There is a long-standing debate about whether the increased AD risk associated with APOE4 is due to a ‘loss of function’ or a ‘gain of function’.[48] The concept of Cys and disulfide deficiency, which assigns a loss of protective, physiological function (inability to form disulfide bridges) to ApoE4 that in turn predisposes to a gain of toxic function (accelerated production of toxic peroxidized lipids), offers a straightforward mechanism that can reconcile both interpretations of ApoE4 biology (Fig 4). This evidence concerns the gene APOE and Alzheimer disease.