Herein, we tested a recently proposed working model of apolipoprotein E (apoE)-mediated sulfatide metabolism/trafficking/homeostasis with two well-characterized amyloid precursor protein (APP) transgenic (Tg) animal models of Alzheimer's disease (AD) (i.e., APP^V717F and APPsw) on a wild-type murine apoE background or after being bred onto an Apoe^−/− background. As anticipated, lipidomics analysis demonstrated that the sulfatide levels in brain tissues were reduced beginning at approximately 6 months of age in APP^V717F Tg, Apoe^+/+ mice and at 9 months of age in APPsw Tg, Apoe^+/+ mice relative to their respective non-APP Tg littermates. This reduction increased in both APP Tg mice as they aged. In contrast, sulfatide depletion did not occur in APP Tg, Apoe^−/− animals relative to the Apoe^−/− littermates. The lack of sulfatide depletion in APP Tg, Apoe^−/− mice strongly supports the role of apoE in the deficient sulfatide content in APP Tg, Apoe^+/+ mice. Collectively, through different animal models of AD, this study provides evidence for an identified biochemical mechanism that may be responsible for the sulfatide depletion at the earliest stages of AD.