APOE and Alzheimer disease: However, some key issues need to be directly addressed to provide definitive evidence for a metal:ApoE interaction, including the following: (1) Do metals (apart from zinc) have differential affinities for the three ApoE isoforms?; (2) Is the stability or degradation of ApoE isoforms affected by metal binding?; (3) Are changes in neuron- and astrocyte-specific ApoE expression/transportation caused by altered metal levels in AD?