Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) and tau neuropathology, neuroinflammation, lipid dysregulation, and progressive loss of cognitive functioning. We have evidence that early dietary interventions with ω6/ω3 polyunsaturated fatty acids (PUFAs) can protect against cognitive decline and lastingly alter microglia and brain lipid profile in the context of early-life stress​. PUFAs can directly modulate microglia. In the context of AD, it is unknown if lipid and PUFA derivatives (oxylipins) are dysregulated in the brain, how these relate to Aβ pathology and microglia and whether an early diet enriched in ω3-PUFAs could mitigate AD-related cognitive decline, pathology, neuroimmune and lipid dysregulations.Wildtype and APP/PS1 transgenic mice were fed a standard-like diet (ω6/ω3 = 15:1) or an enriched diet (ω6/ω3 = 1:1) from postnatal day 2-42. At 6 months of age, mice underwent cognitive testing and hippocampi and cortices were isolated for oxylipin, lipidomic and phagocytosis assays (n = 8/group) or brains were perfused for immunohistochemical staining of Iba1, CD68 and Ab.In the APP/PS1 mice fed the diet enriched with ω3-PUFAs, we observed a reduction of Ab plaque load in the hippocampal CA and entorhinal cortex, reduced microglial CD68 expression and an increased Iba1 coverage. Functionally, ω3-PUFA enrichments increased microglial phagocytosis of Ab, without affecting phagocytosis of synaptosomes. Untargeted lipidomics and oxylipin analysis are currently ongoing. This study demonstrates the impact of ω3-PUFAs in long-term modulation of microglia and highlights the potential of early ω3-PUFAs in nutritional intervention strategies in the context of AD.