APOE and Alzheimer disease: APOE-4 carriers with AD have increased levels of brain and cerebrospinal fluid Aβ and have more extensive plaque pathology [208, 209]; however, with a genomic-based approach, by using an APOE knock-in mouse, which expresses each human allele under the endogenous regulatory elements, on a defined C57BL6/J background, Mann et al. [207] were able to demonstrate that the presence of APOE significantly increases brain Aβ levels, irrespective of genotype, this indicating an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS.