Background: Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can lead to cognitive impairment and neurodegeneration. Experimental high fat diet (HFD) induced obesity with T2DM causes neurodegeneration with brain insulin resistance. Objective: Since ceramides are neurotoxic, cause insulin resistance, and are increased in T2DM, we investigated their potential role in neurodegeneration. Methods: C57BL/6 mice were pair-fed HFD or control diets for 4-20 weeks. Pro-ceramide genes and biochemical indices of neurodegeneration were measured. In vitro experiments directly examined neurodegenerative effects of ceramides. Results: Chronic HFD feeding gradually increased body weight, but after 16 weeks, liver weight surged (P<0.001) due to triglyceride accumulation (P<0.001), and brain weight declined (P<0.0001). HFD increased pro-ceramide gene expression in liver (P<0.05-P<0.001), but not brain. Temporal lobes of HFD fed mice had increased ubiquitin (P<0.001) and 4-hydroxynonenal (P<0.05 or P<0.01), and decreased tau, β-actin, and choline acetyltransferase levels (P<0.05-P<0.001) with development of NASH. Ceramide treatment of neuronal cultures caused cell death, oxidative stress, mitochondrial dysfunction, and insulin resistance. Conclusions: In obesity, T2DM, or NASH, excess hepatic production of neurotoxic ceramides that readily cross the blood-brain barrier causes cognitive impairment with brain insulin resistance via a liver-brain axis of neurodegeneration.