Here we propose the overarching hypothesis that the super-ability (for ApoE2), intermediate ability (for ApoE3) or inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges, is the central molecular determinant accounting for the disparate effects of APOE alleles on AD risk and amyloid-β and Tau pathologies in humans. This evidence concerns the gene MAPT and Alzheimer disease.