Updated project metadata. Alzheimer’s disease (AD) is the leading cause of late onset dementia. However, to date, no efficient therapy for AD is available. Here, we identified a neuroprotective role of the liver contributing to brain amyloid-β (Aβ) homeostasis. The hippocampus is a crucial region for learning and memory and is one of the brain areas most affected by AD. To investigate brain mechanisms underlying the neuroprotective role of the liver in AD pathology, we performed proteomics analysis of hippocampus extracted from 5×FAD::Alb-CreERT2;Ephx2−/− mice and control littermates. After quality control, we identified 67 protein expressions that were differently regulated between the two genotypes, including nine proteins in the Kyoto Encyclopedia of Genes and Genomes pathway of AD