Apolipoprotein E (ApoE) e4 is a most common risk factor for Alzheimer's disease (AD). The reduction or total ApoE, but in particular, ApoE e4 allele reduces the AD pathology. The goal of this proposal is to design the innovative therapeutic siRNA molecules targeting ApoE, and especially ApoE e4 allele, in AD-affected brain regions and modulation of AD pathogenesis.Therapeutic oligonucleotides comprise a new class of drugs expected to impact human health. We have identified a completely new class of chemistry, Di-hsiRNAs, that shows unprecedented distribution and silencing activity (60%-90%) in the brain after a single bolus infusion via CSF.We have confirmed full extend of silencing lasting for a month (longer term studies are ongoing). In addition, no detectable activation of innate immune response or neurodegeneration was noted at dose levels more than 20x higher than efficacy. Thus we have identified two chemically distinct classes of therapeutic siRNAs-PC-DHA-hsiRNA and Di-hsiRNA - that support wide distribution and potent gene silencing in CNS tissues after CSF infusion. This clinically relevant technology platform establishes a route toward development of innovative therapeutics for AD. We, and other have shown that the allele-specific silence (targeting disease-associated mutant allele) can be achieved by hsiRNA molecules. We have demonstrated the efficiency of silence by FM-hsiRNAs in vivo for two neurodegenerative disorders. The human cell lineages and AD animal models with humanized AD-genes (APOE, APP, PSEN1) are available to perform this studyChanging the administration route and nature of conjugates, we can achieve selective silencing of APOE in brain or in liver only or even in specific cell types in brain by novel long-term efficient and non-toxic compound. This is a novel and promising strategy for target directed modulation of AD pathology.