APOE Allele Switching as a Therapeutic Approach for Alzheimer's Disease

Abstract In comparison to the highly protective E2 allele of Apolipoprotein E (APOE), the E4 allele has been associated with a host of detrimental effects, including, but not limited to, increased amyloid deposition, more severe tau pathology, heightened neuroinflammation, cerebrovascular dysfunction, and various metabolic deficits. With its strong risk profile and varied biological mechanisms, APOE itself has emerged as an attractive candidate for gene therapy. In addition to providing a much-needed preclinical model for ongoing and future trials, exploration of E4 to E2 allele ‘switching’ has the potential to help answer several fundamental and longstanding biological questions in the field. For example, which ApoE-synthesizing cell-type(s) drive AD pathogenesis in E4 carriers and which are most protective in those with E2? Are E4-associated deficits set in stone at birth (developmentally), or is later-life APOE editing a feasible approach to mitigate AD neuropathology and cognitive dysfunction? To this end, we have generated a series of novel APOE ‘switch’ (4s2) mouse models that allow for temporal and cell-specific allele switching from E4 to E2. Our preliminary data confirms that these 4s2 mice synthesize a full- length human ApoE4 at baseline, and importantly, when crossed to various inducible CreERT2 strains, the switch successfully leads to efficient recombination and expression of human ApoE2 in cell types of interest. Given the remarkable protective effects of E2 carriage and the various roles of ApoE at differing steps of AD pathogenesis, we hypothesize that astrocyte-specific allelic switching to E2 will simultaneously rescue multiple metabolic, immune, and neuropathological deficits associated with E4. We propose to leverage these unique mouse models to determine the therapeutic window for CNS-specific E4 to E2 allele switching to simultaneously mitigate metabolic deficits, neuroinflammation, cerebrovascular dysfunction, amyloid pathology, and cognitive dysfunction. If successful, this proposal will provide an essential preclinical model for ongoing and future clinical trials, and will provide critical new information regarding ideal cell-, region- and temporally-specific opportunities for therapeutic ApoE modulation.