PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) currently affects 5.7 million Americans in the United States and yet there is no cure or treatment that can halt the disease progression. The ε4 allele of apolipoprotein E gene (APOE4) is the strongest genetic risk factor for late-onset AD. Currently, many therapeutic approaches aim to reduce two pathological hallmarks of AD: extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. Although some Aβ antibodies targeting Aβ plaques have significantly reduced plaque levels in mice, clinical trials in humans often result in adverse side effects that increase the occurrence of microhemorrhages and edema or Amyloid Related Imaging Abnormalities (ARIA). Recently in a phase 1b study, the monoclonal anti- Aβ antibody aducanumab showed potential by significantly reducing Aβ plaques from the brain and slowed cognitive decline. However, ARIA occurred in almost half of the patients receiving higher dosage of the treatment. ARIA likely occurs when Aβ antibodies bind to Aβ in blood vessels called cerebral amyloid angiopathy (CAA). Consequently, an immune response is activated that leads to weakening or rupturing of these vessels. Our lab has recently generated and characterized a series of antibodies against apoE and apoE4, a lipoprotein that is often found in Aβ deposits both in the parenchyma and vasculature. Particularly, one of our apoE antibodies reduced parenchymal Aβ plaques by preferentially targeting nonlipidated, aggregated apoE. We also have preliminary experiments suggesting that this apoE antibody can recognize apoE in CAA. Because CAA co-occurs in 90% or more of patients with AD, Aβ antibodies like aducanumab that recognize many epitopes in the plaque may over-recruit immune cells to elicit a massive immune response. On the other hand, our apoE antibody recognizes a small but abnormal conformation of apoE found in plaques. By binding to just a small portion of the plaque, we hypothesize that less neuroinflammation will be evoked. Thus, the objective of this proposal is to determine if our apoE antibody is efficacious in reducing CAA and inflammation that is secondary to antibody treatment compared to the murine version of aducanumab (Aim 1). Secondly, we will also assess the effects of chronic apoE antibody treatment on promoting healthy blood vessel function compared to aducanumab (Aim 2). By employing a novel immunotherapeutic strategy targeting apoE and apoE4, we will test if this treatment approach aimed to lower CAA deposition and restoring function in the cerebrovasculature can provide the field with a novel disease-modifying treatment for AD and CAA.