Protein signatures of microglia from mice exposed to the HFHS diet revealed an involvement of adipocytokine signaling and highlighted innate activation characteristics, and likewise included a higher abundance of proteins including Ndufs2, Ndufs1 and Mapk1 that are involved in Alzheimer’s disease and which are particularly related to mitochondrial dysfunction. Here, MAPK1 is linked to early-onset autosomal dominant Alzheimer disease.