We thus propose that the super-ability (for ApoE2), intermediate ability (for ApoE3) or complete inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges is the central molecular determinant accounting for the dose-dependent protective, neutral, and harmful effects of APOE2, APOE3, and APOE4 alleles, respectively, on Aβ and pTau pathology and AD risk. The gene discussed is APOE; the disease is Alzheimer disease.