While this increase has been consistently observed by independent groups in vivo in APOE targeted-replacement mice in AD models (Tai et al., 2011), due to perhaps independent roles of APOE genotype on other aspects of the disease (e.g., Aβ plaque levels), it is not clear whether the increase in cytokines by APOE4 is due to the increase in pathology, or due to a direct effect of APOE4 on cytokine production, which could contribute to the increase in pathological changes. This evidence concerns the gene APOE and Alzheimer disease.