We reach four principal conclusion from this study: 1) rs429358 alone is responsible for the association of APOE with dementia; 2) The association of APOE with dementia is substantially mediated by its effect on CNS Aß42 levels; 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism; and 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE.