The role of apo E4 in chronic disease progression is well understood but its role may be secondary compared to the primary role the anti-aging protein Sirt 1 has in nuclear receptor and transcriptional regulation involved with NAFLD, insulin resistance, mitochondrial function, neurodegeneration, cardiovascular disease, and AD [2,29,30,31,32,33,34,35]. Here, APOE is linked to Insulin resistance.