INS and Alzheimer disease: Previous studies have reported various mechanisms underlying the effects of APOE4 on AD and other dementing disorders; APOE4 affects (1) Aβ aggregation and clearance, (2) tau phosphorylation and tangle formation, (3) lipid/cholesterol transport and clearance, (4) glucose and mitochondrial metabolism, (5) inflammation, (6) vascular function including BBB, (7) insulin and VEGF signaling, and (8) synaptic and neuronal function [39].