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The inflammatory response at the onset of pathology engages activation of pro-resolving, pro-homeostatic LMs followed by a gradual decrease. We used an APP knock-in (<jats:italic>App<\/jats:italic>\u00a0KI) AD mouse that accumulates\u00a0\u03b2-amyloid (A\u03b2)\u00a0and presents cognitive deficits (at 2 and 6\u00a0months of age, respectively)\u00a0to investigate LMs, their precursors, biosynthetic enzymes and receptors, glial activation, and inflammatory proteins in the cerebral cortex and hippocampus at 2-, 4-, 8- and 18-month-old in comparison with wild-type (WT) mice. We used\u00a0LC-mass-spectrometry and MALDI molecular imaging to analyze LMs and\u00a0phospholipids, and immunochemistry for proteins. Our results revealed an age-specific lipid and cytokine profile, and glial activation in the <jats:italic>App<\/jats:italic> KI mice. Despite an early onset of A\u03b2 pathology, pro-inflammatory and pro-resolving LMs were prominently increased only in the oldest age group. Furthermore, the LM biosynthetic enzymes increased, and their receptor expression decreased in the aged\u00a0<jats:italic>App<\/jats:italic>\u00a0KI mice. Arachidonic acid (AA)-containing phospholipid molecular species were elevated, correlating with decreased\u00a0cPLA2 activity. MALDI molecular imaging depicted differential\u00a0distribution of phospholipids according to genotype in hippocampal layers. Brain histology disclosed increased microglia proliferation starting from young age in the\u00a0<jats:italic>App<\/jats:italic>\u00a0KI mice, while astrocyte numbers were enhanced in\u00a0older ages. Our results demonstrate that the brain lipidome is modified preferentially during aging as compared to amyloid pathology in the model studied here. 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