SRP343627 PRJNA775977 GSE186756 mRNA sequencing of brain and liver in multiple Alzheimer's Disease mouse models after treatment with either a Non-Targeting Control siRNA or an siRNA targeting mouse Apoe mRNA The most common genetic risk factor for late onset Alzheimer Disease (AD) is the APOE4 allele, with evidence for gain- and loss-of-function as a primary mechanism. ApoE knockout in mice abrogates AD phenotypes but causes severe atherosclerosis due to the role of liver ApoE in cholesterol homeostasis. Previous attempts to therapeutically block brain-specific ApoE in adult models of AD only modestly reduced ApoE expression and no significant impact on amyloid burden. Here, we optimized a divalent siRNA (di-siRNA) to selectively silence ApoE in brain (>2 months). By measuring transcriptomic changes upon knockdown of ApoE in the CNS in multiple mouse models of AD, we find that ApoE knockdown results in an upregulation of the innate immune response, likely through activation of microglia. Additionally, we find that the changes in the transcriptome were similar, but not identical, two weeks and two months post-treatment. We find that mild reduction of ApoE in the liver does not cause widespread transcriptomic changes, but near complete knockdown of ApoE in the liver results in the dysregulation of many lipid metabolism-related pathways. Overall design: For the brain samples in each mouse model and each treatment (NTC or ApoE siRNA) timepoint (2 Weeks or 2 Months post-treatment) the sample size was 10-20 mice. For the liver samples in each treatment (NTC or ApoE siRNA, bilateral intracerebroventricular or subcutaneous injections) the sample size was 3-4 mice. GSE186756