In the current study, we took advantage of the APPOSK mouse model where AD-like pathology and neurodegeneration occur in the absence of amyloid plaques, and demonstrated that oligomeric amyloid-beta (Aβ) induces accumulation of free PUFAs and lysophosphatidylcholine by activation of brain cPLA2 and iPLA2 within myelin-rich and pyramidal neuron-rich regions, respectively, via MAPK-mediated phosphorylation in a PKC-independent manner. This evidence concerns the gene PLA2G6 and Alzheimer disease.