Effect of Apo E genotype and diet on the hepatic clearance of Alzheimer’s disease amyloid beta and brain lipids in Apo E knockin mice

The apo E4 allele of apolipoprotein E (apo E) is currently is the major genetic risk factor identified for Alzheimer’s disease (AD). In Western countries high fat high cholesterol diets associated with downregulation of the anti-aging gene Sirtuin 1 contribute to abnormal brain cholesterol and amyloid beta metabolism. Sirtuin 1 is associated with obesity, the metabolic syndrome, cardiovascular disease and neurodegeneration. Apo E mediates hepatic amyloid beta clearance (peripheral sink amyloid beta hypothesis) with amyloid beta clearance markedly slower in apo E4 knockin compared with apo E3 knockin mice. High fat high cholesterol diet has marked effects on hepatic clearance and metabolism of amyloid beta. In apo E4 knockin mice HFHC feeding had differential effects with alteration not only on brain lipid composition but also on the contribution of abnormal liver metabolism to brain metabolic disruption. Apo E isoforms diet drugs and effects on hepatic amyloid beta metabolism and brain amyloid beta homeostasis will be discussed.