenilin 1 (PS1) mice. Lipid rafts in wild-type mice undergo age-dependent modifications, that is, decreased cholesterol and sterol esters levels, augmented sphingomyelin and saturated fatty acid content, and increased phospholipids/cholesterol ratio. These age-dependent changes were more dramatic and occurred earlier in APP/PS1 mice; other lipid classes (e.g. sulfatides) and essential long-chain polyunsaturated fatty acids (including docosahexaenoic and arachidonic acids) were also affected. Steady state anisotropy measurements demonstrated that APP/PS1 animals exhibit more viscous (membrane-ordered) lipid rafts and that this is mainly attributable to reduced unsaturation of phospholipids and increased sphingomyelin levels rather than to changes in cholesterol. In summary, we demonstrate that aging is accompanied by alteration of the physicochemical structure of lipid raft microdomains. This "lipid raft aging," a metaphenomenon, is considerably exacerbated by the induced amyloid burden in APP/PS1 genotype.