Alzheimer＇s　disease　(AD)　patients　have　an　increased　incidence　of　Type　2　diabetes　(T2D);　however,　the　underlying　mechanisms　are　not　well　understood.　Since　AD　is　considered　a　multifactorial　disease　that　affects　both　the　central　nerves　system　and　periphery　and　the　dysregulation　of　hepatic　lipid　and　glucose　metabolism　play　critical　roles　in　T2D,　we,　therefore,　aim　to　explore　the　influence　of　AD　genotype　on　the　liver　during　the　progress　of　high-fat　diet　(HFD)-induced　T2D.　Fourteen-week-old　female　APP(SWE)/PSEN1dE9　(AD)　mice　and　age-,　gender-matched　wild-type　controls　C57BL/6J　(WT)　mice　were　fed　a　HFD　(45%　kcal　fat　content)　or　a　standard　chow　diet　(chow,　12%　kcal　fat　content)　for　22weeks.　The　effects　of　diet　and　genotype　were　analyzed.　Mouse　primary　hepatocytes　were　used　to　decipher　the　underlying　mechanisms.　HFD　induced　significantly　higher　body　weight　gain,　more　severe　hyperglycemia,　glucose　intolerance　and　hepatic　insulin　resistance　in　AD　mice　than　in　WT　mice.　However,　AD　mice　showed　reduced　HFD-induced　hepatic　steatosis,　and　SREBP-1-mediated　lipogenic　signaling　was　activated　by　HFD　in　WT　mice　but　not　in　AD　mice.　In　addition,　14-week-old　AD　mice　exhibited　higher　expression　of　NF-B　p65,　p-JNK　and　p-p38MAPK,　as　well　as　higher　hepatic　and　serum　contents　of　IL-6　and　TNF.　In　mouse　primary　hepatocyte　cultures,　IL-6　and　TNF　inhibited　high-glucose　plus　insulin-induced　activation　of　SREBP-1-mediated　lipogenic　signaling　and　biosynthesis　of　non-esterified　fatty　acid　and　triglyceride.　Early　inflammation-associated　factors　most　likely　diminish　HFD-induced　hepatic　lipid　deposition　by　inhibiting　SREBP-1-mediated　de　novo　lipogenesis,　thus　driving　substrate　flux　to　glucose　production　for　hyperglycemia　and　hepatic　insulin　resistance　in　T2D　development.